NRLF 
 
 B M 210 3DD 
 
MEDICAL 
 
 Dr. Howard Herrington 
 
 Memorial 
 
^<Z/7-^-*-- 
 
 f 
 

INFECTION AND IMMUNITY 
 
 By 
 
 VICTOR C. VAUGHAN, M.D. 
 ANN ARBOR, MICH. 
 
 CHICAGO 
 
 AMERICAN MEDICAL ASSOCIATION 
 1915 
 
COPYRIGHT, 1915 
 
 BY THE 
 
 AMERICAN MEDICAL ASSOCIATION 
 
19)5' 
 
 This monograph is a part of the Commemoration Volume, issued 
 by the American Medical Association at its meeting in San Francisco, 
 June 22 to 26, 1915, as a tribute to the medical sciences, which made 
 possible the building of the Panama Canal and the Panama Pacific 
 Exposition. 
 
 31727 
 
FOREWORD 
 
 The development of modern medicine, its influence on civilization, 
 and its role in the advancement of the welfare of the nation are mat- 
 ters which concern us all. While our lives are short and we are soon 
 to pass away, our children and their descendants will possess and 
 occupy the land, at least we hope that this may be true. No nation 
 can be great so long as disease prevails widely among any classes. 
 Modern medicine has become largely a social service. Preventive 
 medicine is the keystone of the triumphal arch of modern civilization. 
 Displace it and the whole structure will fall. Widespread epidemics 
 lead to national decay. Infection has overthrown nations and has 
 blotted out civilizations in the past. We are aware of the fact that 
 the future of this country does not depend wholly on the medical man, 
 but he should be ready at all times to do his part in assisting in the 
 progress of the nation. Medicine consists of those facts, gathered 
 from the various sciences, which can be utilized in the prevention or 
 cure of disease. That nation which does not encourage scientific inves- 
 tigation, must fall into the rear. It is, therefore, the duty of the state 
 to favor research medicine. Every physician who treats an infectious 
 disease renders a service to the individual under his treatment, and at 
 the same time he renders a greater service to the community in pre- 
 venting the spread of the disease. 
 
 The present volume is an incomplete and imperfect statement of 
 what medicine has done, is doing, and an indication of what it may do 
 for the common good. The attempt has been made to present these 
 facts in non-technical verbiage so that any intelligent citizen may 
 read, comprehend, and appreciate them. The medical profession feels 
 that it has a patriotic duty to perform in the advancement of the best 
 interests of the people. It offers its services, and begs an intelligent 
 appreciation of what it has done, is doing, and may do. 
 
CONTENTS 
 
 Infection 17 
 
 Historical Introduction 19 
 
 Bacteria 27 
 
 Avenues of Infection 35 
 
 Tuberculosis 39 
 
 Leprosy 51 
 
 Asiatic Cholera 57 
 
 Typhoid Fever 65 
 
 Anthrax 77 
 
 Dysentery 87 
 
 Typhus Fever 93 
 
 Plague i Ill 
 
 Symptomatic Anthrax 127 
 
 Malignant Edema 131 
 
 Gas Phlegmon 132 
 
 Glanders 133 
 
 Botulism Sausage Poisoning 137 
 
 Malta Fever 139 
 
 Pneumonia 143 
 
 Tetanus 149 
 
 Streptococcic Infection 153 
 
 Staphylococcic Infection 161 
 
 Diphtheria 167 
 
 Immunity 175 
 
 Introduction 177 
 
 Phagocytosis 183 
 
 Specific Precipitins 197 
 
 Agglutination 201 
 
 Opsonins 207 
 
 Germicidal Sera 213 
 
 The General Principles and Mechanism of Infection and Immunity 223 
 
 The Index . 
 
CHAPTER I 
 
 INTRODUCTION 
 
 The purpose of this writing is to state the essential facts of infec- 
 tion and immunity accurately and simply, so that they may be under- 
 stood by the intelligent, non-professional man. The reduction and 
 ultimate eradication of unnecessary disease and the consequent pro- 
 longation of life with improved health constitute a patriotic obligation 
 which every citizen should strive to appreciate and to do his part in 
 its performance. 
 
 The further developments of medicine, both curative and pre- 
 ventive, depend on scientific investigations. The public is the bene- 
 ficiary and should in every way encourage medical research. By the 
 application of discoveries already made, the burden of disease has 
 been lightened, sickness has become less frequent and less prolonged, 
 a greater degree of health has been secured, the efficiency of the 
 individual and of the nation has been increased, and life has been 
 lengthened and made more enjoyable. The Federal government and 
 the states should sustain and promote scientific research. That gov- 
 ernment is the best which secures for its citizens the greatest freedom 
 from disease, the highest degree of health and the longest life, and that 
 people which most fully secures the enjoyment of these blessings will 
 dominate the world. 
 
 Medicine consists of the application of scientific discovery to the 
 prevention and cure of disease. All else which may go under the 
 name of medicine is sham and fraud. Without advancement in the 
 physical, chemical, and biologic sciences, there can be no progressive 
 movement in medicine. Scientific knowledge is gained only by obser- 
 vation and experiment. Before the time of Jenner, we are told by 
 the historian, it was unusual to meet in London one whose face was 
 not marked by smallpox. There was a popular belief that one who 
 had cowpox was immune to smallpox. Jenner put this belief to a 
 scientific test. The result was the discovery of vaccination, and this 
 secured the abolition of this disfigurement and a marked reduction 
 in mortality. In 1849, a village doctor, with a crude microscope, 
 
10 INTRODUCTION 
 
 studied the blood of animals sick with anthrax and compared it with 
 that of healthy ones. He discovered the anthrax bacillus. This work 
 was extended by Davaine, Pasteur, Koch, and others, and from this, 
 the science of bacteriology has been developed. The particulate causes 
 of many infectious diseases have been recognized, isolated, and their 
 effects on animals demonstrated. Many of the mysteries of contagion 
 have been revealed and the conditions of the transmission of disease 
 made known. The fundamental principles of preventive medicine have 
 been developed into a science which is to-day the most potent factor 
 in the progress of civilization. Finlay suspected a certain mosquito 
 to be the carrier of the virus of yellow fever. Reed and his co-workers 
 demonstrated the truth of this theory, the work of Gorgas has freed 
 Havana from the pestilence, and the construction of the Panama Canal 
 is an accomplished fact. 
 
 Laveran discovered Plasmodium malariae. Ross studied its life his- 
 tory, and the fetters of a disease that has so long retarded the progress 
 of man, have been broken. Mitchell and Reichert investigated the 
 poisonous properties of snake venom. Sewall immunized animals with 
 it. Ehrlich studied the similar bodies, abrin, ricin and diphtheria 
 toxin, and von Behring and Roux gave the world antitoxin, the 
 magical curative value of which has greatly reduced the mortality 
 from diphtheria. The experiments of Villemin demonstrated the con- 
 tagious nature of tuberculosis, long suspected and frequently denied. 
 The diligent research of Koch resulted in the recognition and isolation 
 of the causative agent, and since this discovery the mortality of the 
 Great White Plague in Europe and the United States has been dimin- 
 ished more than half. It is, then, within the range of sanity to look 
 forward to the time when the former "Captain of the hosts of death" 
 will be known only by the fearful records he once made in the history 
 of man's struggle to be relieved from the heavy tribute paid to 
 infection. 
 
 We boast of a great civilization, but this is justified only within 
 limits. Science more nearly dominates the world than at any time in 
 the past. Learning permeates the masses more deeply, but credulity 
 and ignorance are widely prevalent. In this country of nearly one 
 hundred millions, there are thousands whose greed impedes the prog- 
 ress of the whole, tens of thousands whose ignorance retards their 
 
INTRODUCTION 11 
 
 own growth, and other thousands who live by crime and procreate 
 their kind to feed on generations to come. We have our schools, 
 colleges, and universities, while our almshouses, insane asylums, and 
 penal institutions are full. In our cities we see the palatial homes 
 of the very rich, the splendid temples of trade and commerce, the 
 slums of want and poverty, and the homes, both rich and squalid, of 
 vice and crime. No nation in this condition can be given a clean bill 
 of health. Our hilltops are illuminated by the light of knowledge, but 
 our valleys are covered by the clouds of ignorance. We have not 
 emerged from the shadows of the dark ages. The historian of the 
 future will have no difficulty in convincing his readers that those who 
 lived at the beginning of the twentieth century were but slightly 
 removed from barbarism, as he will tell that the school, saloon, and 
 house of prostitution flourished in close proximity; that the capitalist 
 worked his employees under conditions which precluded soundness 
 of body; that the labor union man dynamited buildings; that while 
 we sent missionaries to convert the Moslem and the Buddhist, ten 
 thousand murders were committed annually in the midst of us, and 
 that a large percentage of our mortality was due to preventable disease. 
 Evidently there is much to be done before we pass out from the 
 shadows of ignorance into the full light of knowledge. In this great 
 work for the betterment of the race the medical profession has impor- 
 tant duties to perform. I do not mean to imply that the uplift of 
 mankind devolves wholly on the medical man. The burdens are too 
 many and too diversified, the ascent is too steep and the pathways 
 are too rough for one profession to hope to reach unaided the high 
 plateau we seek. Moreover, other callings have no right, and should 
 have no desire to shirk the moral responsibilities which rest alike on 
 all. But in past ages, medical men have been the chief torch bearers 
 of science, whose light is the only one in which man may safely walk, 
 and we must keep and transmit this trust and honor to those who 
 follow us. I know of no scientific discovery, from the ignition of 
 wood by friction to the demonstration of the causes of infection and 
 the restriction of disease, which has not sooner or later assisted in the 
 betterment of the race. It may be added that nothing else has so aided 
 man in his slow and halting progress from the pestilential marshes 
 of ignorance to the open uplands of intelligence. 
 
12 INTRODUCTION 
 
 In so great a work as the eradication of preventable disease, all 
 intelligent people must cooperate. The law must support by proper 
 enactments, and these must be enforced with justice and intelligence; 
 it must recognize that the right to enjoy health is quite as sacred as 
 that to possess property; that to poison men in factories and mines, 
 to pollute drinking-water supplies, to adulterate foods, and to drug 
 with nostrums, is manslaughter. Religion must teach the sanctity of 
 the body as well as that of the soul, that ignorance is sin and knowledge 
 virtue, that parenthood is the holiest function performed by man, and 
 that to transmit disease is an unpardonable sin. The teacher must 
 know hygiene as well as mathematics. The capitalist must recognize 
 that improvement in health and growth in intelligence increase the 
 efficiency of labor. There never has been a time when scientific medi- 
 cine has had so many and such efficient and appreciative helpers as 
 it has to-day. Our sanitary laws are for the most part good, but 
 their administration is weak, on account of ignorance. The pulpits 
 of the land are open, for the most part, to the sanitarian. The 
 respectable newspapers are most effective in the crusade against 
 quackery and disease. The philanthropist has learned that the advance- 
 ment of science confers the greatest and most lasting benefits on man. 
 
 There is a moral obligation to be intelligent. Ignorance is a vice 
 and when it results in injury to anyone, it becomes a crime, a moral, 
 if not a statutory one. To infect another with disease, either directly 
 or indirectly, as a result of ignorance, is an immoral act. The purpose 
 of government is to protect its citizens, and a government which fails 
 to shelter its citizens against infection is neither intelligent nor moral. 
 To transmit disease of body or mind to offspring is an unpardonable 
 sin. In a reasonable sense it is worse than murder, because it projects 
 suffering into the future indefinitely. 
 
 That medicine has become a fundamental social service must be 
 evident. To return one incapacitated by illness or injury to the con- 
 dition of self-support, benefits not only the individual, but the com- 
 munity, inasmuch as it increases its productive capacity. Infirmity is 
 a direct burden on the individual and scarcely less direct on the com- 
 munity. Weakness in any part diminishes the strength of the whole. 
 It is a fully established principle in social economy that widespread 
 intelligence and growth in knowledge are beneficial to the' state. It 
 
INTRODUCTION 13 
 
 was in full recognition of this that the framers of the ordinance of 
 1787 wrote into that immortal document: "Religion, morality and 
 knowledge being necessary to good government and the happiness of 
 mankind, schools and the means of education shall forever be encour- 
 aged." The territory of the Northwest, the government of which was 
 created in this ordinance, was at that time a vast waste of forest and 
 prairie, furnishing a scant and precarious subsistence for savage tribes 
 and attracting to its borders a few of the most hardy sons of civiliza- 
 tion. The knowledge, for whose growth and diffusion the wise provision 
 was made, has drained the malarial marshes, converted wild prairie 
 and tangled wood into fruitful orchards and fertile fields, dotted the 
 whole area with neat villages, reared great cities, linked all parts with 
 steam and electric roads, and provided comfortable homes and abundant 
 food for millions. The men who wrote the ordinance of 1787 left a 
 great inheritance which is temporarily in our possession. Let us write 
 into this great document: "Every ill which can be relieved shall be 
 removed, and every preventable disease shall be prevented." The 
 wisdom of our fathers has secured for us a greater measure of health 
 and a longer term of life; let us do as well for those who are to 
 possess this fair land in the next generation. Let us live not only 
 for ourselves and the present, but for the greater and more intelligent 
 life of the future. 
 
 Not myself, but the truth that in life I have spoken, 
 Not myself, but the seed that in life I have sown 
 Shall pass into ages all about me forgotten 
 Save the truth I have spoken, the things I have done. 
 
 All things are relative and health is no exception. With a greater 
 degree of health among all, religion will become more effective for 
 good, morality will have a deeper significance and a wider applica- 
 tion, and knowledge will multiply and distribute its blessings more 
 widely. 
 
 After the last epidemic of the plague in London, in 1665, the death- 
 rate, so far as it can be ascertained, fell to between seventy and eighty 
 per 1,000. During the next century it fell as low as fifty, but fluctu- 
 ated greatly with recurring epidemics of typhus and smallpox. In the 
 nineteenth, it gradually and quite constantly decreased and is now 
 about fourteeen. In 1879-80, the first year in which the mortality 
 
14 
 
 INTRODUCTION 
 
 statistics of the United States possess sufficient accuracy to be of any 
 value, the death-rate in the registered area was 19.8; in 1912 it was 
 13.9 a decrease of 30 per cent. During the same time the mortality 
 from typhoid fever has decreased 50 per cent. ; that from scarlet fever 
 89 per cent. ; that from diphtheria 84 per cent. ; that from tuberculosis 
 54 per cent. Hoffman states that had the death-rate for tuberculosis 
 in 1901 continued, there would have been 200,000 more deaths from 
 this cause from that date to" 1911 than actually did occur, so that the 
 actual saving of lives from death by tuberculosis accomplished in that 
 decennium averaged 20,000 a year. Preventive medicine measures its 
 successes by the number of lives saved, and 20,000 a year preserved 
 from death from one disease is no small triumph. In the last century 
 the average of human life has been increased fifteen years and this 
 increase could be duplicated in the next twenty years if the facts we 
 now possess were effectively employed. Hoffman further states that 
 the addition to the material wealth of this country secured by the 
 reduction of deaths from tuberculosis within ten years amounts approx- 
 imately to 6,200,000 years of human life, covering its most productive 
 period. Medicine discovered the facts which have made this great 
 work possible and has directed their application. With evidence of 
 this kind before them, will our lawmakers listen to those who demand 
 recognition as practitioners of medicine without proper qualifications ? 
 The following figures give the death-rates from all causes and 
 from each of certain infectious diseases in the registered area of the 
 United States since the census of the year of 1879-80 : 
 
 
 .L-'CciLllO pCI 
 
 
 Year 
 
 1,000 from 
 
 Scarlet fever 
 
 Typhoid fever 
 
 Diphtheria 
 
 Tuberculosis 
 
 
 all causes 
 
 
 
 
 (all forms) 
 
 1879-80 
 
 19.8 
 
 54.0 
 
 34.0 
 
 112.6 
 
 326.2 
 
 1889-90 
 
 19.6 
 
 13.6 
 
 46.3 
 
 97.8 
 
 267.4 
 
 1899 
 
 17.8 
 
 11.6 
 
 33.8 
 
 45.2 
 
 205.2 
 
 1900 
 
 17.6 
 
 10.2 
 
 35.9 
 
 43.3 
 
 201.9 
 
 1901 
 
 16.5 
 
 13.1 
 
 32.3 
 
 34.0 
 
 196.9 
 
 1902 
 
 15.9 
 
 12.6 
 
 34.3 
 
 30.8 
 
 184.5 
 
 1903 
 
 16.0 
 
 12.2 
 
 34.1 
 
 31.7 
 
 188.5 
 
 1904 
 
 16.5 
 
 10.8 
 
 31.7 
 
 28.3 
 
 200.7 
 
 1905 
 
 16.0 
 
 6.7 
 
 27.8 
 
 23.6 
 
 192.3 
 
 1906 
 
 15.7 
 
 7.7 
 
 31.3 
 
 25.7 
 
 180.2 
 
 1907 
 
 16.0 
 
 10.0 
 
 29.5 
 
 23.6 
 
 178.5 
 
 1908 
 
 14.8 
 
 11.9 
 
 24.3 
 
 21.5 
 
 167.6 
 
 1909 
 
 14.4 
 
 11.4 
 
 21.1 
 
 20.4 
 
 160.8 
 
 1910 
 
 15.0 
 
 11.6 
 
 23.5 
 
 21.4 
 
 160.3 
 
 1911 
 
 14.2 
 
 8.8 
 
 21.0 
 
 18.9 
 
 158.9 
 
 1912 
 
 13.9 
 
 6.7 
 
 16.5 
 
 18.2 
 
 149.5 
 
 1913 
 
 14.1 
 
 8.7 
 
 17.9 
 
 18.8 
 
 147.6 
 
INTRODUCTION 15 
 
 Preventive medicine, still in its youth, has accomplished great 
 things. As I have stated, within the past thirty years in this country 
 the mortality from tuberculosis has been reduced more than half, and 
 with scarlet fever and diphtheria, the results have been more striking. 
 Within the past ten years, the average life has been increased four 
 years. Great epidemics which once devasted continents are no longer 
 known in the more intelligent parts of the world. In fact, it may be 
 said that the death-rate is now an excellent measure of intelligence. 
 In 1911 the death-rate in London was 15 per thousand, while that of 
 Moscow was 27.3. Preventive medicine is the keystone of the trium- 
 phal arch of modern civilization and its displacement would precipitate 
 mankind into relative barbarism. Should the health administrators of 
 any great commercial center fail, for even a few months, to exercise 
 the function of restricting disease, the history of the epidemics of 
 the middle ages might be repeated. Great things have been done, 
 but greater tasks lie before us, and their accomplishment depends on 
 the scientific wisdom of the medical profession and the intelligence 
 of the people. Without the harmonious adjustment of these forces 
 the greatest efficiency cannot be secured. While the mortality from 
 tuberculosis has been reduced half in the past thirty-five years, we 
 must not assume that the total eradication of this disease will be 
 accomplished in the same number of years. Only the more progressive 
 members of the profession have taken the initiative, and only the more 
 intelligent members of the community have responded. Intelligence 
 and the sense of moral responsibility must grow as the work proceeds. 
 It remains for all who have the welfare of the race at heart to plan 
 wisely and carry fonvard courageously the campaign against greed, 
 ignorance and disease. 
 
PART I 
 INFECTION 
 
CHAPTER II 
 
 HISTORICAL INTRODUCTION 
 
 The oldest and most persistent belief holds that disease is an 
 infliction imposed on man by some supernatural power. This doctrine 
 was handed down by tradition to the earliest civilizations, was incor- 
 porated in their records and is held by many to-day. Some have 
 attributed disease to evil spirits and others have regarded it as a 
 dispensation of their gods. The Babylonians regarded disease "as 
 the work of demons which swarmed in the earth, air and water, and 
 against which long litanies and incantations were recited." In the 
 hand of the Jehovah of the Jews disease was a whip of chastisement 
 which fell at will on the chosen people or their enemies. "I will put 
 none of those diseases upon thee which I have brought upon the 
 Egyptians ; for I am the Lord that healeth thee." There is no book 
 of the middle ages down to the eighteenth century, describing an 
 epidemic which does not attribute it to the wrath of God. Job 
 ascribed his own pains to the "arrows of the Almighty." Luther 
 wrote that "pestilence, fever and other severe diseases are naught else 
 than the devil's work." Cotton Mather described disease as "flagellum 
 Dei pro pecatis mundi." 
 
 "The American Indian medicine man or the Asiatic Samoyed does 
 his best to frighten away the demons of disease by assuming a terrify- 
 ing aspect, covering himself with the skins of animals so as to resemble 
 an enormous beast walking on his hind legs, resorting to such demon- 
 strations as shouting, raving, slapping his hands or shaking a rattle, 
 and pretending (or endeavoring) to extract the active principle of the 
 disease by sucking it through a hollow tube. . . . We may smile 
 at these phases of Shamanistic procedure, but, except for the noise, 
 they are not essentially different from the mind-medicine or faith- 
 healing of our own day. Both rely upon psychotherapy and sug- 
 gestion, and for a sick savage, the fantastic clamor made about him 
 might be conceivably as effective as the quieter methods of Christian 
 Science, to a modern nervous patient." (Garrison.) 
 
20 HISTORICAL REVIEW 
 
 A doctrine quite as old, but with a smaller following at present, 
 taught that all the joys and ills of man are determined by the position 
 of the heavenly bodies. Even within the present generation there are 
 those who believe that famine, war and pestilence are determined by 
 the spots on the sun or by the juxtaposition of certain planets. Our 
 great lexicographer, Noah Webster, wrote a book to prove that epi- 
 demics are due to earthquakes and other terrestrial disturbances. 
 
 Hippocrates taught that epidemics are due to a pestilential condi- 
 tion of the air. This theory dominated the medical profession for 
 more than two thousand years, and still colors some of our conceptions 
 of infection. Quite naturally, such a theory is liable to many modifi- 
 cations. How does the air become pestilential? This question has 
 been answered in numberless ways. Some say it is made so by evil 
 spirits; by an angered God; by the influence of heavenly bodies; by 
 terrestrial disturbances ; by prevailing winds ; by emanations from earth 
 or water; etc. It is natural for man to believe in the evil genius of 
 the locality in which ills befall him. In 1898, intelligent army officers 
 told with bated breath that the word "Chickamauga" means river of 
 death. They believed that the epidemic of typhoid there prevalent 
 was due in part, at least, to the miasm of the locality and the disease 
 was called "Chickamauga fever." The word malaria (mal aria) owes 
 its origin to this theory. In war, unburied bodies of men and animals 
 were supposed to fill the air with deadly decomposition products. It 
 was fear of this that secured burial of the numerous victims of the 
 plague in the great epidemics of the middle ages. This fear had, in 
 part at least, a religious basis, and burial was regarded not only as 
 a necessary sanitary measure, but as a compliance with a divine com- 
 mand. The unburied dead became a reproach to the living ; from the 
 decomposing body noxious and fatal emanations polluted the surround- 
 ing air, and with this threatening weapon, the dead demanded the 
 honor of Christian burial. 
 
 Lowlands and swamps were supposed to be places in which noxious 
 vapors were generated and from which they spread, poisoning the air 
 of the surrounding country. These localities were shunned, especially 
 after sunset, and the fear of breathing night air became well nigh 
 universal. We now know that the real truth in this belief was made 
 
HISTORICAL REVIEW 21 
 
 plain by the discovery of the transmission of malaria by mosquitos. 
 The latest scientific support of the theory of miasm appeared in the 
 teachings of the great sanitarian of Munich, Pettenkoffer. When he 
 began his work in the Bavarian capital, about the middle of the nine- 
 teenth century, that city was known as a hotbed of typhoid fever. 
 Fecal matter was deposited in shallow vaults and the drinking-water 
 was taken from shallow wells. The whole city was honeycombed with 
 these privies and wells, and the people were drinking strong infusions 
 of their own excrement. Pettenkoffer taught that the fecal matter 
 undergoes a ripening process in the soil and thereby becomes the cause 
 of typhoid fever. Responding to his teachings, the people of Munich 
 introduced a complete sewerage system and brought a pure drinking- 
 water from a distant mountain lake. This resulted in the eradication 
 of typhoid fever and Pettenkoffer 's theory was justified by the result. 
 We now know that the typhoid bacillus needs no ripening process 
 during the interval which elapses from its passage from the bowels 
 of one to its entrance into the alimentary canal of another. Petten- 
 koffer's theory did not assume that the noxious agent in the fecal 
 matter is a living organism, but rather held that the ripening process 
 consists of chemical changes. From this, there grew up the idea of 
 the de novo origin of typhoid fever. The fecal matter of uninfected 
 individuals was supposed to undergo ripening processes in the soil 
 and the products of these changes, finding their way into either water 
 or air, distributed the disease. This theory was not only plausible, 
 but was in accord with the then known facts. It found ready support, 
 especially among army medical officers. However healthy men 
 appeared to be when they went into camp, even in locations which 
 could not have been contaminated previously, after a few weeks, 
 typhoid fever appeared and spread in proportion to the filthiness of 
 the camp and the inefficiency of the methods of fecal disposal. Men 
 of the highest intelligence and widest experience became firm sup- 
 porters of the de novo origin of typhoid fever which they regarded 
 as a filth disease. They believed that the disease was spread by gases 
 generated in any kind of filth, but more especially by those developed 
 in fecal matter. 
 
 The theory of miasm was applied not only to typhoid fever and 
 malaria, but to all diseases, especially those appearing in epidemic 
 
22 THEORY OF MIASM 
 
 form. With sound sense, the Greek Father of Medicine said that 
 when a large number of people fall ill simultaneously the cause must 
 be sought in that which is common to all, and what can that be save 
 the air they breathe ? It was observed, however, that while the whole 
 community was breathing the same air, many remained well ; some had 
 eruptive diseases; others diarrheal disturbances; and still others, res- 
 piratory affections. This necessitated the division of men into groups 
 according to temperament. With the same factor in the air the result 
 would vary with the temperament of the individual. 
 
 The study of the cholera epidemics of the nineteenth century 
 removed the last scientific support of the theory of miasm. It had 
 long been a matter of observation and record that epidemics travel 
 from east to west. This was noted before the Christian era. It was 
 frequently observed in classical times, and the cholera pandemics gave 
 opportunity for collecting exact data on this matter. It was found 
 that cholera, which is endemic about the delta of the Ganges, becomes 
 pandemic on the occasion of certain religious pilgrimages. The faithful 
 followers of Mohammed from all points of the compass gather at 
 Mecca. Some come from the home of cholera, bringing the infection 
 in their bodies. From their discharges others become infected, and 
 as the great concourse disperses, bands of returning pilgrims carry the 
 infection with them, and the disease widens its area. It travels just 
 as fast and no faster than man travels. It goes where he carries it 
 and nowhere else. When an individual drops the infection, some one 
 else must pick it up and carry it on or it ceases to spread. The gen- 
 eral direction of the spread of infection has always been from east to 
 west because the great lines of human travel have led from this point 
 of the compass, but it was found in the study of the cholera epidemics 
 that whenever and wherever the paths of travel deviated from the 
 general direction, the infection showed the same deviation. In other 
 words, it became evident that infected man carried the infection in 
 his own body. However, when the pandemics spread over Europe it 
 was noticed that, while no place became infected unless visited by 
 some infected individual, the disease established itself in certain locali- 
 ties and failed to do so in other places. This observation gave some 
 support to the theory of miasm. In some soils the seeds of the disease 
 grew and multiplied while in others they did not. When the water- 
 
GERM THEORY 23 
 
 supply of a locality became infected, the disease spread among its 
 consumers. Budd of London was probably the first to detect the role 
 of infected water in the dissemination of Asiatic cholera. Finally the 
 discovery of the specific bacteria of cholera and other diseases removed 
 the last support of the theory of disease originating in miasmatic 
 conditions of the atmosphere. 
 
 The "germ theory" of disease found lodgment in the brain of an 
 occasional genius many centuries ago. Just who first suggested it 
 and when are not easily determined, but the argument ran something 
 as follows: Alexandria was free from the plague. A ship from a 
 port where it prevailed came with sick on board. Those associated 
 with the new arrivals acquired the disease and it spread in an ever 
 widening circle until it prevailed throughout the city and extended in 
 a similar manner to other countries. The disease must be due to a poison 
 of some kind. It cannot be a chemical poison, like arsenic, but it must 
 be a living thing which finds its way from the body of the sick to those 
 of the well where it grows and multiplies and in so doing causes the 
 symptoms of the disease and death. Thus, man's reason, stimulated 
 by exact observation, caused him to conclude that an epidemic must 
 be due to a contagium vivum. He might theorize concerning this 
 living thing, but he could not demonstrate its existence. It was too 
 small for him to see. In the first century of the Christian era Varro 
 wrote that there are swamps in which grow animals so small that they 
 cannot be seen. They enter the body through the mouth and nose 
 and cause disease. Others wrote to the same effect. Probably the 
 first to see bacteria was the Dutch scientist and lens maker, Leeuwen- 
 hoek, who near the end of the seventeenth century described the 
 "animalculae" which he found under his microscope in the examination 
 of tartar from the teeth and diarrheal stools. In 1849 a village doctor 
 on the Rhine, with a crude compound microscope, saw rod-like bodies 
 in the blood of animals sick with anthrax and failed to find them in 
 the blood of healthy animals. The science of bacteriology may be 
 said to owe its birth to these observations. Independently, this work 
 was continued by Brauel, Davaine and others, but the founder of 
 exact and systematic knowledge concerning the causal agents of dis- 
 ease was the great Frenchman, Louis Pasteur. 
 
24 PASTEUR'S WORK 
 
 Space permits only a brief and incomplete statement of the work 
 of Pasteur, and in doing this the chronological order will not be fol- 
 lowed. He overthrew the doctrine of spontaneous generation. 
 Although Harvey, two centuries earlier, had laid down the dictum, 
 omne vivum ex vivo, there were those who held that this does not 
 hold for the lowest forms of life. As Abel says, "Homer wrote of 
 autochthonus men who sprang from the soil; the sixteenth century 
 saw recipes for the manufacture of mice and frogs, and in later days, 
 it was claimed that lower forms of animal life must have developed 
 spontaneously because the Bible makes no mention of their having 
 been taken into the ark by Noah." It was essential to the development 
 of bacteriology, which depends so largely on sterilization, to dispose 
 of spontaneous generation and to show that lower, as well as higher, 
 forms of life breed true. This Pasteur did with the aid of Tyndall, 
 and others. He showed that fermentation is due to the growth of 
 living organisms, and that each kind of fermentation, like that in 
 beer, wine and milk, is due to specific organisms. Furthermore he 
 showed that a temperature high enough to kill these organisms arrests 
 fermentation. By this process, now known as pasteurization, he pre- 
 served beer, wine and milk. Among this line he went further still 
 and demonstrated that putrefaction, like fermentation, is due to bac- 
 terial growth. Lister utilized this discovery in the development of 
 antiseptic surgery from which aseptic surgery has come. If each 
 kind of fermentation has its specific organism, why may not each dis- 
 ease have its specific bacterial cause? Exposure to smallpox does not 
 develop typhoid fever. The answer to this question has been given by 
 the discovery of the specific causal agents of many diseases, and 
 when found and tested, their specificity is demonstrated. The anthrax 
 bacillus grown through a hundred generations and then inoculated 
 into susceptible animals induces anthrax still. Pasteur found that 
 certain specific bacteria can be so attenuated by unfavorable condi- 
 tions of growth that they will not develop the disease in susceptible 
 animals, but do impart to them immunity to infection with virulent 
 strains. In this way he prepared vaccines for chicken cholera, swine 
 eryripelas and anthrax. He also developed the successful treatment of 
 hydrophobia, now used in every part of the world. 
 
HISTORICAL REVIEW 25 
 
 The great German scientist, Koch, extended and developed the 
 work of Pasteur. His solid media and bacterial stains made the 
 growth, indentification and separation of bacteria comparatively easy. 
 His untiring labor led to the discovery of the specific bacteria of 
 Asiatic cholera and tuberculosis, and has placed in man's hands the 
 possibility of completely eradicating these and other infectious diseases. 
 
 The work so firmly established by Pasteur and Koch has been 
 amplified by many workers in many lands and has led already to 
 marked reduction in both morbidity and mortality from the infectious 
 diseases. Much has been accomplished in the attempt to lift the 
 burden of unnecessary disease from man, but greater tasks lie 
 before us. 
 
 This article will be limited to the bacterial diseases and only the 
 more common of these can be included. 
 
CHAPTER III 
 
 BACTERIA 
 
 Morphology. Bacteria are microscopic, unicellular organisms 
 which appear in three fundamental forms. The spherical forms are 
 known as cocci and may be single, in chains or in bunches. The indi- 
 viduals may be perfectly spherical, elliptical or lancet-shaped. The 
 individual pus coccus has a diameter of from 0.4 to 1 micron.* The 
 cylindrical forms are known as bacilli. Some have plane and others 
 convex or rounded ends. Bacilli differ greatly in length, the longest 
 pathogenic bacillus, that of malignant edema, being 9 microns, and 
 the shortest, that of influenza, being 0.5 of a micron. Growth is in 
 the direction of the long axis and multiplication by transverse fission. 
 The shape of the spirilla is sufficiently indicated by the name. Involu- 
 tion forms will not be discussed. 
 
 Spore Formation. The only spore-forming pathogenic bacteria 
 are those of anthrax, symptomatic anthrax, tetanus and malignant 
 edema. The spores are of endogenous origin, are highly refractive to 
 light, and resistant to heat, and chemical disinfectants. No bacillus is 
 known to form more than two spores and this is practically confined 
 to saprophytic organisms. The appearance of two spores in an anthrax 
 bacillus is rarely seen. The purpose of spore formation is not mul- 
 tiplication but preservation; it is a resting stage. Spore formation is 
 a result of the concentration of the nuclear substance. The spore may 
 be formed in any part of the cell, but the location in the same species 
 is usually constant. In some bacteria the spore does not exceed the 
 diameter of the cell; in others it is larger. A large spore located at 
 one end of a bacillus gives it a "drum-stick" appearance ; when in the 
 middle, it forms a "spindle-shaped" organism. Untoward conditions, 
 such as scarcity of food, the presence of deleterious agents and an 
 accumulation of metabolic products, favor the development of spores. 
 
 * A micron is one thousandth of a millimeter and is the equivalent of 1/25,400 
 of an inch. 
 
28 BACTERIA 
 
 The bacterium passes into the resting state and awaits more favorable 
 conditions. When these arrive, whether it be days or years later, the 
 spore passes into the vegetative form and reproduction and multipli- 
 cation begin anew. 
 
 Multiplication. When bacteria reach a certain size, which is fairly 
 constant in the species, the cells divide. In bacilli and vibrios fission 
 occurs at right angles to the long axis. In cocci the cleavage may 
 occur in only one plane forming streptococci; in two planes forming 
 staphylococci ; or in three planes, forming sarcinae. The rapidity of 
 multiplication and growth to maturity varies with conditions. It has 
 been estimated that if fission occurs hourly without interruption, in 
 forty-eight hours the descendants of a single individual would number 
 more than 200,000,000. However, such a rate of multiplication can 
 hardly occur since growth would be checked by scarcity of food or 
 by the accumulation of excreta from the bacteria themselves. The 
 rate of multiplication under most favorable conditions is the best 
 measure of the intensity of life processes, and in the case of pathogenic 
 bacteria, of virulence. The "generation period" is the time interval 
 between fissions in the same bacillus. This varies greatly with varying 
 conditions. Some of these conditions seem inherent in the strain while 
 others are more variable. Under most favorable conditions the 
 cholera bacillus has been found to divide about every half hour. When 
 a culture tube is inoculated there is a variable period during which 
 there is no multiplication, then fission begins. As the culture grows 
 older the rate of multiplication falls on account of the accumulation 
 of metabolic products. In infection the rate of multiplication is 
 determined by the number of bacteria introduced as well as by other 
 conditions. However, one strain of the same species may multiply 
 a thousand times as fast as another. 
 
 Antagonism. As happens in all forms of life, the most destructive 
 agents to bacteria are other bacteria. It is fortunate that this is true, 
 and man and other animals profit greatly by the conflict continually 
 being waged between different species of bacteria. A drinking-water 
 supply becomes contaminated with the typhoid bacillus which flourishes 
 for a few days and is then completely destroyed by other bacteria. 
 So true is this that by the time the disease has developed among 
 
BACTERIA 29 
 
 those who drink the water, there are no longer typhoid bacilli in the 
 water. The bacteriologic examination of drinking-water after an 
 epidemic has developed, is in the large majority of instances, a useless 
 procedure. A city's water-supply should be examined daily in order 
 to be of value. The weapons used in this warfare among bacteria 
 are many and varied. Some simply eat up the food supply and the 
 invaders die of starvation. Others produce waste products which are 
 harmful to other species. Anthrax bacilli planted in sterile cholera 
 cultures are greatly weakened. Sterile cultures of the pyocyaneus 
 dissolve anthrax bacilli. Some change the reaction of the common 
 medium by the development of acid or alkali and their enemies die. 
 The streptococcus kills the plague bacillus, and thus the conflict of 
 nations and races goes on among the unicellular organisms much as 
 it does among the lords of creation. 
 
 Symbiosis. Some species form allied armies and contend against 
 a common enemy or overrun a foreign country. The pus bacteria are 
 found in many combinations and most men die from diseases in 
 which these cocci play an important part. After the tubercle bacillus 
 has fed on one's lungs for years and prepared the soil, some pus 
 germ finds its way in before death and contributes largely to its com- 
 ing. The cancer cell opens up ports of entry through which pus 
 organisms enter. The lesions of syphilis are plundered and looted by 
 the hordes of cocci. Thus, as Mayo has pointed out, sepsis plays an 
 important role in the last acts of the three great tragedies of life; 
 tuberculosis, cancer and syphilis. Some pathogenic bacteria receive 
 aid from organisms which by themselves are harmless. The tetanus 
 bacillus is much more virulent when it enters the animal body in 
 company with certain saprophytes. When alone, the phagocytes 
 speedily fall on and devour it, while certain products of the growth 
 of its friend repel the phagocytes. 
 
 Capsules. Some bacteria are surrounded by mucilaginous capsules. 
 When two or more individuals are attached, the capsule usually 
 includes the group, and when many are imbedded in one large capsule 
 the whole is known as a zooglia. The capsule is believed to be formed 
 for protective purposes, since many bacteria develop them only when 
 in the animal or when grown in animal fluids, secretions or excre- 
 
30 BACTERIA 
 
 tions. The presence of deleterious agents, such as arsenic, seems to 
 favor the development of capsules. 
 
 Flagella. All bacteria show passive movements when suspended 
 in fluids and watched under the microscope. Such motion is known 
 as molecular or Brownian and is common to all finely divided par- 
 ticles when suspended in fluid. Apart from this, certain bacteria are 
 capable of active motion, which is accomplished by the contractions 
 of flagella or whips. Those without flagella have no active motion. 
 There may be only one whip at one end, as in the cholera bacillus; 
 a single whip at each end, as in many saprophytic vibrios; a bunch of 
 whips at one end as in certain large saprophytic vibrios ; and many 
 whips distributed over the cell, as in the typhoid bacillus. The flagella 
 seem to be outgrowths from the ectoplasm and they may be removed 
 from certain bacteria by shaking and then centrifuging, or by filtra- 
 tion through porcelain. Their presence favors agglutination, which 
 however, is not wholly dependent on them. 
 
 Oxygen Need. Pasteur observed that some bacteria grow best 
 when supplied with oxygen, while others have their optimum growth 
 when this element is excluded. The former he designated as aerobic 
 and the latter as anaerobic. Further study has divided bacteria accord- 
 ing to their need of oxygen into the following classes : 
 
 1. Obligate aerobes are those which will not grow save in the 
 presence of free oxygen. This does not mean that they must have 
 an abundant air-supply, because some do grow when the oxygen 
 tension is only one-hundredth that of the air. Among the pathogenic 
 bacteria, the plague and influenza bacilli and the pneumococcus and 
 gonococcus belong to this group. An excess of oxygen may prove 
 harmful to even the obligate aerobes. 
 
 2. Facultative anaerobic bacteria are those that grow best in the 
 presence of oxygen, but may grow when this element is wholly 
 excluded. Many pathogenic organisms belong to this class, such as 
 the cholera vibrio, anthrax and typhoid bacillus and pus cocci. 
 
 3. Obligate anaerobes are bacteria which grow only in the absence 
 of free oxygen. In this group are the bacilli of tetanus, symptomatic 
 anthrax and malignant edema. These bacteria obtain their oxygen 
 if they utilize this element at all, from the combined oxygen in their 
 
BACTERIA 31 
 
 pabulum. Pasteur found that fermentation is due to obligate anaerobes 
 and he defined fermentation as life without oxygen. However, this 
 does not mean that all life without oxygen results in fermentation. 
 The growth of bacteria of this group is favored by the presence of 
 reducing agents in the medium. Anaerobic bacteria may grow in the 
 presence of free oxygen provided there are present aerobic organisms 
 which absorb all the oxygen. The development of tetanus is favored 
 by puncture wounds, also by the presence of aerobic bacteria. 
 
 Structure. In the higher plants and animals, all cells capable of 
 multiplication consist of protoplasm and nucleus. There has been 
 much controversy among bacteriologists concerning the structure of 
 the bacterial cell. Some say that this cell has no nucleus because, with 
 the analine dyes, it stains uniformly. Others say it is all nucleus 
 because the staining which it takes throughout is nuclear. These are 
 the two extremes, but most agree that the greater part of the bacterial 
 cell consists of nuclear material. Fats and waxes have been accumu- 
 lated especially by those organisms, as the tubercle bacillus, which 
 have lived so long as parasites. Food material, inorganic salts, fer- 
 ments and various extractives are present in the bacterial cell, but 
 for the most part it is of nuclear composition. Its chief function is to 
 multiply, and this is accomplished in the simplest possible way by 
 nuclear division. Most authorities define bacteria as low forms of 
 plant life. The one characteristic and constant constituent of the plant 
 cell is cellulose. This certainly does not exist in the pathogenic bacilli 
 and bacteria are not plants. This seems certain unless we radically 
 change our conception of the plant cell. Bacteria may be more 
 properly defined as nuclei, probably protected by a protein ectoplasm. 
 I and my students have devoted many years of work to this subject 
 and we have shown that chemically the greater part of the bacterial 
 cell is nuclear substance. It contains two carbohydrates, one of which 
 has been located in the nucleic acid group while the position of the 
 other has not been determined. It yields phosphorus and xanthin 
 bases and when broken up with acids or alkalies supplies mono-amino 
 and diamino acids. Chemically, bacteria are nucleoproteins. It has 
 been assumed by some that, chemically, bacteria are of simple struc- 
 ure. This is pure assumption and rests solely on the fact that, 
 
32 BACTERIA 
 
 morphologically, bacteria are relatively simple. Biologically and 
 chemically their structure is as complicated as that of the highest cells 
 of the animal body. In common with all proteins, bacterial cellular 
 substance contains a powerful poison. This is true alike of pathogenic 
 and non-pathogenic bacteria and true of all proteins bacterial, vege- 
 table and animal. 
 
 In fact, bacteria in their essential parts are living molecules, of 
 definite chemical composition and structure. In different species the 
 molecular composition differs. As Benecke has shown, the pyocyaneus 
 requires for its growth, in addition to protein substances, two ele- 
 ments, potassium and magnesium. The former cannot be replaced by 
 sodium or ammonium, nor the latter by calcium. The tubercle bacillus 
 needs glycerin in order to assimilate amino-acids, carbohydrates and 
 organic acids. Cramer found that the cholera bacillus assimilates as 
 much as 95 per cent, of the nitrogen in alkaline bouillon, and at most 
 3 per cent, of that in Uschinsky's solution. The obligate parasites 
 feed only on the fluids and tissues of the animal body and some only 
 on some particular species of animal. The influenza bacillus grows 
 only on media containing hemoglobin or some chemically related 
 body. 
 
 Metabolism. Every living thing must feed, assimilate and elim- 
 inate. It thrives and multiplies when food is abundant and conditions 
 of life are favorable. It hungers and dies when the food supply fails. 
 These things are as true of unicellular as of multicellular forms of 
 life. All bacteria, even the anaerobic, absorb oxygen and eliminate 
 carbonic acid. In this gaseous exchange more oxygen is absorbed than 
 is eliminated in the form of carbonic acid. This shows that some 
 oxygen is used in nitrogen metabolism. When the food supply is 
 suddenly withdrawn in the midst of rapid multiplication, the death- 
 rate is great, and greater among the young than among the older 
 individuals. Fisher has shown that when a growth of cholera bacilli 
 twenty-four hours old is suddenly transferred to salt solution, all the 
 organisms die within thirty-six hours. With older cultures some live 
 bacilli are found much later and with a seven-day culture, some will 
 be found to be alive after fifty days. When the food supply is gradu- 
 ally withdrawn the death-rate is not so high and the more hardy 
 
BACTERIA 33 
 
 individuals retain their vitality for months and even years, especially 
 at low temperature. The respiratory quotient remains constant in 
 the same species under identical conditions and is a measure of rate 
 of growth and multiplication. 
 
 All living cells must depend on the pabulum within their reach. 
 This must be digested or broken up into particles which will fit into 
 the bacterial molecule. This is accomplished by agents which we 
 designate as ferments or enzymes. Each species of bacteria elaborates 
 its own specific enzymes, the functions of which are to cut the 
 pabulum into proper blocks and to place these blocks in the structure 
 of the cell. These enzymes are specific in two senses. First, they are 
 specific in origin; the ferments produced by typhoid bacilli are not 
 identical with those of anthrax bacilli. Secondly, they are specific 
 in their action. Given the same pabulum, the shape and size of the 
 blocks into which it is split differ with the ferment acting on it. 
 Besides, a given ferment cannot act on all pabulum. What is food to 
 one bacterium may be of no value to another. 
 
 Pathogenitity. Why is it that one bacterium is capable of induc- 
 ing disease while another is harmless? The answer to this is quite 
 clear. Some bacteria can feed only on dead matter. Their ferments 
 will not prepare the fluid and tissues of the animal body for the 
 sustenance of their cells; or it may be that the ferments of the body 
 cells digest these bacteria and prevent their growth. These bacteria, 
 which compose the great majority of existing species are known as 
 saprophytes. There are other bacteria which can digest, absorb and 
 eliminate the constituents of the fluids and tissues of the animal body 
 and which are not digested by the body cells. These are parasites and 
 their growth and reproduction in the body cause disease and conse- 
 quently such bacteria are said to be pathogenic. Such an organism 
 may be able to grow in one species of animal and not in others. It 
 is pathogenic only to those animals in which it can grow. It may be 
 able to grow in certain individuals of a species and not in others. To 
 the man who has had smallpox or has been properly vaccinated, the 
 smallpox virus is not pathogenic. Vaccination has developed in the 
 body cells the function of producing a ferment which digests small- 
 pox virus and consequently this cannot grow and multiply in the body 
 of the vaccinated man. 
 
CHAPTER IV 
 
 AVENUES OF INFECTION 
 
 The Skin. While certain parasites, molds and fungi may be 
 implanted on a healthy skin by contact, either direct or indirect, there 
 is no known bacterium which will penetrate the healthy, unbroken 
 cutaneous covering of man under natural conditions. When pus bac- 
 teria are vigorously rubbed into the skin, especially when incorporated 
 in a salve, impetigo, furunculosis and even abscess formation may 
 result. Experimental infection of the lower animals has been induced 
 in a similar manner with plague, glanders, anthrax, tuberculosis and 
 recurrent fever. The plague bacillus may penetrate the unbroken and 
 unshaven skin of the guinea-pig and cause general infection. The 
 protection afforded by the skin is wholly mechanical. Infection 
 through the skin may result: (a) from the bites of animals, as rabies 
 from the bite of the dog; (b) from the bites of insects, as malaria and 
 yellow fever, transmitted by mosquitoes, and plague and other dis- 
 eases transmitted by fleas and possibly by other insects; (c) from 
 wounds, as syphilis, tuberculosis, diphtheria, tetanus, pus infections, 
 et cetera. 
 
 The Eye. Local infection of the conjunctiva is a common acci- 
 dent. Gonorrheal infection is the most common cause of ophthalmia 
 neonatorum. Primary anthrax, tuberculosis, diphtheria and syphilis 
 in the eye have been observed. Animals have been inoculated through 
 normal eyes with glanders, plague and rabies. 
 
 The Nose. Notwithstanding the marked germicidal character of 
 the nasal secretions, this organ furnishes lodgment for many bacteria 
 and is the seat of primary glanders and leprosy. Flexner has induced 
 poliomyelitis in apes by inoculating the nasal mucosa with the filterable 
 virus, and a minimal quantity of a plague-bacillus culture placed in 
 the nose of a rat leads to general infection. 
 
 The Mouth. The pavement epithelium of the normal mouth fur- 
 nishes a fairly good mechanical protection against the local introduc- 
 
36 AVENUES OF INFECTION 
 
 tion of bacteria into the lymph and blood, but this cavity does not 
 receive the sanitary attention it should. Tartar is permitted to accu- 
 mulate about the teeth and cause atrophy of the gums. Particles of 
 food lodge between and about the teeth and furnish suitable material 
 for the growth of bacteria. Carious teeth are neglected and ports of 
 entry are directly opened up. Normal saliva has a distinct bacteri- 
 cidal action, but this is without practical effect on the pneumococcus, 
 the bacilli of diphtheria and tuberculosis, the spirochete of syphilis and 
 the organism of actinomycosis. The crypts of the tonsils offer places 
 for the lodgment and growth of bacteria, and from these localities 
 some of them find their way into the lymph and blood. Some hold 
 that tuberculosis frequently has its primary location in the tonsils 
 from which it passes through the lymph vessels to the apices of 
 the lungs. 
 
 Many pathogenic bacteria pass through the nose and mouth with- 
 out causing local infection. It is not pleasant to state, but it is true 
 that much which is discharged from the bowels of one goes into the 
 mouth of another. This may be by short or long circuit, but the 
 result is likely to be unfortunate in either case. We drink water 
 infected with typhoid discharges and milk drawn with unclean hands, 
 and polluted with the excrement of man and beast. We enjoy fruits 
 and vegetables from orchards and gardens strewn with filth. We eat 
 bread and meat handled without gloves by baker and butcher, and 
 for all of this we pay heavy toll, as is shown by the morbidity and 
 mortality statistics. 
 
 The Lungs. There has been much discussion whether tubercu- 
 losis is most frequently acquired by inhalation or by deglutition. Ani- 
 mals have been experimentally infected by both of these avenues by 
 numerous investigators from Villemin down to the present day, but 
 the opponents of the inhalation theory say that even when bacilli are 
 drawn with the air through the nose or mouth, they are deposited in 
 the pharynx and are swallowed. The reply to this is that colored bits 
 of dust when inhaled may be carried directly to the apices of the lungs 
 where they may be recognized. Furthermore, attention is called to 
 the inhalation of coal dust by miners and the resulting condition of 
 the lungs, known as anthracosis. The dog is quite readily infected 
 
AVENUES OF INFECTION 37 
 
 with tuberculosis by inhalation, rarely or not at all by feeding. The 
 number of bacilli necessary to infect a guinea-pig by inhalation is 
 less than one one-thousandth of that necessary to infect by feeding. 
 When animals are infected by inhalation, the lesions can be detected 
 in the lungs long before they appear after feeding. 
 
 The evidence that infection does result from inhalation and that 
 the primary seat of the infection is in the apices of the lungs in the 
 great majority of cases of pulmonary tuberculosis seems to be indis- 
 putable. On the other hand, it is equally certain that infection may 
 develop by way of the intestinal tract. The frequency with which 
 primary tuberculosis due to the bovine bacillus, occurs in the abdom- 
 inal organs of children leaves no room to question. The contention of 
 Koch that infected milk might be neglected in our attempts to eradi- 
 cate tuberculosis is not supported by the results of the most thorough 
 study that has been devoted to it. There is probably no avenue of 
 infection which has not been traveled by the bacillus tuberculosis. 
 
 The Stomach. There is probably no specific infectious disease 
 which develops primarily in the stomach. Indeed, the acid secretion 
 of this organ, while by no means affording constant or full protection 
 against intestinal infection, undoubtedly does much in this direction. 
 The ubiquitous pus germ does develop a gastric ulcer now and then, 
 but a more favored site for this process is in the duodenum. In the 
 intervals between digestion all kinds of harmful bacteria may pass the 
 portals of this viscus in safety and some of them make a successful 
 passage even when digestion is at its height. It is not wise to depend 
 on the gastric juice to sterilize our food. 
 
 The Intestine. There is general agreement that the intestine of 
 the infant is more permeable to bacteria than that of the adult. Young 
 guinea-pigs are easily infected with anthrax by feeding, while adults 
 are not. Even attenuated cultures will infect a larger number of the 
 young than virulent cultures will in adults. Like results have been 
 reached by experiments with tuberculosis. Platte fed guinea-pigs a 
 few days old and adults with tubercle bacilli, 80 per cent, of the former 
 and 30 per cent, of the latter became infected. Ficker found that 
 many bacteria easily penetrate the intestinal walls of suckling animals, 
 while they have no effect on adults. These facts correspond with 
 observations on the summer diarrheas of infants. Milk that proves 
 
38 AVENUES OF INFECTION 
 
 highly injurious to infants is without harmful effect on adults. In 
 the fetus digestion is wholly parenteral and it continues to be partially 
 so during the nursing period, and the intestinal walls of infants are 
 more permeable to both formed and unformed substances than are 
 those of the adult. According to von Behring, the great majority of 
 cases of tuberculosis are due to infection from milk in infancy. The 
 bacilli are retained in the lymphatic glands and invade other organs, 
 especially the lungs, later in life. 
 
 Calmette teaches that in every period of life tuberculosis generally 
 enters the body through the intestinal walls where it leaves no lesion 
 and from which it travels to other organs. It has been shown that the 
 tubercle bacillus may pass through the intestinal walls without leaving 
 any recognizable lesion, but it is not so certain that this is the usual 
 port of entry. Even in the adult, the intestine seems to be the most 
 vulnerable point in bacterial invasion. It is the exclusive port of 
 entry for cholera, dysentery and typhoid. The most virulent cholera 
 bacillus injected under the skin in amounts which would fatally infect 
 by the intestine, would be without serious effect. The list of animal 
 infections, which are essentially intestinal, embraces anthrax, chicken 
 cholera, the hemorrhagic septicemias, hog cholera, and mouse typhoid. 
 
 It is a noteworthy fact that in experimental infection by feeding, 
 larger numbers of bacilli must be employed than can possibly be 
 required in natural infection. It has been inferred from this that in 
 natural infection the intestinal conditions must be especially favorable 
 to the multiplication of the organisms. This has led to the assumption 
 that slight intestinal disturbances predispose to typhoid and other 
 intestinal infections. This was carefully investigated by the board 
 which studied typhoid fever among our soldiers in 1898, and was 
 found to be without support. Soldiers, who were frequently on sick 
 report with diagnoses of gastric catarrh, intestinal indigestion, etc., 
 furnished actually a smaller percentage of typhoid fever than those 
 who had not been on sick report for any cause. Moreover, many of 
 the short and intermittent disturbances, under a variety of diagnoses, 
 were found by the Widal test to be typhoid fever. Some have claimed 
 that the normal intestine is not easily traversed by bacteria, but the 
 difficulty in this is to know when the intestnial walls are in a healthy 
 condition and when they may have suffered slight injuries. 
 
CHAPTER V 
 
 TUBERCULOSIS 
 
 History. That the people of ancient Egypt were afflicted with 
 tuberculosis has been demonstrated by an examination of the bones of 
 mummies. We have no means of estimating the extent of this disease 
 among these people. The writings of the great Greek physician, Hip- 
 pocrates, show that he was quite familiar with various forms of tuber- 
 culosis. The period of the Roman and Byzantine Empires added noth- 
 ing to the knowledge of the ancients on this subject. During the 
 seventeenth and eighteenth centuries there was much discussion con- 
 cerning tuberculosis, but no experimental investigation into its nature. 
 
 In the seventh decade of the nineteenth century, Villemin, who 
 should be regarded as the founder of modern knowledge of tubercu- 
 losis, conducted a series of exact experiments which settled for all 
 time disputes concerning the contagiousness of this disease. He inocu- 
 lated many and varied animals in diverse ways with the sputum and 
 other products from tuberculous lesions in men and cattle, and in 
 all developed tuberculosis. He established not only the unity of the 
 various (tuberculous manifestations in man but demonstrated the 
 existence of tuberculosis in cattle. He went further and showed that 
 certain nodular diseases, which had been confounded with tuberculosis, 
 were distinct from it. He found that the inoculation of animals with 
 other than tuberculous products did not lead to the development of 
 this disease. He overthrew the theory of heredity in this disease and 
 established the fact that it does not result from colds or other ills. 
 He went so far as to suggest house infection as an important factor 
 in the dissemination of the disease. Men who tried to contradict the 
 findings of Villemin experimentally, confirmed him in practically every 
 detail. 
 
 In 1882, Koch, after long and patient studies succeeded in isolating 
 the specific bacillus, growing it in pure culture, and demonstrating its 
 pathogenicity. 
 
40 TUBERCULOSIS 
 
 The Bacillus. The specific causal agent of tuberculosis is a rod- 
 like organism whose length varies from one-fourth to one-half the 
 diameter of a red blood corpuscle (1.23 to 4.12 of a micron). It is 
 slender and non-motile. It was formerly believed that this, like other 
 bacteria, should be classed among microscopic plants, but the most 
 exact chemical studies have failed to show the presence of cellulose in 
 their structure. This organism does not take the ordinary basic 
 aniline stains readily, but when treated with certain stains, such as 
 carbol-fuchsin, and heated, it stains deeply and retains the color even 
 after washing with dilute mineral acid. For this reason it is known 
 as an acid-fast bacillus and it has been found that this group contains 
 a number of micro-organisms whose relationship has been a matter of 
 great interest. By special staining, tubercle bacilli are easily detected 
 in sputum and other excretions from tubercular lesions. 
 
 There is still some discussion whether or not this bacillus forms 
 spores. The low temperature at which it is destroyed and the fact 
 that it is speedily killed by sunlight renders spore formation highly 
 improbable. In old cultures, branched forms are occasionally seen. 
 The tubercle bacillus contains large amounts of fat and wax and it is 
 probable that these protect this organism from the destructive action of 
 the secretions of the body cells. It has been a parasite for so long that 
 it has developed this method of protecting itself. It grows slowly both 
 on artificial media and in the animal body. It is not its purpose 
 to kill its host but to feed on him as long as possible. Unaided it 
 seldom does kill, but the necrotic tissue caused by its growth forms a 
 suitable medium for the lodgment and growth of other bacteria and 
 tuberculosis usually terminates as the result of a mixed infection. So 
 long as the infection is unmixed, the progress of the disease is slow. 
 As a rule, there is no sputum until the infection becomes a mixed one ; 
 consequently when one waits for a diagnosis of this disease until the 
 bacilli are found in the sputum, he waits too long. The physician of 
 thirty years ago believed tuberculosis an incurable disease, because at 
 that time he could not make a diagnosis until there was a troublesome 
 cough with much expectoration, marked emaciation and a long-con- 
 tinued hectic fever. All patients that reached this stage died. After 
 Koch's discovery of the bacillus, diagnosis had to await the detection 
 of this organism in the sputum. Again, it was too late. With 
 
TUBERCULOSIS 41 
 
 improved methods the disease can be recognized in most instances 
 while it is still an unmixed infection and amenable to proper treat- 
 ment. 
 
 The behavior of the bacillus outside the animal body is a matter of 
 great importance in attempting the restriction of this disease. For- 
 tunately, under ordinary conditions, the tubercle bacillus does not 
 multiply outside the animal body. It is rapidly overgrown and starved 
 out by saprophytic organisms. It has been a parasite so long that the 
 range of temperature at which it will multiply is limited. Even in pure 
 cultures, protected from other organisms and provided with an abun- 
 dance of suitable food, it grows but slowly at a temperature only a 
 few degrees below that of the body. It needs oxygen and when the 
 supply of this element is short, growth is slow. 
 
 However, the practical question is, How long will it retain vitality 
 and virulence outside the body? Multiplication as a saprophyte is 
 under ordinary conditions not at all probable, but how long will the 
 organism thrown off from the body in the sputum remain a source 
 of danger? This depends on many conditions. A mass of sputum 
 deposited on a glass plate and allowed to stand at ordinary room tem- 
 perature and in diffuse light may contain virulent bacilli for six 
 months. When the sputum is spread on a plate in a very thin layer 
 and submitted to the direct sunlight, only a few hours are necessary 
 to destroy its virulence; when only placed near a window, days are 
 necessary, and sputum deposited on carpets, rugs, bedding, handker- 
 chiefs, clothing, etc., may retain its virulence for months. Sputum 
 on walks and floors dries and is scattered by winds and drafts and 
 may be inhaled or deposited on food. The fly may carry the organism 
 to food. Heat immediately kills the tubercle bacillus when suspended 
 in water or milk on boiling. Lower temperatures must be maintained 
 for longer periods of time. According to Forster the following Centi- 
 grade temperatures must be continued for the periods mentioned in 
 order to be effective: 55 for four hours; 60 for one hour; 65 for 
 fifteen minutes; 70 for ten minute; 80 for five minute; 90 for two 
 minutes; 95 for one minute. 
 
 Milk should be boiled at least three minutes to insure the destruc- 
 tion of this bacillus. In thoroughly baked or roasted meat the bacilli 
 are destroyed, but in the rare portions they may retain their vitality. 
 
42 TUBERCULOSIS 
 
 Dry heat must be carried to a higher degree or continued for a longer 
 time. Low temperatures are without effect. On account of their fat 
 and wax content tubercle bacilli are highly resistant to disinfectants. 
 Mercuric chlorid 1 :500 and 5 per cent, phenol (carbolic acid) are not 
 efficient in the sterilization of sputum even when the contact continues 
 for twenty-four hours. The ordinary gaseous disinfection of rooms 
 with formaldehyd is unreliable in case of infection with this bacillus. 
 Sputum from the tuberculous should be burned. 
 
 The Bovine Bacillus. It has been shown, largely through the work 
 of Theobald Smith, that the human and bovine tubercle bacilli are not 
 identical. They show certain well-marked and characteristic differ- 
 ences in shape, size, rapidity and manner of growth, in response to 
 stains and in pathogenicity. Some years ago Koch announced that in 
 the crusade against tuberculosis in man we can afford to neglect milk 
 as a causative agent. This assertion led to much investigation into 
 the resemblances and differences between these varieties of the 
 tubercle bacillus. With the cultural and tinctorial differences we need 
 not concern ourselves at present. 
 
 Cattle are highly resistant to infection with the human variety. 
 Cattle have been fed for months with large quantities of the human 
 bacillus without developing an infection. Some of the material 
 accumulates in the mesenteric glands and undergoes calcification but 
 the animal does not develop tuberculosis. In ordinary infecting doses, 
 intravenous injection is without effect. With larger amounts the ani- 
 mal may be poisoned as might result from similar treatment with any 
 one of a number of foreign proteins. The human bacilli when thus 
 injected into a cow may live for months and may be detected in the 
 milk. Intraperitoneal injections are without effect and the same is 
 true of those given subcutaneously, except that large quantities may 
 cause a local inflammation and this may extend to neighboring glands. 
 Inhalation is without effect. It is safe to say that cattle are free from 
 the possibility of being infected with tuberculosis from man. 
 
 The guinea-pig is highly susceptible to both varieties, but the 
 bovine kills it quicker. The human variety is uncertain in its action 
 on rabbits. If it develops at all, it does so slowly and as a rule 
 requires some weeks and possibly months to cause death. On the 
 
TUBERCULOSIS 43 
 
 other hand, this animal succumbs in most instances in about three 
 weeks to the bovine variety. Intravenous, intraperitoneal, intraocular 
 and subcutaneous inoculations result in generalized fatal tuberculosis. 
 
 Cattle, which as we have seen are highly resistant to the human 
 variety, succumb readily to the bovine, whatever the method of inocu- 
 lation. Calves fed on pure cultures or on the milk of tuberculous 
 cows speedily develop the disease, which usually begins in the forma- 
 tion of ulcers in the upper intestine and extends to the mesenteric, 
 lymphatic and retropharyngeal glands. Infection may result from a 
 single feeding. Calves from tuberculous cows are free from infection, 
 but one nursing from the mother may infect. The inhalation of a 
 very minute portion (0.01 mg.) of a pure culture is followed by the 
 development of pulmonary tuberculosis. 
 
 Sheep, hogs and goats are highly susceptible to the bovine variety, 
 much less so to the human. 
 
 It seems safe to say that tuberculosis among our domestic animals 
 results generally from infection with the bovine rather than the human 
 variety. However, some facts need to be stated. Tuberculosis is 
 common among chickens and it is quite natural to suppose that these 
 animals become infected by picking up human or bovine material, but 
 experiments show that chickens are immune to both these varieties. 
 Feeding, intravenous and subcutaneous inoculations of these varieties 
 do not develop tuberculosis in chickens. The bacilli retain their vital- 
 ity in these fowls for a long time but fail to develop tuberculosis in 
 the hosts, as has been demonstrated by inoculation of susceptible 
 animals, such as the guinea-pig. Apes seem to be equally susceptible 
 to the human and bovine varieties. 
 
 Having ascertained that our domestic animals do not run great 
 risk in being infected with the human variety, let us see what danger 
 there is to man from infection with the bovine variety. Is it wise to 
 follow the advice of Koch and neglect milk as a factor in the causation 
 of tuberculosis in man ? This important question has been investigated 
 in this country by Park and Krumwiede, by an English commission, 
 by two German commissions, and by many individuals in various parts 
 of the world. In 1,441 deaths from tuberculosis in man, the variety 
 of the bacillus has been determined. In 117 of these (8.1 per cent.) 
 the bovine variety alone has been found. In seven cases (0.5 per 
 
44 TUBERCULOSIS 
 
 cent.) the infection has been found to be a mixed one, both varieties 
 being present. This, however, does not tell the whole story. 
 
 In pulmonary tuberculosis in adults the bovine variety is rare (4 
 cases out of 732) . In tuberculosis of the bones and joints, at all ages, the 
 bovine variety occurs more frequently (5 cases out of 98). In menin- 
 geal tuberculosis at all ages the frequency is still greater (3 cases out 
 of 32). In general tuberculosis at all ages there is a further increase 
 (33 cases out of 172). In tuberculosis of the glands of the neck, the 
 proportion is still higher (45 cases out of 157). In tuberculosis of 
 the abdominal organs the presence of the bovine variety reaches its 
 highest point (30 cases out of 99). 
 
 When we study the proportion of the two varieties in adults and 
 in children, we get more practical information. In children 23.8 per 
 cent, of generalized tuberculosis, 40 per cent, of tuberculosis of the 
 cervical glands and 49 per cent, of tuberculosis of the abdominal 
 organs are due to infection with the bovine variety. It is quite natural 
 that the greater number of cases of bovine tuberculosis should be 
 found among children. These figures demonstrate that the character 
 of the milk cannot be neglected with safety in the crusade against 
 tuberculosis. At the same time, they show that the chief source of 
 infection in man is the human variety and that as a rule tuberculosis is 
 transferred from man to man. 
 
 The Avian Type. The barnyard fowl is frequently tuberculous. 
 Much of the poultry that comes to market, when properly inspected, 
 shows enlarged livers filled with yellowish tuberculous nodules. This 
 variety of the tubercle bacillus can be distinguished morphologically 
 and culturally from other forms. Chickens are easily infected by 
 feeding, developing intestinal and hepatic tuberculosis and loss of 
 weight. Intravenous injection, even of a minute quantity, leads to 
 rapid emaciation and death may result before macroscopical changes 
 are in evidence. In less rapid cases the liver shows the characteristic 
 enlargement and nodules. Intraperitoneal and intramuscular inocula- 
 tions are slower, but in time develop the disease. Ducks and pigeons 
 may be infected, but in nature the disease is much less frequent in 
 these than in chickens. 
 
 The testimony concerning the susceptibility of the guinea-pig to 
 this variety of the tubercle bacillus is conflicting. Evidently it is less 
 
TUBERCULOSIS 45 
 
 than that shown by this animal to either the human or bovine variety. 
 Rabbits seem to be more susceptible, though typical tubercular nodules 
 are not always developed in these animals, many dying from septi- 
 cemia. Calves fed on the avian bacillus may develop local tubercu- 
 losis in the intestine and mesenteric glands, but this seems to have little 
 effect on the growth and health of the animal. Subcutaneous injec- 
 tions in cattle cause an inflammatory reaction which may extend to 
 neighboring glands, but fail to develop general tuberculosis. In the 
 studies of the varieties of tubercle bacilli found in man, already 
 referred to, three cases of infection with avian bacilli were found. 
 However, it is not certain that these people were not also infected 
 with one of the other varieties. In at least three other cases the avian 
 bacillus has been found. 
 
 That the flesh of tuberculous fowls frequently comes to the table 
 is beyond dispute. The methods of cooking probably kill all the bacilli. 
 Besides, the appearance of the liver is so striking that this organ is 
 removed before dressed fowl comes under the eye of the consumer. 
 No observant cook could overlook so abnormal an organ as the liver 
 in a well-developed case of tuberculosis gallinaceus. 
 
 The Piscidian Variety. Fish, amphibians and reptiles are suscep- 
 tible to a form of tuberculosis due to a variety of the bacillus which 
 is not capable of growth at the temperature of the body in mammalians 
 and, therefore, cannot be a source of infection in man. One would not 
 knowingly eat a tuberculous fish, but if he unknowingly does so, 
 tuberculosis will not result. 
 
 Other Acid-Fast Bacilli. There are several well-known and thor- 
 oughly studied saprophytic bacteria which have a close resemblance 
 to tubercle bacilli in their reactions towards certain stains. They are 
 not easily stained by ordinary dyes, but when thoroughly stained with 
 carbol-fuchsin or similar agents the color is not removed by washing 
 with dilute mineral acid. These organisms are classed with tubercle 
 bacilli as "acid-fast" organisms. These have been especially studied 
 by Moeller who has defined several species or varieties. One point of 
 interest is that they may be mistaken for tubercle bacilli. This is likely 
 to occur because one of them is found on timothy hay and is known as 
 "Moeller's timothy" bacillus and another is found in cow dung. So 
 far as they have been tested they are not pathogenic to any animal. 
 
46 TUBERCULOSIS 
 
 Whether or not all of these acid-fast organisms have been evolved 
 from a common ancestor is a fruitful field for theoretic discussion. 
 No one has, as yet, converted one of these into a pathogenic organism, 
 though this has been tried by frequent passage through animals. They 
 may produce local reactions which closely resemble those developed by 
 inoculation with one of the pathogenic types, but they do not cause 
 general tuberculosis. That their cellular structure is similar, chem- 
 ically at least, to that of the virulent types is shown by the following: 
 (1) their similar behavior toward stains, (2) their local effects, (3) 
 animals sensitized to one of these saprophytic forms are partially sensi- 
 tized to the virulent types. 
 
 Many attempts have been made to convert one virulent type into 
 another. The human and avian types have been carried through many 
 cows and the human and bovine varieties have been carried through 
 chickens. The results of this work have been by no means uniform. 
 Some investigators have convinced themselves that transformation 
 from one type to another is easily and quickly secured, while another 
 man, equally competent, repeats the work and is sure that such a 
 transformation never results. The conditions under which such work 
 must be done render mistakes easily possible and to obtain satisfactory 
 and convincing proof seems quite impossible. 
 
 For instance, one man attempts to carry the human type succes- 
 sively through many calves in order to transform it into the bovine 
 variety. At last he inoculates a calf and later finds in that animal a 
 typical bovine organism. The experimenter claims that he has dem- 
 onstrated a transformation, but his critic says the tuberculosis found 
 in the last calf is not a result of the inoculation, but is a true bovine 
 tuberculosis from a wholly different source. 
 
 One of the most convincing experiments in favor of a transforma- 
 tion in type is that of Nocard. He placed a culture of the human 
 type in a collodion sack and introduced the sack into the abdominal 
 cavity of a chicken; after some weeks he transferred the sack to the 
 abdominal cavity of a second chicken and after another interval to a 
 third. After this he found that the type had been changed to avian. 
 
 This has been repeated by two other investigators, one of whom 
 confirms and the other denies Nocard's claim. The solution of the 
 question concerning the relation of the saprophytic acid-fast bacilli to 
 
TUBERCULOSIS 47 
 
 the pathogenic, and of the different types of the latter to one another 
 must await future investigations. 
 
 Avenues of Infection. The most important of these lies in the 
 respiratory organs. The nose serves as a filter and its secretion is 
 germicidal. Besides, there is free exit for accumulations, and the ease 
 with which sneezing is induced by slight irritation and air can be 
 forced through it by blowing the nose, tends to keep this cavity clean. 
 The nose is seldom, probably never except in wounds or abrasions of 
 the mucous membrane, the seat of a primary tuberculous infection. It 
 may be secondarily involved in tuberculosis of the lungs. Mouth 
 breathing increases the chances of infection. The retronasal pharynx 
 is less easily kept clean and is more frequently the site of infection, 
 but this also is generally secondary. The tonsils frequently, even in 
 non-tuberculous persons, are found to contain tubercle bacilli. 
 Whether these glands do more than retain the bacilli is not known. 
 The larynx is more frequently the seat of primary infection, and is 
 involved sooner or later in about one-fourth the cases of pulmonary 
 tuberculosis. 
 
 Infection of the trachea and large bronchi is rare. The primary 
 seat of most cases of pulmonary tuberculosis is in one of the apices 
 of the lungs. This is due to the fact that bacilli having reached these 
 localities are not easily dislodged. This is true of inhaled particles 
 of any kind and when these are hard and rough they cause slight 
 wounds which form suitable places for the entrance and growth of the 
 bacilli. This accounts for the greater susceptibility to tuberculosis of 
 those engaged in dusty occupations, especially marble cutters and 
 steel filers. 
 
 The next most favorable avenue for tuberculous inoculation is 
 through the digestive organs. Carious teeth provide a port of entry 
 and the infection introduced in this manner finds its way into the 
 adjacent glands. Sore and raw gums due to deposits of tartar and 
 the fermentation of lodged particles of food, offer additional points 
 of entry not only for the tubercle bacillus but for other pathogenic 
 organisms. These facts emphasize the importance of oral hygiene, 
 which is greatly neglected in both children and adults. Tubercle 
 bacilli have been detected in carious teeth, in tartar and in the coating 
 
48 TUBERCULOSIS 
 
 on the tongue. Demme reports four childdren who were infected by 
 a nurse who was accustomed to put the spoonful of food to her lips 
 and tongue in order to test its temperature in feeding the children and 
 I have seen a mother chew the food given her children. The esoph- 
 agus and stomach are seldom or never the sites of tuberculous 
 lesions. The food quickly passes the esophagus and the acidity of 
 the stomach contents protects that organ. In most cases of infection 
 by way of the alimentary tract the bacilli find lodgment in the small 
 intestine, through the walls of which they may pass without leaving a 
 recognizable lesion. 
 
 There are three forms of tuberculous skin affection, tuberculosis 
 verrucosa, lupus and tuberculous ulcer. These may be due to scratch- 
 ing with infected finger nails, cuts with infected knives or wounds 
 with other infected instruments. Tuberculosis of the skin is especially 
 frequent among butchers. A general infection may result through 
 the skin. Several cases of infection through the rite of circumcision 
 have been reported and medical students have been infected in dissect- 
 ing tuberculous bodies and surgeons in doing operations and making 
 postmortems. In all these instances the infection extends to the near- 
 est lymph glands and then on to the next. The point of entry may or 
 may not show a lesion. Infection of the joints and bones is always 
 secondary. 
 
 Sources of Infection. The most abundant source of infection is 
 dried tuberculous sputum. So long as the sputum is moist it is not 
 distributed through the air. When deposited on sidewalks, the sputum 
 adheres to the feet or may cling to the clothing and in either case 
 is carried into the house where it becomes more dangerous. The 
 greatest danger is in closed rooms in which sputum has been deposited 
 on the floor. Cornet made the following experiment which illustrates 
 how infection may be spread. A carpet which had been contaminated 
 with infected sputum some days before was spread on a floor. Cages 
 containing 48 guinea-pigs were placed at different levels in the room 
 and the carpet was vigorously swept with a broom until the room was 
 filled with a cloud of dust. Of the guinea-pigs exposed to this dust, 
 all but one became tuberculous. The same investigator sponged the 
 walls of a room occupied by a tuberculous patient who expectorated 
 
PSEUDOTUBERCULOSIS 49 
 
 on the floor, and the material absorbed by the sponge was injected 
 into guinea-pigs with positive results. 
 
 Fliigge has called attention to the fact that in coughing, sneezing 
 and even in speaking the consumptive may eject an infected spray. 
 Not only is there immediate danger from the inhalation of the spray 
 but subsequent danger from the dried droplets which may fall on the 
 floor or furniture. The house-fly walks in sputum, eats it, and subse- 
 quently may feed on food, or drink or even drown himself in milk. 
 As we have seen, the milk of tuberculous cows is a source of danger, 
 especially to children. Cream and butter from such milk may contain 
 tubercle bacilli. There is less danger in meat on account of the cook- 
 ing, but meat when made into sausage is eaten raw by some people. 
 
 Tuberculosis is in no proper sense an inherited disease. When 
 the mother suffers from general tuberculosis, the placenta may be 
 involved and the child may be infected in utero. This is congenital, 
 not inherited, tuberculosis, and only a few cases of this are known. 
 
 PSEUDOTUBERCULOSIS 
 
 We are indebted for our knowledge of this disease largely to 
 French investigators who recognized it as early as 1883. It is desig- 
 nated a tuberculosis because in its lesions, the histologic changes 
 closely resemble, though they are not identical with, those seen in 
 true tuberculosis. It is caused by wholly different bacilli, of which 
 there are several varieties, and none of these is acid-fast. They are 
 easily stained, the stains are easily washed out with dilute mineral 
 acids and the bacilli are destroyed by relatively weak disinfectants. 
 Besides, the bacilli do not contain the large amounts of fats and waxes 
 found in true tubercle bacilli. 
 
 The most important manifestation of this disease is in sheep and it 
 is said that 15 per cent, of these animals in Australia and 10 per cent, 
 in Argentina, as they come to the market, are infected. The bacillus 
 which infects sheep is a long (1-3 microns), non-motile, non-liquefying 
 organism which grows easily and abundantly on gelatin, coagulated 
 serum and agar, and in bouillon. Unlike the tubercle bacillus, it 
 produces a soluble toxin. An antitoxin has been prepared which pro- 
 tects against the toxin but not against the bacillus, and consequently, 
 while of great scientific interest, is of no practical importance in pro- 
 
SO PSEUDOTUBERCULOSIS 
 
 tection against infection. Sheep are supposed to acquire the infection 
 largely through feeding. 
 
 As the disease is slowly progressive and most sheep are slaugh- 
 tered, the condition is usually not recognized during life. 
 
 This variety of the bacillus is pathogenic, not only to sheep but, 
 experimentally at least, to goats, rabbits, guinea-pigs and mice, but not 
 to chickens and pigeons. A second variety of this organism is patho- 
 genic to mice, especially to gray mice. It is not known to be patho- 
 genic to any other animal. Bouillon cultures of this variety become 
 slightly cloudy and deposit abundant coffin-lid crystals (ammonio- 
 magnesium phosphate). 
 
 A third variety seems to be pathogenic to many rodents and may 
 cause epidemics in rabbits and guinea-pigs. This produces crystals 
 in both gelatin and bouillon cultures and does not elaborate a soluble 
 toxin. A fourth variety infects children and several cases have been 
 reported by French physicians. The cat is suspected as a carrier. 
 
CHAPTER VI 
 
 LEPROSY 
 
 History. This disease prevailed among the Egyptians as early as 
 2,400 years before Christ. The records show that it existed in India 
 and China at least 1,000 years B. C. Whether the word leprosy as 
 used in the Old Testament was confined to this disease or included 
 other loathsome conditions, has been a matter of dispute among 
 scholars and remains without definite settlement. Some say that the 
 Israelites became infected with this disease in Egypt and the claim 
 is made that on account of the prevalence of this disease among them 
 they were driven out of that country. The Persian wars apparently 
 led to its introduction into Greece, and with the Roman subjugation 
 of Greece it was diffused over Italy, in parts of which it had existed 
 long before this time. During the first and second centuries of our 
 era it became quite common in Italy and gradually spread over the 
 greater part of Europe. It had become so common and had awakened 
 so much apprehension in France in the sixth and seventh centuries 
 that the segregation of lepers was begun. 
 
 With the general scientific awakening of the fifteenth and sixteenth 
 centuries, more attention was given to the restriction of this disease. 
 It is said that the number of leprosaria in France reached 1,500 and 
 that in the whole of Europe it was as great as 19,000. Lepers were 
 generally known as Christ's poor, and the leprosaria were under the 
 special care of the order of St. Lazarus, and were directed by priests, 
 who were themselves lepers. The attempt was made, and it must 
 have been on the whole successful, to segregate all lepers in these 
 institutions. When a leper went abroad he wore a peculiar garb and 
 at night he carried a bell. Recognized by these signs he was shunned. 
 During the seventeenth century the number of lepers in Europe rap- 
 idly decreased until the disease practically disappeared, "except on the 
 fringe of the continent." However, traces of it have continued, espe- 
 cially in Norway and parts of Russia. It has continued in Asia and 
 Africa. Whether the North American Indians or the Aztecs of 
 
52 LEPROSY 
 
 Mexico were infected with this disease in pre-Columbian days is still 
 a matter of dispute, with the evidence clearly in favor of the negative 
 side. Leprosy was probably introduced into what is now the terri- 
 tory of the United States by slaves from Africa in the last quarter 
 of the eighteenth century, and first appeared in Florida. Since that 
 time and even up to the present there are occasional fresh importa- 
 tions from Norway, China, Russia and the islands of the Pacific. 
 
 Present Distribution. This ancient disease is still distributed over 
 all tropical and temperate regions. There is no nation wholly free. 
 There are colonies or nurseries here and there and every century some 
 seed from at least one of these finds growth in some other locality. 
 Some of these nurseries have been in continuous existence since the 
 dark ages. Such is the colony at Bergen where, according to Hansen, 
 there was leprosy as early as the eleventh century and probably earlier. 
 The seeds have never been entirely destroyed and the number of lepers 
 fluctuates with the effectiveness of restriction. From 1836 to 1856 the 
 number of lepers in Bergen multiplied more than three times. This 
 led to stricter regulations and by 1907 the number had fallen to about 
 two-thirds of what it was in 1836. From this nursery at Bergen, seed 
 has been scattered to the furthermost parts of the earth and daughter 
 colonies have been established in Russia and in the United States. 
 
 The guess as to the number of lepers now living runs from one 
 to two million. These are mere guesses and it is not probable that 
 the exact number of lepers in any country is known. Certainly we 
 do not know how many there are in the United States. According to 
 Brinkenhoff there were, in 1909, 146 officially reported cases, but this 
 includes only 50 in Louisiana where, according to Dwyer, there are 
 at least 300. Pollitzer makes the number in this country 530 and 
 Ashmead thinks it reaches 3,000. The former is undoubtedly too low 
 and the latter probably too high. We should have a national lepros- 
 arium. To longer neglect to provide one is not only short-sighted but 
 well-nigh criminal. It is true that state laws provide that lepers shall 
 be isolated, but this is only on paper and without the possibility of 
 enforcement. Neither state nor nation has any provision for the 
 isolation of these unfortunates, and the way in which some of them 
 have been tossed from pillar to post is not a credit to our civilization. 
 
LEPROSY 53 
 
 Even in Louisiana where there is a state colony, isolation is not effec- 
 tively carried out. 
 
 The Bacillus. The bacillus discovered by Hansen of Bergen is 
 believed to be the specific cause of leprosy, although all the condi- 
 tions necessary to establish this fully have not been complied with. 
 This organism is a long (1.5-6 microns), slender (0.2-0.5 micron) 
 rod, which is acid-fast and belongs to the same group as the tubercle 
 bacillus! It takes fuchsin and similar stains more readily than the 
 tubercle bacillus and loses the stain more easily when washed with 
 dilute mineral acid. However, these differences are so slight and vary 
 so much with different strains of both organisms, that they do not 
 give a means of positive differentiation. The leprosy bacillus is oftener 
 found in bundles and these are larger than those of the tubercle 
 bacillus. This is not always distinctive, however. Much effort has 
 been made to find some certain method by which the microscopic dis- 
 tinction between the two organisms may be determined. An expert 
 in this work may distinguish these in many instances, but ordinarily 
 it is not easy. The bacillus of leprosy may be mistaken not only for 
 the tubercle bacillus, but it may be confounded with nonpathogenic 
 acid-fast organisms, such as the smegma bacillus. The leprosy organ- 
 ism seems more truly parasitic than the tubercle bacillus and so far 
 it has not been grown satisfactorily on artificial media, unless the 
 method of Clegg be an exception. This American investigator uses 
 a bouillon to which amebas'from dysenteric stools have been added. 
 This preparation is inoculated with leprosy tissue and some observers 
 have succeeded in obtaining a growth which at the last report had 
 been carried to the tenth generation. Attempts to inoculate the lower 
 animals with leprosy material have not been convincing. A number 
 of men have submitted themselves to this experiment and still the 
 result is left in doubt. In several cases this test has been negative. 
 In others it has been positive, but in all of the latter the tested indi- 
 viduals have been associated more or less intimately with lepers. The 
 Hawaiian convict, who had his choice between suffering the death 
 penalty and inoculation, developed local lesions but these soon dis- 
 appeared. For nearly two years he remained apparently well and 
 then developed the disease, of which he died after four years. This 
 
54 LEPROSY 
 
 test cannot be considered final, because the disease had affected some 
 of his family. 
 
 The fact that the Hansen bacillus is found in all lepers, when a 
 thorough examination is made, must for the present be accepted as a 
 justification of the belief that it is the causal agent. However, many 
 problems in the etiology of this disease remain unsolved. This bacillus 
 may be aided by some other causal agent or it may be infective only 
 in certain conditions or states of health or in certain deviations from 
 health. It seems safe to say that the evidence available at present 
 indicates that leprosy is a transmissible disease, but that it requires 
 more intimate contact for its transmission than most of the other bac- 
 terial affections. Its history, even when studied most superficially, 
 indicates its contagiousness. Such a colony as that at Bergen has 
 brought it down continuously for at least eight hundred years. When 
 a leper finds his way into a region where the disease has never been 
 known, it slowly spreads. In this way, cases have developed in Min- 
 nesota, Michigan, Iowa and elsewhere in this country. From Norway 
 the disease has been transplanted to the Baltic provinces of Russia, 
 where the number at present is estimated at more than one thousand. 
 In Finland there is a leprosarium which was established in 1355 and 
 in 1908 it housed 87. 
 
 Avenues of Infection. Supposing that the disease first manifests 
 itself at the site of inoculation, there is reason for believing that the 
 bacillus finds its entrance through wounds of the surface. It is a 
 common observation in leprous countries that those who go barefooted 
 are more frequently attacked than those who wear shoes, and that the 
 first recognizable lesions are on the feet. Two French physicians 
 report that among 2,437 cases under their observation in Cochin- 
 China, 526 were general from the start, 550 showed the first lesions on 
 the feet, 420 on the hands, 321 simultaneously on feet and hands, and 
 337 on the face. It is an old belief that infection frequently develops 
 in the nose. Heiser found nasal ulceration in 799 out of 1,200 cases 
 and others have reported even larger percentages. In recognizing this 
 disease, one of the first things to do is to stain the nasal secretion 
 of the suspected person for the bacilli. Among the healthy associated 
 with lepers the bacilli are frequently found in the nose. There is 
 
LEPROSY 55 
 
 no reason for thinking that it develops from deep breathing in of the 
 bacillus, because the lungs are never primarily involved. 
 
 The possibility of the transmission of the disease through the 
 agency of insects has been considered, but its wide geographical dis- 
 tribution does not render this view probable. The relation of fish diet 
 to leprosy, so earnestly advocated by the late Jonathan Hutchinson, has 
 not found wide support. 
 
CHAPTER VII 
 
 ASIATIC CHOLERA 
 
 History. We have no positive knowledge of Asiatic cholera before 
 1816. It is assumed by some that it had long existed in endemic 
 form in the region about the delta of the Ganges and it is reported to 
 have appeared in the Goa district (Portuguese Settlement) as early 
 as 1543 and in the Pondicherry (French Settlement) in 1768, but 
 there is no positive knowledge of these facts. In 1816 this infection 
 began its first recorded travels and reached countries so remote that 
 it could be regarded as pandemic. The time assigned by Haeser to 
 the first great excursion of this infection extended through seven 
 years (1816-1823). It traveled slowly at that time, before the gen- 
 eral use of steam transportation, and did not get beyond the confines 
 of Asia and Africa. To the east and south it visited Borneo, Java, 
 the Philippines and China. To the west and north it spread through 
 Arabia, Persia, Syria, Egypt and Northern Africa. It lingered in 
 various localities for some years, after which it was known only in 
 its home until 1826 when the second visitation began. This continued 
 for eleven years, terminating, according to Hirsch, in 1837. This 
 time it spread over the greater part of Europe and America. It broke 
 up into parties which traveled different routes, some by sea and some 
 by land. The faithful from further India brought it to Mecca where 
 it found ready but slow transportation to all points of the compass. 
 Nothing more was known of the infection outside its own domicile 
 until 1846. The third pandemic reached the farthermost parts of the 
 earth and lasted until 1862. It killed in France alone, in 1853-54 nearly 
 one hundred and fifty thousand and it pursued the gold seeker on his 
 way across the plains to California. The fourth pandemic was well 
 in evidence by 1864 and continued until 1875. As the records show, 
 it found 114,683 victims in Prussia alone on this trip. The fifth pan- 
 demic began in 1883, spread over the eastern hemisphere and reached 
 New York harbor, but was refused admission. This time the number 
 of victims in European Russia alone is given at 800,000. The notable 
 
58 CHOLERA 
 
 outburst at Hamburg belongs to this period. In 1902 cholera for the 
 sixth time became pandemic. It was disseminated by 400,000 pilgrims 
 gathered together at Mecca. Since that time and up to the present it 
 has been found in various parts of Europe and has repeatedly reached 
 our own shores, but has not been permitted to gain a foothold. 
 
 In all these excursions, among all kinds and conditions of men, 
 in every degree of civilization, in the tropics and amid the snow and 
 ice of northern Russia, in the thronged city and in the emigrant's 
 wagon, with high and low, slave and master, wherever it has traveled, 
 cholera has maintained its individuality and has shown no modification 
 in manner of attack or variation in the symptoms induced in its victims. 
 Its vehicle of transport has been man's body and it has followed the 
 lines of human travel, on foot, on horse or camel, by stage or ox 
 team, by steam, on land and sea. The sick and dying have scattered 
 its progeny around the world. The science of preventive medicine is 
 the only detective who can trace this criminal, the only officer who 
 can arrest it and the only executioner who may finally remove it for 
 all time from the earth. 
 
 The Bacillus. In 1883 the German government sent a commission 
 with the distinguished bacteriologist, Robert Koch, at its head, first 
 to Egypt and then to India to ascertain the cause of this disease. Many 
 months were spent in the study of the discharges of the sick, the post- 
 mortem examination of the dead and the investigation of the food 
 and drinking-water of the infected. The result was the discovery of 
 the infective agent, and this has placed in man's hands the possibility 
 of completely eradicating this disease. The bacillus is a slightly curved 
 rod, averaging about 1.5 micron in length and one-third this in breadth, 
 but with many variations. Frequently, many individuals are attached, 
 end to end, forming something like the letter S. It is known as the 
 comma bacillus or the cholera vibrio. It is distinguished from similar 
 vibrios by having a single flagellum or whip at one end. Its rapid 
 motility in suspension is due to this whip. Sometimes the form is 
 ovoid, often much longer and shows a long whip. It is easily recog- 
 nized in the stools by an expert and the diagnosis in suspected cases is 
 easy and certain. It takes the ordinary basic stains easily and deeply, 
 but in order to stain the whip a mordant dye is desirable. It grows 
 
CHOLERA 59 
 
 rapidly on gelatine plates at 22 C. (71.6 F.), forming, within twenty- 
 four hours, colonies visible as small bright points. 
 
 Under a low power the colonies appear like fine bits of glass 
 strewn over the gelatine. They are easily distinguished from colonies 
 of Bacterium coli, found in normal stools, by their greater refraction. 
 After forty-eight hours the gelatine under and about the colony begins 
 to liquefy, forming a small funnel or crater in the bottom of which 
 lies the colony. Old subcultures develop colonies on gelatine plates 
 which are less characteristic than those freshly obtained from cholera 
 stools. In gelatine stick cultures the bacillus grows along the line and 
 looks like a white thread. Liquefaction begins at the top and extends 
 downward forming a funnel-shaped depression. Colonies grown on 
 agar plates are also quite characteristic. On other media it grows 
 quickly, especially so in alkaline 1 per cent, peptone solution. The 
 cholera bacillus does not grow in the absence of air and consequently 
 is known as an obligate aerobe. 
 
 The cholera bacillus grows most abundantly at or a few degrees 
 above body temperature and does not wholly cease to multiply until 
 the temperature is at or below 8 C. (46.4 F.). Freezing does not 
 destroy it and it retains its virulence after having been frozen in 
 ice for several days. It is quickly destroyed by drying. A drop of a 
 bouillon culture placed on glass and allowed to dry in the diffuse 
 light of a room shows no growth when placed in proper medium after 
 two hours. When exposed to direct sunlight life is destroyed in even 
 less time. This indicates that the bacillus does not form spores and 
 that the disease is not air borne. 
 
 Boiling destroys the bacillus instantly; at 80 C. (176 F.) five min- 
 utes is long enough to destroy its vitality and a temperature as low 
 as 55 C. (131 F.) has the same effect after half an hour. It is also 
 highly susceptible to chemical agents. One per cent, carbolic acid, 
 1 : 3,000,000 corrosive sublimate and feebly acid solutions kill it within 
 a few minutes. According to Harding one part of chlorin to one mil- 
 lion parts of water destroys the bacillus within fifteen minutes. In 
 distilled water it soon dies but in ordinary drinking-water or tank- 
 water, such as is used in India, it may retain its vitality and virulence 
 for weeks and even months. According to Hankin the organism soon 
 
60 CHOLERA 
 
 dies in the water of the Ganges, which is feebly acid. How quickly 
 it dies in stools depends on many conditions such as dampness and light. 
 
 No lower animal, however intimate the contact with infected men 
 may be, is known to develop cholera. This disease seems to be, at 
 least under natural conditions, confined exclusively to the human 
 species. Furthermore, no one has succeeded in inducing a true cholera 
 in an animal by inoculation. However, some of the attempts to accom- 
 plish this purpose have been partially successful and are of sufficient 
 interest to justify brief review. Filter paper impregnated with cholera 
 cultures fed to mice induces diarrhea, but filter paper alone has the 
 same effect. Large quantities of cholera cultures fed to pigs cause 
 death, but cultures of many other bacteria produce like results. 
 
 Nikali and Rietsch opened the abdominal cavities of guinea-pigs, 
 tied the bile duct in order to exclude the bactericidal action of this 
 fluid, and injected cholera cultures into the duodenum. In the intes- 
 tines of the recovered animals the cholera bacilli multiplied and the 
 epithelial lining of the intestines was found altered. Other bacteria 
 behave in a similar manner. Koch neutralized the stomach contents 
 with soda and then introduced cholera culture into this organ through 
 a tube. At the same time the animals were stupefied with opium from 
 which they soon recovered, but the next day became ill and died on 
 the second or third day in collapse. After death the intestine was 
 found to contain a colorless fluid consisting of a pure culture of the 
 comma bacillus. Like results may be secured with other vibrios. 
 Indeed, Metschnikoff did better in his experiments on rabbits with 
 the Vibrio Maszanah which is known to be quite different from Koch's 
 comma bacillus. He polluted the teats of a mother rabbit with this 
 culture and found that at least half of the nursing young died of a 
 choleraic diarrhea. Moreover, when the sick young rabbits were placed 
 in a cage with healthy fellows from another litter, many of the latter 
 became infected. Thomas injected cholera cultures into the ear veins 
 of rabbits. After a few days the animals died, and inflammatory 
 changes were found in the walls of the intestines and cholera bacilli 
 in the intestinal content. 
 
 Many bacteria when injected intravenously find their way into 
 the intestine and may induce the same changes in the intestinal walls. 
 Cholera cultures injected into the abdominal cavities of guinea-pigs 
 
CHOLERA 61 
 
 cause a fatal peritonitis. Many saprophytic organisms will act in the 
 same way and quite as promptly. It is safe to say that all attempts 
 to induce genuine and distinctive Asiatic cholera in the lower animals, 
 made up to the present time, have failed, and that we know no animal 
 susceptible to this disease under either natural or experimental con- 
 ditions. To man alone belongs the function of serving as host, pre- 
 server and distributor of the comma bacillus. Without man to supply 
 warmth, shelter, food and transportation, the cholera bacillus would 
 soon disappear from the face of the earth. 
 
 Every man who goes into battle is not killed; likewise not every 
 man who swallows the cholera bacillus becomes infected and of the 
 infected all do not die. The cholera bacillus is highly susceptible to 
 acids, and the acidity of the stomach is a protective agency. But the 
 acidity of the stomach is widely variable among people and scarcely 
 less so in the individual from time to time. Infected drink, taken when 
 the stomach is empty and non-acid, is likely to carry its infection on 
 into the alkaline intestinal content. Bacilli protected by masses of 
 food, difficult of digestion, may also pass through. In the midst of 
 cholera epidemics, many harbor the bacillus and distribute it in their 
 stools without being at all affected by it Others are only slightly ill 
 and there is every degree of gravity up to those in which the disease 
 is fatal within a few hours. 
 
 In typical cases of cholera the bacillus does not find its way through 
 the intestinal walls. It multiplies so abundantly in the intestinal con- 
 tent that it starves out all other bacteria and after death there is a 
 pure culture in the intestine. It not only grows abundantly, but its 
 cells speedily die and in doing so the poison contained in their struc- 
 ture is liberated, exerts its local effects on the intestinal walls, is 
 absorbed and produces the symptoms of the disease, and death. In 
 fact, cholera as an infection is limited to the alimentary canal; as an 
 intoxication it kills. 
 
 In acute cholera the bacillus is found only in the intestine and gall- 
 bladder after death. All other organs and tissues are sterile. The 
 intestine is converted into a great culture flask from which the chemi- 
 cal poison, elaborated by the bacterial growth, diffuses into the blood, 
 while the water from the blood diffuses into the flask. This results 
 in the condensation of the circulating blood, the drying out of the 
 
62 CHOLERA 
 
 tissues, the suppression of urine, perspiration, saliva and even of the 
 tears. The cholera poison, irritating the intestinal wall, increases 
 peristalsis until it becomes most painful and leads to the ejection of 
 large volumes of rice-water stools. The constant nausea and vomiting 
 render even drinking quite impossible. Through mouth and anus the 
 culture flask is discharged while it is constantly replenished by the 
 withdrawal of water from the blood and tissue. In the acute form, 
 a few hours suffice to dry out the tissues so thoroughly that death 
 results. 
 
 Several cases of laboratory infection with the cholera bacillus have 
 been reported. The first of these occurred in Koch's laboratory in 
 1884. A careless worker infected himself. Dr. Oergel of Hamburg 
 died from accidental infection with the cholera bacillus. Some half- 
 dozen additional laboratory infections have been reported. Besides 
 these accidental infections, several have intentionally swallowed cul- 
 tures. The most notable instance of this kind were the Munich pro- 
 fessors, Pettenkoffer and Emerich. They alkalized their stomachs and 
 then drank the dilute cultures. The former suffered only a severe 
 diarrhea, but the other passed into the algid stage with suppression 
 of urine and barely escaped with his life. A similar instance occurred 
 in Paris under the observation of Metschnikoff. It has been observed 
 in these cases that the period of incubation is short, from twenty-four 
 to forty-eight hours. 
 
 The cholera poison, on which much work, ending in diverse and 
 even contradictory conclusions, has been done, is probably the protein 
 poison found in all proteins. Ordinarily this poison is without effect 
 when given by mouth on account of the slowness with which it passes 
 the intestinal wall, but with the lumen of the intestine filled with an 
 abundant cholera culture, the walls are so injured that the poison is 
 rapidly absorbed. The cholera poison is not more active than that 
 obtainable from other bacteria, both pathogenic and non-pathogenic, 
 also from other proteins both vegetable and animal. 
 
 Sources of Infection. Every case of cholera means that some one 
 has swallowed bacilli which have come from the stools of some one 
 else. The route may have been quite short and direct or may have 
 been long and circuitous. The bacilli bred in the intestine of one indi- 
 
CHOLERA 63 
 
 vidual may find their way into the mouth of another, or many gen- 
 erations of bacilli may lie between the two subjects. In all instances, 
 the connection is sure and certain. This disease spreads in no other 
 way. The only infected discharges from the cholera patient are those 
 that come from the alimentary canal. The vomited matter may con- 
 tain virulent bacilli but this is rarely the case on account of the great 
 susceptibility of the organism to acid solutions. Practically the only 
 infectious discharge is the stool. Among filthy people the stool may 
 go quite directly to the mouth by the hands. Mothers often infect 
 their children in this way and sometimes it is transferred from child 
 to parent. 
 
 This contact infection is illustrated in the voyage of the Carlo R. 
 which sailed from Naples, Aug. 1, 1893, for Brazil, with 1,472 steer- 
 age passengers. The ship's water was not infected. On the outward 
 trip cholera appeared. On reaching South America the vessel was 
 not permitted to dock and was compelled to return. The double 
 voyage occupied two months and during this time there were 141 
 deaths among the steerage passengers. Scarcely less direct is the 
 transference from soiled clothing or bedding or when the infected 
 stools are deposited on fruits and plants which are subsequently eaten. 
 The less cleanly people are, the more liable to harbor this disease. 
 
 Before the discovery of the bacillus, Pettenkoffer had observed 
 that, in its European visitations, this infection spared certain localities. 
 These were relatively clean places, such as would not afford oppor- 
 tunity for contact infection. The great outbreaks, such as that at 
 Hamburg in 1892, are due to infection of the general water-supply. 
 At that time Hamburg used the unfiltered water from the Elbe. At 
 first there were a few cases among those employed about the wharves. 
 Finally the pollution extended up the river and reached the city 
 water-supply. The first case was recognized early in August and the 
 explosion came on the 20th of the same month and by the 31st the 
 number of new cases per day reached one thousand. Hamburg and 
 Altoona are one city, but separated administratively. On one side of 
 the street the houses are in Hamburg and on the other in Altoona. 
 The latter had a separate and uninfected water-supply and was free 
 from the disease except among those who drank from the Hamburg 
 water. 
 
64 CHOLERA 
 
 Certain cities in Italy, notably Naples and Genoa, have in recent 
 years been mildly infected and the disease has been kept alive by 
 contact infection, but their water-supplies being free from pollution, 
 severe outbreaks have not developed. Suspected persons and their 
 families and neighbors should be tested by an examination of their 
 stools and kept under observation so long as these contain the bacilli. 
 A convalescent may carry the organism in his intestine and expel it 
 in his feces for sixty days after recovery. Many who do not develop 
 the disease carry the bacilli and distribute them in their stools. 
 
CHAPTER VIII 
 
 TYPHOID FEVER 
 
 History. In his writings on epidemics, Hippocrates (fifth century 
 B. C.) describes certain continued fevers with moderate disturbances 
 of the bowels, much wasting and delirium, lasting sometimes forty 
 days, and recovering rarely by crisis, more frequently irregularly. 
 These can hardly be other than cases of typhoid fever. Galen 
 observed similar cases and described them under the names "hemitri- 
 taeus" (used by Hippocrates) and "febris semitertiana." These 
 names were used for centuries. In the seventeenth century Spigelius 
 writing under the title "De Febre Semitertiana" reports necropsies in 
 which spots and sloughs were observed in the intestine. Similar 
 lesions were found and reported by other Italian physicians. Near 
 the middle of the same century an English physician, Willis, made 
 necropsies and observed like changes in the intestine. About the 
 same time, the father of English medicine, Sydenham, described a 
 fever lasting from fourteen to thirty days with a tendency to diarrhea, 
 delirium and epistaxis. 
 
 In the eighteenth century many contributions to the knowledge 
 of this disease were made. Morgagni described the intestinal ulcers, 
 perforations, and enlarged mesenteric glands and spleen. Tissot of 
 Lausanne gave a good description of the disease as did Huxham of 
 England. The latter's picture is sketched in the following words : 
 
 The patient at first grows listless and feels slight chills and sudors with 
 uncertain flushes of heat and a kind of weariness all over. This is always 
 attended by a heaviness and dejection of spirit. A nausea and disrelish of 
 everything soon follow. Though a kind of lucid interval of several hours inter- 
 venes, yet the symptoms return with aggravation, especially towards night ; the 
 head grows more heavy, the heat is greater, the pulse quicker; a great torpor 
 or obtuse pain affects the head and is commonly succeeded by some degree of 
 delirium. In this condition the patient often continues five or six days, seem- 
 ing not very sick; about the seventh or eighth day the giddiness, pain or heavi- 
 ness of the head becomes much greater, often delirium appears with universal 
 tremors and muttering, the tongue grows often very dry, often very thin stools 
 
66 TYPHOID FEVER 
 
 are discharged; now, nature sinks apace; the pulse may be said to tremble and 
 flutter rather than to beat; the sick man becomes quite insensible; and the 
 delirium ends in a profound coma; and that soon in an eternal sleep. 
 
 Up to the nineteenth century all the continued fevers with delirium 
 were known under the general name "typhus," which means smoky 
 or cloudy, and refers to the mental state. Early in the seventeenth 
 century some of the more observant physicians began to suspect that 
 two quite distinct diseases were included under the diagnosis of 
 typhus and on this point there grew up a discussion which continued 
 for two hundred years. In order to gain knowledge to settle this 
 question, necropsies were frequently resorted to and most minute and 
 exact studies of the lesions were made. In a medical way the dispute 
 became partially at least an international one. French physicians, led 
 especially by Bretonneau of Tours, held that in their necropsies they 
 found, quite usually, lesions, inflammatory and ulcerative, in the ileum, 
 while British physicians for the most part failed to find such changes. 
 
 The great clinicians of Paris in the early part of the nineteenth 
 century were Trousseau and Louis and these were earnest in present- 
 ing their views. At that time many of the brighter young medical men 
 of this country went to Paris to continue their studies. There they 
 heard the lectures and saw the necropsies. Stopping in Great Britain 
 in their visits to and from Paris, they heard lectures and saw necrop- 
 sies. In France ulcers were found in the intestines; in England they 
 were not. In this country some necropsies revealed intestinal lesions 
 while others did not. It soon became evident that there were two 
 distinct diseases, differing not only in the lesions found after death but 
 in onset, progress, and in other respects. The old name, typhus, was 
 retained for the form without intestinal lesions and the new term 
 "typhoid" given to that with such lesions. Louis selected the new 
 name, and in giving it he said: "I have long searched for a word 
 to express the anatomical character of this disease which would not 
 be disagreeable to the ear, and having failed to find such an one, I have 
 adopted the expression 'affection typhoide/ as being at least free from 
 inconveniences." Bretonneau had used the designation "dothin- 
 enterie" meaning pustule in the intestine. The word "typhoid" is 
 unfortunate and not so good as the English designation "Enteric 
 
TYPHOID FEVER 67 
 
 fever." The Germans know it as "Abdominal typhus." Gerhard of 
 Philadelphia is generally given the credit of finally settling the dispute 
 concerning the duality of the old typhus. Valliex wrote in 1839: 
 "Gerhard established for the first time the very important fact that 
 there can exist, and that there do exist, at the same time in the same 
 country two diseases that may be clearly distinguished and in which 
 one can predict during life the lesions which will be found after death. 
 These diseases are typhoid fever and the true typhus." 
 
 Early in our civil war, medical officers reported fevers which in 
 their opinion differed from typhoid fever as seen in the north. The 
 first board, appointed (1861) to investigate this matter, reported that 
 "the fever prevalent among the soldiers was bilious remittent fever, 
 which, not having been controlled in its primary stage, has assumed 
 that adynamic type which is present in enteric fever." A second board 
 was convened (1862) for the purpose of revising the sick report. 
 Major Woodward, the chief of this board, insisted that "the prevailing 
 fevers of the army of the Potomac were hybrid forms, resulting from 
 the combined influences of malarial poisoning and of the causes of 
 typhoid fever," and he insisted that they should be reported as "typho- 
 malarial fever." This designation became official July 1, 1862, and 
 from that time to June 30, 1866, 57,400 cases, with 5,360 deaths, 
 were reported under this name. 
 
 While Woodward's designation of the disease was adopted, his 
 understanding of its nature was quite generally ignored. He believed 
 it to be a hybrid resulting from coincident malarial and typhoid 
 infections while the greater part of the profession understood it to 
 be a severe form of malarial infection. In Woodward's opinion typho- 
 malaria was quite as severe and fatal as typhoid, because it was 
 typhoid in one already infected with malaria or vice versa. He also 
 believed that a trace of scurvy, often unrecognizable until typhoid 
 infection developed rendered the latter more grave. The majority of 
 physicians and the laity regarded typho-malaria as a severe malaria, but 
 much less grave than typhoid ; the new term took a part of the sting out 
 of the diagnosis of typhoid and many a practitioner in the kindness of 
 his heart, in his desire to spare patients and friends, found the com- 
 pound word a welcome subterfuge. With the mobilization of troops in 
 the war with Spain (1898) the same fever spread rapidly through 
 
68 TYPHOID FEVER 
 
 the camps, small and large, north and south of the Mason and Dixon 
 line, and was recorded on sick reports under a multitude of names, 
 chiefly malaria, but often typho-malaria and many other designations 
 hitherto and subsequently unused. The board of medical officers 
 appointed to investigate, employing scientific methods of diagnosis, 
 soon showed that malaria was very infrequent and that more than 
 99 per cent, of the cases were typhoid. Among nearly 20,000 cases, 
 12 of coincident malarial and typhoid infection were found and even 
 in these the malarial manifestations were suppressed during the course 
 of the typhoid. A man already malarial is not immune to typhoid or 
 vice versa, but even in coincident infection there is no peculiar or 
 characteristic symptom complex. It follows that "typho-malaria" in 
 any sense is a misnomer and should not be used. 
 
 Malaria is not the only infection which may be coincident with 
 typhoid. Cases, though few in number, have been reported in which 
 typhoid has been coincident with the following : Malta fever, recurrent 
 fever, anthrax, Asiatic cholera, diphtheria, miliary tuberculosis, scarlet 
 fever, and both amebic and bacterial dysentery. These facts simply 
 show that the above mentioned infections establish no immunity to 
 typhoid nor does this disease protect the individual against other bac- 
 terial invasions. Of more importance are the secondary infections 
 which may develop in typhoid. The intestinal lesions open ports of 
 entry especially for pus-producing bacteria, which may develop 
 abscesses in various parts of the body, and these are slow to heal and 
 difficult to reach. 
 
 The Bacillus. In 1880 Eberth discovered short, motile bacilli in 
 the spleen and mesenteric glands of those dead from typhoid fever. 
 Four years later Gaffky isolated this organism and secured pure cul- 
 tures. An almost endless amount of research has been devoted to the 
 Bacillus typhosus with the hope of finding easy means of sure recog- 
 nition under all conditions. There is an extensive group of bacilli 
 with the typical typhoid at one extreme and the typical colon bacillus 
 at the other and with many intermediate varieties. It is easy enough 
 to distinguish the extremes, but it still remains quite impossible to 
 locate exactly every member of this group. The colon bacillus is a 
 normal dweller in the intestinal tract and causes trouble only when it 
 
'TYPHOID FEVER 69 
 
 finds its way into some place where it has no business. Normal feces 
 contain colon bacilli in great numbers. 
 
 When the typhoid bacillus finds its way into man's intestinal tract 
 it is likely to develop typhoid fever. The stool of the typhoid victim 
 is laden with the Bacillus typhosus. Between the extremes of the 
 typho-colon group, there are two varieties of the B. typhosus, Para- 
 typhus A and B, B. enteritidis, mouse typhoid, dysentery bacilli and B. 
 fecalis alcaligenes. A typical typhoid bacillus is highly motile; it 
 does not coagulate milk ; it does not redden litmus milk ; it forms blue 
 colonies on plates of gelatine colored with litmus; when grown in 
 whey colored with litmus it produces only a slight cloudiness and at 
 most only slightly reddens the medium; when grown in fermentation 
 tubes in a solution containing grape sugar it develops no gas; when 
 grown in agar colored with neutral red it does not change the color 
 or develop any gas; when grown in peptone solutions or bouillon it 
 does not develop indol. A typical colon bacillus is non-motile ; it does 
 coagulate milk ; it reddens litmus milk ; it forms red colonies on plates 
 of gelatine colored with litmus; when grown in whey colored with 
 litmus, it produces a marked cloudiness and deeply reddens the 
 medium; when grown in fermentation tubes in solutions of grape 
 sugar, it develops gas abundantly; when grown in agar colored with 
 neutral red it does develop gas and changes the color; when grown 
 in peptone solution or bouillon it develops indol. It will be seen from 
 these facts that it is easy to distinguish between a typical typhoid and 
 a typical colon bacillus, but there are varieties of each which may 
 contradict any one of these statements, while the intermediate organ- 
 isms differ from one another and in their own varieties. It follows 
 that only an expert in this line is fitted to locate exactly the members 
 of this large group of organisms. However, with proper training one 
 becomes quite expert and the identification of typhoid bacilli in the 
 stools and urine of suspected cases becomes less difficult than one 
 would suppose from the above statements. 
 
 The recognition of this organism in drinking water remains so diffi- 
 cult in spite of all the work that has been done that it is seldom 
 attempted and the fitness of a water for drinking purposes is deter- 
 mined by the number of colon bacilli in a given volume of the water. 
 This is easily done by counting the number of red colonies which 
 
70 TYPHOID FEVER 
 
 develop on litmus gelatine plates or on gelatine containing some 
 other color affected by the colon bacillus in a similar manner. The 
 number of red colonies developing on such plates is taken as an indi- 
 cation of the extent to which the water carries fecal contamination. 
 If fecal matter from healthy people finds its way into the water that 
 from those infected with the typhoid bacillus may, and the only safe 
 procedure is to condemn all waters bearing fecal matter. This does 
 not mean that the colon bacillus in any of its varieties will cause 
 typhoid fever. 
 
 Nothing like typhoid exists so far as we know in any of the lower 
 animals. Moreover, with the possible exceptions to follow, all 
 attempts to induce a chronic fever with the typhoid lesions in animals 
 by inoculation with the specific bacillus have failed. Injected in large 
 enough doses it kills, but without infection. The dead bacillus does 
 the same thing. This shows that the cellular substance contains a poi- 
 son, but this is true of all bacteria, both pathogenic and non-pathogenic. 
 Grunbaum claims to have developed typhoid fever in a chimpanzee 
 and Weinberg reports positive results with apes infected with certain 
 intestinal parasites, which inflict on the mucous membrane wounds 
 through which the bacillus find entrance. While our domestic animals 
 do not become infected with this bacillus, they may bear it from place 
 to place on their bodies or distribute it in their excretions. Several 
 cases of accidental laboratory infection and a few acquired inten- 
 tionally have occurred. These demonstrate the pathogenicity of the 
 bacillus for man. 
 
 Sources of Infection. It is true of typhoid fever, as it is of 
 Asiatic cholera, that every case of infection is due to the transference 
 of the fecal matter of the infected either by a short or a long circuit, 
 to the alimentary canal of another, There is, however, this important 
 difference ; cholera is widely disseminated only at certain times and in 
 certain places, while typhoid is well-nigh ubiquitous. Up to the pres- 
 ent time there is no part of the world absolutely free from this disease 
 for any great length of time. In one sense typhoid is a filth disease 
 inasmuch as it is scattered through the excretions of the human body, 
 especially in the urine and feces. No wonder that it was thought that 
 typhoid may originate de novo. Now, we know that this is not true, 
 
TYPHOID FEVER 71 
 
 but until the discovery of the causal agent this truth was difficult of 
 demonstration. 
 
 It follows from what has been said that the prevalence of typhoid 
 in any community is largely determined by the personal cleanliness 
 of the inhabitants and largely by the method of disposing of human 
 excreta. In the past typhoid has been the most destructive disease in 
 armies, miners' camps, exploring parties and wherever the disposal 
 of fecal matter has been primitive and imperfect. The dissemination 
 of this disease among our soldiers in 1898 was thoroughly investigated, 
 and some of the conclusions may be not only of interest but of value to 
 civilians. 
 
 During the Spanish war of 1898 every regiment constituting the 
 first, second, third, fourth, fifth and seventh army corps developed 
 typhoid. This includes all the soldiers assembled in that war except 
 those who went to the Philippines and consequently were not investi- 
 gated by the board. More than 90 per cent, of the volunteer regiments 
 developed typhoid within eight weeks after going into camp. The 
 disease developed in certain of the regular regiments within from 
 three to five weeks after going into camp. These facts negative an old 
 claim that sudden change from civilian to military life favors the 
 development of this disease. The disease became epidemic in small and 
 large camps, in those in the north as well as in those in the south. 
 It had been held that simply bringing large numbers of men together 
 was enough in and of itself to cause a typhoid epidemic. Some had 
 argued that change of climate alone caused the disease. 
 
 At that time typhoid was so widely and abundantly distributed in 
 this country, the chances were that whenever and wherever one thou- 
 sand or more men should be brought together, an average of four in 
 this number would reach the camp already infected. Those who came 
 with the infection would scatter the seeds before the disease in them 
 would be recognized. The number of cases in the different camps 
 varied directly with the methods of disposing of the excretions. The 
 disease was disseminated by contact, by flies and by water. Contact 
 infection was the most important factor. The grounds were covered 
 in some places with feces. The men tracked this infected matter into 
 their tents, soiled the floors, blankets, clothing, and tents. Men were 
 detailed to act as orderlies at the hospitals where they handled bed 
 
72 TYPHOID FEVER 
 
 pans and otherwise polluted their clothing and person, and then 
 returned to their mess tents and handled food for themselves and 
 passed it to their neighbors without even washing their hands. It 
 was estimated that in some regiments at least 60 per cent, of the cases 
 were contracted through lack of personal cleanliness and the conse- 
 quent pollution of clothing, bedding, tentage, food, etc. Flies served 
 as carriers of the infection. They swarmed over infected matter in 
 the latrines and then visited and fed on the food prepared for the 
 soldiers at the mess tents. In some instances when lime had recently 
 been spread over the fecal matter in the latrines, flies with their feet 
 whitened with lime were seen on the food. Flies carry the bacilli on 
 their bodies mechanically and pollute what they subsequently touch and 
 they eat infected matter, swallowing the bacilli, which they subse- 
 quently deposit with their own excretions. In some camps the water- 
 supply was contaminated by the natural drainage from the infected 
 earth. 
 
 At Jacksonville, Fla., it was probable that infection through inhala- 
 tion was a minor factor in the spread of the disease. Change of loca- 
 tion did not rid the soldiers of the infection, because they carried it 
 with them, in their intestines, on their hands, in their clothing, blankets 
 and tentage. They even transported the infection with them to Cuba 
 and Porto Rico. These are fair samples of the dissemination of 
 typhoid not only in military but in civil life, for the difference is only 
 one of degree. Every village is a small camp and every city a larger 
 one. Typhoid in the past was more prevalent in military than in civil 
 life because in our more permanent homes we dispose of our excreta 
 more effectively. Had we not learned to do so, urban life would have 
 remained impossible as it once was. 
 
 It must not be inferred from the above brief account of typhoid 
 in 1898 that our soldiers were less cleanly or more ignorant than those 
 of other nations. When the Franco-German war began, every corps of 
 the German army was infected with typhoid and the second division of 
 the eleventh corps was at that time suffering from a marked epidemic 
 of this disease. The infection was not confined to the Prussians, but 
 extended to every contingent of the German army. The seeds of the 
 disease carried with them rapidly bore fruit, especially among the 
 troops besieging Metz and later at Paris. Within less than two months 
 
TYPHOID FEVER 73 
 
 after war was proclaimed typhoid had extended so extensively among 
 certain divisions of the German troops, notably in the eleventh corps 
 of the Prussian soldiers and in the Wurtemberg division, that more 
 than 15 per cent, of these commands were sick of this disease. The 
 total number of cases among the under officers and men in the Ger- 
 man army during the Franco-German war amounted to 73,396, which 
 was equivalent to 9.31 per cent, of the average strength. The invasion 
 of France began about the middle of July, 1870. During the second 
 half of this month the total number of cases in the German army was 
 345, less than the average for preceding years of peace. In August 
 the number perceptibly increased, amounting to 2.6 per thousand, but 
 not enough to cause apprehension, and up to September it could not 
 be said that there was an unusual prevalence of the disease. Early 
 in this month there was an explosive outbreak and the cases ran up 
 to 12,463, which was equivalent to 15.3 per thousand. In October 
 there were 17,253 new cases. In this month the epidemic reached its 
 climax and fell slowly. 
 
 Typhoid may be transported by an army into regions practically 
 uninhabited. This is illustrated by the Afghan war of 1878-80. Some 
 of the sites occupied by English soldiers were never before peopled. 
 It is not at all likely that the waters of the mountain streams were 
 specifically contaminated with the typhoid bacillus; nor was it likely 
 that the virgin soil covered by these encampments was infected, except 
 as it became so by occupation, and yet typhoid developed at nearly 
 every station occupied by the English troops. Only one explanation is 
 possible. It is known that the English troops drawn from various 
 parts of India were widely infected with typhoid when the invasion of 
 Afghanistan was begun. A similar experience is furnished by the his- 
 tory of French expeditions in Northern Africa. In the Oran cam- 
 paign, in 1885, French commands encamped in desert stations never 
 before occupied, and in these typhoid not only appeared, but devel- 
 oped epidemic proportions. In the English expedition to Suakin in 
 1885 every precaution was taken to supply the troops with pure water. 
 In fact the drinking water was distilled. Notwithstanding, typhoid 
 developed extensively. The east Surrey regiment joined the expedi- 
 tion already infected and it is more than likely that these men infected 
 the latrines and the disease was spread by contact and by flies. In 
 
74 TYPHOID FEVER 
 
 the expedition for the relief of Chitral in 1895 typhoid infection was 
 carried by the soldiers, and when they encamped at Kahr an epi- 
 demic developed. In the invasion of Egypt infected regiments were 
 drawn from Mediterranean stations. On the disembarkment at 
 Ismalia occasional cases began to appear and continued to do so until 
 a serious epidemic manifested itself in the permanent camp at Cairo. 
 In the South African war the English failed to profit by the lesson 
 for which all nations had paid so dearly. The restriction of typhoid 
 in armies was first successfully practiced in the Russo-Japanese war 
 by both parties and this was the first great war in which the victims 
 of typhoid did not greatly add to the death lists. Now, with our 
 knowledge of sanitation, aided by the protection afforded by vaccina- 
 tion, typhoid in both military and civil life should recede rapidly and 
 soon be known only in the records of the past. 
 
 The typhoid bacillus is eliminated from the infected person chiefly 
 in the stools and urine. Vomited matter, the saliva and the discharges 
 from posttyphoidal abscesses may contain the virus, but compared with 
 the stools and the urine these are of minor importance. The stools 
 of every person infected with this disease contain the bacilli, but in 
 widely varying amounts, from a few, difficult of recognition on account 
 of the great numbers and rapid growth of other bacteria, up to a pure 
 culture. As a rule, typhoid bacilli are most numerous in the stools 
 during the third week of the disease, at a time when the intestinal 
 ulcers are sloughing. The stools of all suffering from this disease 
 should be thoroughly disinfected. However, the bacilli may be present 
 in the stools both before the disease is recognized clinically, and long 
 after clinical recovery. In many instances the stools continue to be 
 infected for from six to eight weeks after the subsidence of the fever. 
 In a few instances the individual becomes a constant and chronic car- 
 rier of the infection and may remain so for years. Moreover, every- 
 one who harbors this organism does not develop the disease. Any one 
 of these classes, the convalescent, the carrier and the apparently well 
 man, may infect wide areas and diverse places. The only hope of 
 complete protection lies in provision for the disposal of the excreta 
 of all men in such manner that they cannot find their way, directly or 
 indirectly, by short or long circuit, into the alimentary canal of others. 
 
TYPHOID FEVER 75 
 
 The urine in about 30 per cent, of cases of typhoid is infected with the 
 bacillus and carriers may distribute the infection through this excretion. 
 
 Contact infection is the most common mode in the distribution of 
 typhoid. Different students of epidemiology in widely distant lands 
 agree in this and even go so far as to place practically the same esti- 
 mate on the number of cases originating in this manner. About 60 
 per cent, of all cases of typhoid are believed to be due to contact 
 infection. The board of medical officers in 1898 placed the percentage 
 of contact cases at 62.80, while Drigalski gives it for Germany as 
 64.7. These conclusions seem to have been reached quite indepen- 
 dently, inasmuch as the German makes no mention of the American 
 studies which were conducted nine years before his. Formerly, it 
 was supposed that typhoid is mostly water-borne and the board of 
 officers began their investigations possessed fully of this view, but their 
 studies convinced them that this is an error and first furnished indis- 
 putable evidence that contact is the most important factor in the dis- 
 tribution of typhoid. Contact is both direct and indirect. The board 
 divided the cases between the two as follows : Direct, 35.01 ; indirect, 
 27.79 per cent. In more than 90 per cent, of the cases due to direct 
 contact the hands bear the infection directly to the mouth. Klinger 
 found this to be true in 1,315 out of 1,397 cases. This certainly should 
 emphasize the importance of personal cleanliness. 
 
 In indirect contact infection, clothing, bedding, drinking cups, 
 dishes, foods, etc., may serve in the transport of the infection from 
 one person to another. Soiled clothing may retain virulent bacilli. 
 Soiled blankets shipped from South Africa in the Boer war carried 
 the infection to those who used them in England. In the Spanish war 
 our camps were not rid of infection until the clothing of the soldiers, 
 their beddings and the tents were disinfected. Infected fecal matter 
 deposited on oyster beds render this article of food dangerous. 
 Infected employees in dairies spread the infection through milk and 
 its products. Not infrequently cases are so distributed as to show the 
 route of the milk man. Greens and salads, fruits and berries may 
 become bearers of typhoid infection. 
 
 Water epidemics are explosive in outburst and are characterized 
 by the simultaneous infection of a large number of those who con- 
 sume the water. In flowing water the typhoid bacillus dies out in from 
 
76 TYPHOID FEVER 
 
 five to ten days. In still water it may continue to live for a much 
 longer time. In dead ends of water pipes it may linger for many 
 days; indeed, the statement is made that it has been found in dead 
 ends months after the infection of the general supply has disappeared. 
 Of course, the water is infected with the excretions of man. 
 
 Typhoid infection is widely distributed by boats and cars. At 
 present there is no attempt to disinfect the waste from the water- 
 closets on either of these vehicles of transportation. Some years ago 
 when on account of a break in the locks at Sault Ste. Marie, many 
 downward-bound boats were detained above the intake of the city's 
 water-supply, an explosive outbreak of typhoid developed. From rail- 
 road trains fecal matter is scattered along the roadbed and sometimes 
 this is specifically infected. This filth may be washed into water- 
 supplies or it may be scattered in dust to infect workers on the road 
 and even travelers on trains. The prevalence of typhoid fever is 
 not a credit to any community and is an indication that filth finds its 
 way into the mouths of the inhabitants. 
 
 It is estimated that, taking into consideration the distribution of 
 typhoid fever over a large area and for a long time, about 5 per cent. 
 of it is due to the infection of milk. The bacilli multiply rapidly in 
 milk until it sours. Whether or not pasteurized milk may contain the 
 living bacillus depends on the temperature used in the process and the 
 thoroughness with which it is carried out. A temperature of 62 C. 
 for five minutes is not enough to insure the destruction of this organ- 
 ism in milk. This is the temperature at which this process was for- 
 merly generally carried out, and at which it is now sometimes done. 
 In an improved process the temperature is carried to 85 C., which is 
 high enough to destroy this virus in milk in one minute. In butter 
 this bacillus can live for weeks. 
 
 Attention has already been called to the house fly as a distributor 
 of this disease. In some sections of this country the crusade against 
 this pest has not been pushed with sufficient energy and it is still in 
 evidence both in the privy vault and in the dining room. Ants and 
 other insects distribute fecal matter deposited on the earth and may 
 carry the infection to plants and fruits. 
 
CHAPTER IX 
 
 ANTHRAX 
 
 History. This disease is supposed to be referred to in the book 
 of Exodus (9:10), the reading of which is as follows: "And it became 
 a boil breaking forth with blains upon man and upon beast." 
 
 Homer's acquaintance with anthrax may have inspired these lines 
 (Iliad, B. L): 
 
 "And first the beasts assailed he, the mule and ranging hound, 
 But soon at man his firebolt shot, smiting to the ground." 
 
 The pestilence described in the CEdipus of Seneca is regarded by 
 some as a dramatic description of an anthrax epidemic. The first 
 victims are the domestic animals, one after another, until men and 
 all beasts are being hopelessly devoured by the insatiable anger of 
 the gods: 
 
 The sluggish ewes first felt the blight, 
 
 .For the woolly flock the rich grass cropped 
 
 To its own doom. At the victim's neck 
 
 The priest stood still, in act to strike; 
 
 But while his hand still poised the blow, 
 
 Behold the bull with gilded horns, 
 
 Fell heavily; whereat his neck, 
 
 Beneath the shock of his huge weight, 
 
 Was broken and asunder yawned. 
 
 No blood the sacred weapon stained, 
 
 But from the wound dark gore oozed forth. 
 
 The steed a certain languor feels, 
 
 And stumbles in his circling course, 
 
 While from his downward sinking side 
 
 His rider falls. . . . 
 
 The abandoned flocks lie in the fields ; 
 
 The bull amid his dying herd 
 
 Is pining; and the shepherd fails 
 
 His scanty flock, for he himself 
 
 Mid his wasting kine is perishing. 
 
 The stag no more fears the ravenous wolf; 
 
78 ANTHRAX 
 
 No longer the lion's roar is heard ; 
 The shaggy bear has lost her rage, 
 And the lurking serpent his deadly sting; 
 For parched and dying now he lies 
 With venom dried. 
 
 Another classical description is given by Ovid (Metam. vii). Pliny 
 (Hist. Nat. Lib. xxvi) says: 
 
 We find it stated in the annals, that it was in the censorship of L. Paulus 
 and Q. Marcius (164 A. D.) that carbuncle was first introduced into Italy, a 
 malady which till then had confined itself to the province of Gallia Narbonensis 
 (now Provence). In the year in which I am now writing these lines two per- 
 sons of consular rank have died of this disease ; Julius Rufus and Q. Lecanius 
 Bassus; the former in consequence of an incision unskillfully made by his 
 medical attendant, the latter through a wound upon the thumb of the left hand 
 by pricking a carbuncle with a needle, a wound so small originally as to be 
 hardly perceptible. 
 
 Arabian physicians described anthrax as Persian fever. In the 
 ninth and tenth centuries the disease was widely disseminated over 
 Europe. In the years 1375-76 it is reported that even wild animals 
 died of anthrax. According to Kircher in 1617 most of the domestic 
 animals and 60,000 people died of this disease. It continued to be 
 widely prevalent in Europe down to the time of scientific medicine 
 and isolated epidemics still occur. In the sixties of the last century 
 an outbreak in Russia was investigated by a German commission and 
 reported as anthrax. From 1864 to 1870 in the province of Novgorod 
 more than 65,000 domestic animals (horses, cattle and sheep) and 
 528 people succumbed to this infection. It has been extensively 
 disseminated in South America, especially in Brazil, where it is known 
 as "Garotilha." It is well established in Australia where it has inter- 
 fered greatly with sheep raising. It has found its way into most parts 
 of Asia and Africa. In our own country it has appeared only as local 
 epidemics among cattle and isolated cases among men, known as wool- 
 sorter's disease and malignant pustule. Sobernheim gave the total 
 number of deaths from this disease among cattle, horses, sheep and 
 goats in Germany from 1900 to 1909 inclusive as 55,410. 
 
 Since anthrax is the most typically infectious of all diseases, and 
 since so many theories have been evolved concerning it, we may be 
 pardoned for briefly reviewing the literature. As early as 1805 
 
ANTHRAX 79 
 
 Kausch wrote a monograph on this disease in which he held that it is 
 due to paralysis of the nerves of respiration; but he offered no 
 explanation of the paralysis. Delafond held that anthrax has its 
 origin in the influence of the chemical composition of the soil on the 
 food, thus inducing pathologic changes from malnutrition. The con- 
 tagious nature of the disease was clearly established in 1845 by 
 Gerlach. This was confirmed by the studies of Heuzinger and was 
 endorsed by Virchow in 1855, since which time it has never been 
 questioned. However, as early as 1849 the bacilli had been seen by 
 Pollender. Pollender did not publish his observations until 1855, but 
 he states that they were made in the fall of 1849. First, he examined 
 the blood of five cows dead from anthrax, and compared this with 
 material taken from the spleen of a healthy animal. The examina- 
 tions were not made until from eighteen to twenty-four hours after 
 death, and he states that the blood was stinking, thus indicating that 
 it had become contaminated with putrefactive organisms, but the 
 description which he gives shows that he actually saw anthrax bacilli. 
 He used a crude compound microscope made by Plossl, and he gave 
 his attention to the blood corpuscles, chyle globules, and the bacilli. 
 
 His description of the micro-organisms may be condensed as fol- 
 lows: The third and most interesting microscopic bodies seen in 
 anthrax blood are innumerable masses of rod-like, solid, opaque 
 bodies, the length of which varies from 1/400 to 1/200 of a line, and 
 the breadth averages 1/3,000 of a line. They resemble the "vibrio 
 bacillus" or "Vibrio ambiguosus" They are non-motile and neither 
 water nor dilute acids, nor strong alkalies have any effect on them, 
 and for this reason he concluded that they must be regarded as vege- 
 table organisms. He questioned whether they existed in the blood of 
 the living animal or resulted from putrefaction, but was inclined to 
 believe the former, and thought they might represent the infecting 
 organism, or at least the bearer of the infection. It will be seen that 
 Pollender presented no positive proof that these rod-like bodies had 
 any causal relation to the disease. In 1856 Brauel inoculated sheep, 
 horses and dogs with blood taken from animals sick with anthrax, and 
 in this way demonstrated that the disease could be transmitted to 
 sheep and horses, but not to dogs. He found sheep highly susceptible, 
 horses less so, and dogs quite immune. He also demonstrated the 
 
80 ANTHRAX 
 
 presence of the bacilli in the blood of sick animals before death. It is 
 interesting to note that he fell into an error concerning the motility of 
 the bacilli. He states that when seen in fresh blood they are non- 
 motile, but later they become highly motile. This was, of course, due 
 to contamination. It should be noted that Brauel also made examina- 
 tion of the blood of various domestic animals suffering from other 
 diseases, and demonstrated the absence of the bacillus in these. 
 
 In 1863 Davaine published three valuable papers on anthrax. In 
 the first he states that in 1850 Rayer inoculated sheep with the blood 
 of others dead from anthrax, and in this way transmitted the disease. 
 It appears that Rayer published a short note of this work in the 
 Bulletin de la Societe de Biologic in 1850, but I have not had access 
 to this publication. Davaine's own work was of the greatest value 
 and shows great skill for that time. Probably the most important 
 experiments that he made were those in which he demonstrated that 
 the blood of an animal sick with anthrax is not capable of transmitting 
 the disease to others unless it contains the bacillus. It may be of 
 interest to describe briefly the experiments which led to the establish- 
 ment of this fact. Rabbit A was inoculated with anthrax blood. 
 Forty-six hours later, examination showed no bacilli in the blood of 
 Rabbit A. At that time twelve or fifteen drops of blood were taken 
 from the ear of this animal and injected into Rabbit B. Nine hours 
 later the blood of Rabbit A was reexamined and found to contain a 
 large number of bacilli. This blood was injected subcutaneously into 
 Rabbit C. One hour later Rabbit A died, and twenty hours later 
 Rabbit C died, while Rabbit B remained free from infection. Space 
 will not permit us to follow the literature of anthrax further. Pasteur, 
 DeBarry, Koch and others studied the morphology, life history, and 
 cultural characteristics of the bacillus, and in this way founded the 
 science of bacteriology. 
 
 The Bacillus. This is a long (4-10 microns), slender (1-1.3 
 microns) rod with rounded ends. A drop of blood from the spleen of 
 an animal dead of this disease discloses, even without stain, great 
 numbers of these bacteria. They are non-motile and take the basic 
 aniline dyes easily. Often many bacilli are attached end to end, form- 
 ing what is known as bamboo rods. These are quite characteristic but 
 
ANTHRAX 81 
 
 are not seen in all preparations. Many bacilli show capsules which 
 are less deeply stained and the contrast is quite striking. It is sup- 
 posed that this capsule protects the bacillus against the destructive 
 action of the secretions of the body cells. At least, bacilli taken from 
 infected animals generally show the capsules, while subcultures seldom 
 do. It has been found that cultures grown in fluid blood serum do 
 show the capsule. These facts indicate that the capsule results from 
 some reaction between the organism and blood. It will continue to 
 live, but will not multiply in the absence of air and consequently must 
 be classed as an aerobe. It grows under a wide range of temperature 
 (15 to 43 C), but its optimum growth is at or near the temperature 
 of the animal body (37 to 38 C.). 
 
 It grows easily on all the ordinary culture media. In undis- 
 turbed bouillon it does not produce a uniform cloudiness, but appears 
 in floccules. On gelatine plates after from two to three days at from 
 18 to 20 C. it develops characteristic colonies. Under a low power 
 these are seen to be not compact as is the case with most bacterial 
 colonies, but loosely aggregated. The edges are not smooth and 
 sharply defined, but more or less fringed. These are known as medusa 
 forms and the fringe is due, as is shown under a higher power, to 
 the growth of the rods from the central mass into the surrounding 
 medium. It forms a proteolytic ferment which gradually digests or 
 liquefies the gelatine and the colonies subside into the craters thus 
 formed. In stick gelatine cultures the bacillus grows along the line 
 and branches off on the sides forming a picture which has been vari- 
 ously designated as a brush or as an inverted pine tree; very slowly 
 liquefaction proceeds from the surface downward. On agar plates the 
 colonies are much like those on gelatine, with the exception that on 
 the former spore formation may be observed. Stick cultures on agar 
 are much like those on gelatine, with no liquefaction and a spreading 
 of the growth over the surface of the medium. It coagulates milk 
 and then digests the coagulum. With an abundant supply of oxygen 
 digestion may proceed so quickly that coagula are not seen. 
 
 The anthrax bacillus multiplies by transverse fission, but when 
 it finds the conditions of life unfavorable, it does not have to strive 
 against untoward circumstances; it simply develops seeds or spores 
 and passes into a resting stage. In this state it does not need air or 
 
82 ANTHRAX 
 
 food. It is inactive and is only potentially alive. When conditions 
 become favorable, the spores develop into the vegetative form. The 
 capability of passing from one form to another is a great factor in 
 protecting the bacillus against destructive agencies. Each bacillus 
 produces only one spore. There is, therefore, no multiplication in the 
 exercise of this function. The purpose seems to be solely to protect 
 the life of the individual. When times are good with plenty of air 
 and an abundance of suitable food, life seems to proceed merrily and 
 the organism multiplies abundantly. When times are hard, with inade- 
 quate air or food, the bacillus drops into the resting stage in which it 
 has no needs and awaits a change for the better. When anthrax 
 spores are brought under favorable conditions each spore develops into 
 a rod which for a while carries on one end the waste remnant of the 
 spore. Vegetative life with multiplication by fission begins anew. 
 
 There are some strains of the bacillus which apparently are not 
 able to pass into the resting stage under any conditions. These are 
 known as asporogenous strains. According to Eisenberg, anthrax 
 bacilli are of two varieties or races, of different "biological dignity," 
 one sporogenous and the other asporogenous, and each breeds true 
 through all generations. Roux converts the sporogenous into the 
 asporogenous variety by the following method : 
 
 Bacilli grow with the formation of spores in bouillon to which 
 from two to six parts per ten thousand of phenol has been added. 
 When the phenol has been increased to twenty parts per ten thousand 
 there is no growth. Between these limits the bacilli grow without 
 spore formation. Bacilli kept in these intermediate solutions for from 
 eight to ten days permanently lose even in following generations the 
 ability to produce spores. 
 
 The resistance of the anthrax bacillus depends on the presence or 
 absence of spores. The latter are among the most stabile and resistant 
 forms of pathogenic bacteria. They are more easily killed than the 
 spores of certain nonpathogenic organisms, such as the potato 
 bacillus. Anthrax spores on silk threads supply standards for testing 
 the relative efficiency of disinfectants. Spores in cultures eighteen 
 years old have been found not only viable but capable of developing 
 into virulent vegetative organisms. Bouillon cultures of the vegetative 
 form are sterilized by heat at 80 C. (176 F.) for one minute, while 
 
ANTHRAX S3 
 
 boiling for at least three minutes is necessary to insure the destruction 
 of the spores. Dry heat at 100 C. (212 F.) must be continued for 
 two hours in order to destroy the vegetative form, while three hours 
 at 140 C. (284 F.) are necessary to exterminate the spores. The 
 effect of direct sunlight on the two forms has been studied with vary- 
 ing and even contradictory results. This is easily understood when 
 we think of the many variable factors, such as thickness of layer, 
 intensity of light and temperature, entering into such experiments and 
 influencing the findings. According to Moment, drops of dried bouil- 
 lon cultures, with the air temperature at from 25 to 35 C. (77 to 95 
 F.), are destroyed when exposed to direct sunlight within from six to 
 fifteen hours in the vegetative form and after one hundred hours when 
 spores are present. The ordinary disinfectants, as generally used, 
 destroy the vegetative forms but are not certain in their action on 
 spores. Geppert found that after from two to three hours in corrosive 
 sublimate (1: 1,000) all spores are not killed. 
 
 We may be thankful that this bacillus, armed as it is with so many 
 advantages and possessed of weapons effective against so many species 
 of animals, has some powerful antagonists. Were this not true the 
 world might have been depopulated by the unopposed activity of this 
 microscopic organism. As it is, it is possible that the extinction of 
 certain species of animals may have resulted from this infection. 
 Many other bacteria are markedly antagonistic and destructive to the 
 anthrax bacillus. Chief among those in which this function has been 
 observed and studied is the Bacillus pyocyaneus. In mixed cultures 
 of these organisms the pyocyaneus only survives. It not only survives 
 but it seems to feed on the anthrax bacilli. If across a gelatine plate 
 parallel lines be drawn alternatingly with needles moist with cultures 
 of the two bacilli, the pyocyaneus only will develop. If crosses be 
 made with the needles the pyocyaneus only will develop at the cross. 
 The pyocyaneus develops a bacteriolytic body known as pyocyanase, 
 which readily digests and destroys the anthrax bacillus. This seems to 
 be a proteolytic ferment, but unlike similar bodies it is not destroyed 
 by prolonged boiling. This fact has led to the suggestion that it 
 destroys the anthrax bacillus by osmotic changes. A few drops of a 
 solution of pyocyanase added to a bouillon culture of anthrax leads 
 to a speedy dissolution of the bacilli. Moreover, laboratory animals, 
 
84 ANTHRAX 
 
 sheep, rabbits, and guinea-pigs, infected with anthrax, have been cured 
 by injections of pyocyanase. Among other less thoroughly studied 
 antagonistic bacteria are the staphylococcus, the streptococcus and the 
 pneumonia bacillus. 
 
 Certain fluids of the animal body have a destructive action on the 
 anthrax bacillus. Strange to say, this does not seem to have any 
 marked effect on the susceptibility of the animal to this infection. The 
 blood serum of the rabbit in vitro is markedly bactericidal. Accord- 
 ing to Pane 1 c.c. of such serum will destroy 8,000 anthrax bacilli and 
 still the rabbit is easily susceptible to inoculation with this bacillus. 
 The destructive agent in rabbit's serum seems to be a ferment, inas- 
 much as it is destroyed by a temperature of 56 C. (132.8 F.). The 
 blood of the rat, an animal which has some marked resistance to 
 anthrax inoculation, is highly bactericidal to this organism. This is 
 believed to be due to the relatively high alkalinity of the rat's blood. 
 Fodor showed many years ago that arterial blood is destructive to the 
 anthrax bacillus. 
 
 While mammals are susceptible to anthrax they differ in this par- 
 ticular widely in degree. Epidemics are most common in cattle and 
 sheep and the latter are easily inoculable with pure cultures, while the 
 former are unexpectedly more resistant and require larger doses. 
 Algerian sheep are highly resistant. Hogs are less susceptible than 
 cattle and sheep, and here again there is marked variation in varieties, 
 American and English breeds being more susceptible than those of 
 Hungary. Among our more valuable domestic animals horses are 
 somewhat more resistant than cattle and sheep but in some epidemics 
 they die in great numbers. Dogs are least susceptible but succumb 
 to intravenous inoculations. Goats resemble sheep in susceptibility. 
 Of the smaller laboratory animals, the rat is the least susceptible, 
 while rabbits, guinea-pigs, and mice succumb to every form of inocu- 
 lation. It is said that a single bacillus will kill a guinea-pig. All 
 menagerie animals are susceptible. Birds are highly resistant and 
 epidemics among them are not known, but all may be infected arti- 
 ficially. Frogs are highly refractory but the disease may be induced 
 in them. Snails are said to be wholly refractory. Turtles and fish are 
 susceptible to artificial inoculation, the former readily so. 
 
ANTHRAX 85 
 
 Avenues of Infection. The virus may find admission to the animal 
 body subcutaneously, intravenously, by feeding or by inhalation. A 
 break in the continuity of the skin or mucous membrane may afford a 
 port of entry. Even in feeding the point of entry may be in the 
 mouth, pharynx or esophagus, caused by a slight wound. Especially 
 is this true in animals in which slight wounds may be caused by hard 
 bits of food, dust or other accidental constituents. The dried spores 
 may infect through any of these avenues quite as effectively as the 
 vegetative forms. The spores are especially suitable for infection by 
 inhalation. Moreover, in feeding, the spores are more resistant than 
 the vegetative forms to the acid of the gastric juice. While the blood 
 may be free from bacilli in the first stage of the disease and while in 
 rare non-fatal cases the infection may remain localized, in most 
 instances the blood becomes a vehicle for the transport of the virus 
 and it reaches every part of the body. The bacilli are eliminated from 
 infected animals with the urine and feces. They have been found in 
 milk drawn from sick cows a short time before death. The fetus in 
 utero may become infected. This has been observed in both lower 
 animals and man. In epidemics, fields, barnyards and stalls become 
 infected and the most common port of entry is the mouth. The feces 
 and urine of infected animals pollute all about them and the virus is 
 easily and quickly transferred to the well. Naturally, anthrax devel- 
 ops, in epidemics, among men who are brought into close contact with 
 the sick animals. In Russia from 1904 to 1909 the average annual 
 deaths from anthrax among men numbered sixteen thousand ; in Italy 
 from 1890 to 1900, about two thousand one hundred. In 1910 the 
 number of persons infected with anthrax in Germany is given as 2S7, 
 with 40 deaths. Certain occupations, such as butchers, tanners, sheep 
 shearers, furriers and glove makers, shoemakers, saddlers and harness 
 makers, dealers in hay and grain, and wool-sorters, are especially 
 exposed to this infection. The primary infection in man is most fre- 
 quently through slight wounds on the skin where malignant pustules 
 form. The lungs may be infected through inhalation. Intestinal 
 infection in man, though infrequent, has been reported. Fruit and 
 vegetables may be polluted by the urine or feces of animals and may 
 carry the virus into the alimentary canal. 
 
CHAPTER X 
 
 DYSENTERY 
 
 History. Epidemics characterized by frequent, painful and bloody 
 discharges from the bowels are mentioned in the oldest medical rec- 
 ords. They have been observed in both civil and military life and 
 have at times contributed largely to the high mortality of cities and 
 camps. However, no differentiation of the diseases marked by these 
 general symptoms was possible before the development of the science 
 of bacteriology began. As early as 1875 Losch of St. Petersburg 
 reported the presence of amebas in the stools of a patient with bloody 
 dysentery. Some years later (1886) Kartulis made like reports con- 
 cerning the dysentery of Egypt. These widely separated observers 
 were the first scientific contributors to our knowledge of what is 
 known as amebic dysentery. When work along this line was taken up 
 in dfferent parts of the world, it became evident that there are two 
 forms of this disease, amebic and bacillary. Further discussion of the 
 former will be reserved for another section. 
 
 When it was shown that amebas are not found in many severe 
 epidemics of dysentery, so many investigators in different parts of 
 the world began the search for other causal agents and so many find- 
 ings were reported, that it is now quite impossible to say with abso- 
 lute certainty to whom the greatest credit is due. There have been 
 many claims to priority and it is possible that the names now gen- 
 erally attached to the several bacilli known to produce this disease 
 are not those of the men who first saw them. However, I will not 
 add to the controversy over these matters but will use the names 
 generally employed by writers on this subject. 
 
 In 1898 Shiga showed that amebas were not found in the severe 
 epidemics of dysentery prevalent in Japan at that time, but he did 
 find in the stools during life and in the body after death a well- 
 defined and easily recognized bacillus. Since this organism was found 
 in all cases, and since its cultures were agglutinated by high dilutions 
 of blood serum of those ill with this disease, Shiga felt justified in 
 
88 DYSENTERY 
 
 claiming that he had found the specific cause, and subsequent studies 
 by others have confirmed this claim. This organism is now generally 
 known as the Shiga bacillus. 
 
 Two years later (1900) Flexner, in a report of an expedition to 
 investigate the diseases prevalent in the Philippines, described a bacil- 
 lus found in epidemics on these islands. It also was present in all cases 
 and agglutinated with dilutions of the blood serum of the sick. There 
 was for a time much discussion about the identity of these two organ- 
 isms. It would be profitless to follow these discussions since it is now 
 generally admitted that the differences are sufficient to justify the con- 
 clusion that they are different species, and this is now known as the 
 "Flexner" bacillus. There are two other bacilli capable of causing 
 dysentery. These are varieties of the Flexner organism. One is 
 known as the "His-Russell," and the other as the "Strong" bacillus. 
 
 The Shiga Bacillus. This is a small plump rod with rounded ends. 
 It was at first believed to be motile, but closer study shows that it 
 has no flagellae and no active motion, although it demonstrates the 
 Brownian movements in a marked degree. It is sporeless and ordi- 
 narily it needs frequent transplantation in order to keep it alive. How- 
 ever, according to Martini, if an agar-culture tube be hermetically 
 sealed the rods disintegrate into a granular debris which is not easily 
 stained and shows no rods. If this granular mass, even after a year, 
 be placed in fresh medium, normal rods develop. This observation 
 has been confirmed by similar findings with the plague bacillus and it 
 should be more closely and thoroughly studied. Fresh cultures have 
 a sperm-like odor, while older ones develop trimethyl and ammonia. 
 Very old growths have a strong and penetrating fecal smell. It takes 
 the ordinary stains easily, but the staining is not always uniform ; some- 
 times it is polar. It develops on ordinary media without any char- 
 acteristic exhibitions. Culturally it is distinguished from the Flexner 
 and related dysentery bacilli by the fact that it develops no acid when 
 grown on media containing mannite, maltose or saccharose. The 
 Shiga bacillus is furthermore distinguished from the other organisms 
 by the development of a soluble toxin. This will be discussed in more 
 detail later. 
 
 The Shiga bacillus is not highly resistant to unfavorable condi- 
 tions. It is easily destroyed by the usually employed disinfectants, 
 
DYSENTERY 89 
 
 both the soluble and the gaseous forms. However, it retains both 
 viability and virulence for days when deposited on clothing or food. 
 It soon dies out in running water and epidemics of bacillary dysentery 
 due to infected water are probably rare. In sterilized water it lives for 
 many weeks, but in the presence of the usual saprophytic bacteria of 
 water it soon dies out. 
 
 The Flexner Bacillus. Morphologically, culturally and tinctorially 
 this organism is but little different from the Shiga bacillus. It, how- 
 ever, produces indol in peptone cultures more abundantly; produces 
 acid in mannite cultures; rapidly reduces nitrates to nitrites; and 
 elaborates a soluble toxin, either not at all or only in small amount. 
 These differences in function rather than in form, lead to the con- 
 clusion that the two organisms are of different species. The His- 
 Russell organism is a variety or strain of the Flexner bacillus. It 
 produces indol more slowly, reduces nitrates less energetically, and 
 decomposes mannite, but is without action on maltose and saccharose. 
 The Strong organism is even more closely related to the Flexner 
 bacillus and in fact there seems to be no constant differences when 
 many strains of both are studied. The Shiga bacillus with its sub- 
 varieties is known as the dysentery bacillus rich in toxin production, 
 and the others as poor in this product. The latter are found to be the 
 more stabile. They are not so easily overgrown by saprophytic bac- 
 teria; they retain their vitality for a longer time under adverse con- 
 ditions and they are not so easily destroyed by disinfectants. They 
 may persist for many days in drinking water, for many weeks on 
 clothing, and cultures need to be transplanted only every second or 
 third month. 
 
 Rabbits, mice, dogs, goats and horses are highly susceptible to sub- 
 cutaneous, intra-abdominal and intravenous inoculations with these 
 bacteria, especially the Shiga bacillus. Very minute doses introduced 
 by these avenues cause acute fever with paralytic symptoms in the 
 extremities, diarrheic stools with mucus and blood, then a rapidly fall- 
 ing temperature ending in death: Post-mortem examination shows 
 an inflammatory condition of the kidneys, lungs and the mucous mem- 
 brane of the intestinal tract. The bacilli are found in these cases in 
 the stools, in the blood, and in the various organs. With still smaller 
 doses the disease is more chronic and the lesions are more advanced 
 
90 DYSENTERY 
 
 with necrosis of the intestinal epithelium and ulceration in the large 
 intestine. These effects are produced by both living and dead bacilli 
 of the Shiga type, also with filtered cultures. This shows that the 
 nature of the process is an intoxication rather than a pure infection. 
 Even one one-hundredth of a loop of a culture may induce these 
 symptoms and lesions in mice. Strange to say, the guinea-pig is 
 relatively resistant to this organism. From the researches of Gay we 
 learn that the horse shows marked elevation of temperature, with 
 prostration and labored breathing when treated with one-fourth the 
 minimum fatal dose for guinea-pigs. 
 
 There has been much controversy concerning the nature of the 
 soluble toxin found in cultures of the Shiga bacillus. Some claim that 
 it is a true toxin, a secretion of the bacillary cells, while others con- 
 tend that it is an autolytic product, resulting from the cleavage of 
 the bacilli. Antitoxic sera in variety have been made and have been 
 used for both prevention and cure. Living and dead cultures have 
 been used in the preparation of the toxins, and, as happens when 
 bacterial cell substance is repeatedly injected, many animals die in the 
 process of immunization. There is no standard method of preparing 
 the antitoxin as there is for diphtheria. It follows that the antitoxic 
 sera are not of uniform value and there is still some doubt as to 
 whether their effects should be ascribed to bactericidal or antitoxic 
 properties. Gay has obtained a serum by treating horses with 
 Flexner's bacillus, and has treated cases of dysentery with good results, 
 but Escherich in Vienna did not find it so valuable. Numerous observ- 
 ers have reported great reduction in the mortality in cases of Shiga 
 infection by treatment with the specific antitoxin. 
 
 All attempts to induce typical dysentery in ordinary laboratory ani- 
 mals by feeding with dysentery bacilli have failed. It is true that 
 massive doses may cause some intestinal inflammation with loose stools, 
 but many bacteria will bring about this result. In apes the disease 
 may be induced by feeding, and it is stated that dysentery is sometimes 
 epidemic among these animals. This is certainly true of confined 
 animals, one such epidemic having been observed in Paris, and another 
 in Manila. Subcutaneous injections of dead bacilli in man have been 
 used for vaccination purposes, but quite naturally the value of such 
 a procedure must remain undetermined until it is done on a large 
 
DYSENTERY 91 
 
 number of persons living in the midst of epidemic dysentery. Liidke 
 vaccinated himself in this way, but later became infected while work- 
 ing with living cultures. He, therefore, concludes that if subcutaneous 
 injections of dead cultures have any protective value, it is of short 
 duration. In a local epidemic in an insane asylum Fuksch vaccinated 
 the men and left the women without treatment, and states that the 
 disease did not spread further among the former while it continued 
 among the latter. Shiga in 1898-1900 vaccinated ten thousand 
 Japanese in localities in which dysentery was prevalent and found that 
 this procedure did not reduce the morbidity but had a most marked 
 and gratifying effect on the mortality. In some localities, while the 
 death-rate among the unvaccinated reached from 30 to 40 per cent., 
 there were no deaths among the vaccinated. The same investigator 
 vaccinated large numbers of the Japanese troops in the war with 
 Russia. At this time he suspended dead bacilli in antitoxic serum and 
 made three injections at intervals of three or four days, increasing 
 the size of the dose at each injection. 
 
 There can be no doubt concerning the causal relation of these 
 bacilli to dysentery in man. As has been stated, high dilutions of the 
 blood of those sick agglutinate cultures of these bacilli. This is posi- 
 tive evidence, but there is confirmatory proof. Strong fed pure cul- 
 tures of the Shiga bacillus to two criminals sentenced to death, and 
 both developed typical dysentery. Jehle drank mixed Shiga and Flex- 
 ner cultures and developed the disease on the third day. He found 
 both bacilli in his stools. Several accidental laboratory infections have 
 occurred. 
 
 Each of these bacilli produce typical dysentery with characteristic 
 symptoms and lesions. The Shiga bacillus is the most virulent, but 
 otherwise the results are the same. Close study shows that the varie- 
 ties of these bacilli might be multiplied, but while this is of scientific 
 interest it is not of great practical importance. These bacilli are dis- 
 tributed all over the world, having been found in all climes and among 
 all conditions of men. 
 
 Sources of Infection. Like typhoid fever, dysentery is always due 
 to the transfer of the excreta of one person to the ingesta of 
 another. In the great majority of instances the infection is 
 transferred through contact, which may be direct or indirect. The 
 
92 DYSENTERY 
 
 prevalence of dysentery is determined by the extent to which fecal 
 contamination exists. The disease is most abundant when fecal dis- 
 position is most primitive. With improvement in the latter, the dis- 
 ease grows less. Thirty years and more ago, dysentery under various 
 names, such as "mucous and bloody diarrhea" and "bloody flux," 
 reaped a rich harvest, especially among children, in various sections 
 of this country. As methods of the disposal of fecal matter grew 
 more efficient, the death-rate from this disease decreased. It decreased 
 at first in cities, with the introduction of water closets, then it grew 
 less in villages in which the same improvement was inaugurated and 
 lastly its highest prevalence was in the less progressive and more 
 ignorant communities. Its dependence on ignorance and filth for its 
 dissemination is shown in the frequency of outbreaks in insane asylums 
 and especially in wards occupied by those who pollute themselves, their 
 clothing and bedding, and even the walls of their rooms with fecal 
 matter. In primitive places there are not even privy vaults, and stools 
 are deposited at random on the ground. Everything about the indi- 
 vidual home and throughout the village becomes soiled with fecal 
 matter. These are the localities in which dysentery most abundantly 
 flourishes. With typhoid fever, it has spread through camps and 
 decimated armies. It has accompanied military and civil explorations 
 even into uninhabited regions and has flourished wherever man has 
 found even a temporary abiding place and has surrounded and befouled 
 himself with his own excretions. This does not mean that it may 
 originate de novo, for it does not, but the sick and the well may long 
 harbor the bacilli in their intestines and plant it over wide regions in 
 their stools. Hands, the person, clothing, bedding, food and water 
 may bear the infection. From the dirty hands of the milker, the cook 
 or the waiter these organisms may find their way into the food. Those 
 recovering from the disease may continue for weeks as veritable cul- 
 ture flasks for the growth and distribution of this virus. Others may 
 carry the bacilli without developing the disease themselves. Flies and 
 possibly other insects aid in its distribution. While the bacilli are 
 not spontaneously generated in filth, they are widely disseminated and 
 they flourish in polluted places. 
 
CHAPTER XI 
 
 TYPHUS FEVER 
 HISTORY 
 
 There are medical historians who find evidence of the existence of 
 typhus fever among the ancient Hebrews and their contemporaries, 
 but this is a matter of conjecture. While this disease has long been 
 known as morbus pauperum, associated with want and famine, we 
 must not infer that it is the only fever which develops and thrives 
 among the needy and in times of scarcity of food and other privations. 
 Poverty and overcrowding favor the development and distribution of 
 many infections. Some of the cases reported by Hippocrates in his 
 book on epidemics are certainly suggestive of typhus. 
 
 The following is the report of a case, now believed to have been 
 typhus, made by Hippocrates, as translated by Adams : 
 
 In Thasus the wife of Dealces, who was lodged on the plain, from sorrow 
 was seized with an acute fever, attended with chills. From first to last she 
 wrapped herself up in her bedclothes; still silent, she fumbled, picked, bored 
 and gathered hairs (from the covers); tears and again laughter; no sleep; 
 bowels irritable, but passed nothing; when directed, drank a little; urine thin 
 and scanty ; to the touch of the hand the fever was slight ; coldness of extremi- 
 ties'. On the ninth (day) talked much incoherently, and again became com- 
 posed and silent. On the fourteenth, breathing rare, large, at intervals; and 
 again hurried respiration. On the sixteenth, looseness of the bowels from a 
 stimulating clyster ; afterwards she passed her drink, nor could retain .anything, 
 for she was completely insensible; skin parched and tense. On the twentieth 
 much talk and again became composed; loss of speech; respiration hurried. 
 On the twenty-first she died. Her respiration throughout was rare and large ; 
 she was totally insensible; always wrapped up in her bedclothes; either much 
 talk or complete silence throughout. Phrenitis. 
 
 The great Athenian pestilence so well described by Thucydides was 
 either typhus or the pneumonic form of the plague. Livy and Tacitus 
 tell of many epidemics in the classical period of Rome. Some of these 
 undoubtedly were epidemics of the plague, while the descriptions of 
 others suggest typhus. The dark ages were so overshadowed by dis- 
 
94 TYPHUS FEVER 
 
 ease and superstition that medical records of value are almost wholly 
 wanting. In the siege of Granada in 1489 no less than 17,000 of 
 Ferdinand's soldiers died of a fever which was designated as "Tabar- 
 dillo," on account of the spots appearing on the skin. This term is 
 still one of the Spanish names for typhus. In the sixteenth century 
 two Italian physicians, Fracastorius of Verona and Cardanus of Pavia, 
 described typhus fever so plainly that there can be no doubt about 
 the disease which then prevailed. In four years (1550-1554) more 
 than one million people in Tuscany were destroyed by typhus. Fra- 
 castorius describes the disease as "Febris pestilens," and states that it 
 was vulgarly known as "Lenticulae" or "Puncticula." He says from 
 the fourth to the seventh day red eruptions appear on the arms, chest, 
 and back. They resemble flea bites, only are somewhat larger. They 
 also resemble lentils and from this comes the popular name. The most 
 marked symptoms mentioned are great prostration, feeble pulse, 
 injected conjunctivae, and low muttering delirium. Some are som- 
 nolent while others are excited and wakeful, while in still others these 
 states alternate. The disease lasted from seven to fourteen days, 
 rarely longer. The majority of those who were bled died and a sup- 
 porting treatment proved best. Cardanus and other Italian physicians 
 stated that many of the practitioners of the time mistook this disease 
 for measles, and Massa of Venice wrote on the distinctions between 
 the eruptions of this disease and those of measles and smallpox. About 
 the middle of the sixteenth century this disease was widely prevalent 
 in France and Coyttarus of Poitiers wrote a monograph on it, under 
 the title "De Febribus Purparatis" and somewhat later Ambrose Pare, 
 the distinguished surgeon, wrote of "febris pestilens" which was 
 marked by eruptions resembling the bites of fleas or bed bugs. 
 
 Morbus Hungaricus appeared in the army of Maximilian II in 
 Hungary in 1566, and soon spread over the greater part of Europe. 
 Sennertus and others have left descriptions of this epidemic. The 
 skin was marked by flea-bite eruptions. Headache was intense and 
 followed by delirium. In some, the tongue became black, parotid 
 abscesses developed and gangrene of the limbs occurred. 
 
 Under the title, "Febris maligna puncticularis seu peticularis," 
 Castro of Verona (1580) pictured the symptoms. The pulse is small 
 and weak; the tongue dry and black; the face and eyes greatly con- 
 
TYPHUS FEVER 95 
 
 gested; delirium, followed by stupor deepening into coma; parotid 
 abscesses in some, the eruption appearing about the seventh day and 
 the disease continuing from fourteen to twenty days. Castro says 
 that this disease was known to the French as "La Pourpre;" to the 
 Italians as "Petecchie ;" to the Spaniards as "Tabardillo," and to the 
 Germans as "Fleckfieber." 
 
 During the sixteenth century typhus fever was so prevalent in the 
 jails of England that the disease spread among the court officers when 
 prisoners were brought before them for trial. This happened 
 repeatedly and gave to court sessions the designation of "black assizes." 
 The first of these of which record is left occurred at Cambridge in the 
 thirteenth year of the reign of Henry VIII (1522). The justices, 
 bailiffs, gentlemen and other persons in court were seized with a fever 
 which proved fatal to many. The most notable report of a "black 
 assize" is that at Oxford in the twentieth year of the reign of Elizabeth 
 (1577). The prisoner was Rowland Jenks, a bookbinder and a Roman 
 Catholic, who was charged with treason and profanity of the protes- 
 tant religion. He was sentenced to lose his ears. The trial was held 
 at Oxford Castle, July 4. Several prisoners were brought into court 
 in the couurse of the trial. The chronicle states that "an infectious 
 damp of breath" spread through the room. "Above six hundred sick- 
 ened in one night; and the day after, the infectious air being carried 
 into the next village sickened there more than an hundred more." By 
 the twelfth of August 510 persons perished. "The infection arose 
 from the nasty and pestilential smell of the prisoners when they came 
 out of the jail, two or three of whom had died a few days before the 
 assize began." The disease was marked by loss of appetite, headache, 
 sleeplessness, loss of memory, deafness and delirium, so that the vic- 
 tims behaved like madmen, The Catholics saw in this the scourge of 
 God for the unjust punishment, and the Protestants attributed it to 
 the "diabolical machinations of the Papists." 
 
 During the thirty years war (1619-1648) the whole of central 
 Europe was desolated by war, famine and pestilence. The nature of 
 the epidemic is plainly shown by both medical and lay writers and its 
 ravages were portrayed in both prose and poetry. One verse of a song 
 runs as follows: 
 
96 TYPHUS FEVER 
 
 Per omnes 
 
 Burgundos et quas stagnans Arar irrigat urbes 
 Insolita exarsit febris, quae corpora rubris 
 Inficiens maculis (triste et mirabile dictu) 
 Quarta luce frequens fato pendebat acerbo. 
 Pulsus erat minimus, tremulusque soporque 
 Mens vaga, visque labens; totium crassemque rubensque 
 Interdum tenuae instar aquae. 
 
 In 1658, Morton states that England was one vast hospital filled 
 with the victims of a fever with "maculae latae et rubicundae morbillis 
 similes in toto corpore." The great plague of London (1665) was 
 preceded, accompanied, and followed by typhus and some of the most 
 eminent medical men of the time, notably Sydenham, frequently con- 
 founded plague and typhus in the reports of their cases. Under the 
 title, "Febris Petechialis vera" Hoffmann of Halle (1700) gave an 
 excellent account of typhus and pointed out its distinction from the 
 plague, which he designated "Febris Pestilens." The eighteenth cen- 
 tury saw no abatement of epidemics of typhus. This disease had long 
 afflicted Ireland under the name of "Irish ague," but it was not until 
 1708 that permanent records of its ravages were made. From that 
 time on for more than a century and a half Ireland was afflicted by one 
 epidemic after another, just as fast as new generations supplied a crop 
 of susceptible material. The historian has no difficulty in showing that 
 each exacerbation was coincident with a period of great want and 
 poverty, but this was a chronic condition of the Emerald Isle during 
 this period. The people were oppressed by their rulers, divided among 
 themselves, held in the grossest ignorance and fed on superstition. 
 Most of those who had enough energy emigrated to foreign lands, 
 thus impoverishing their native land of its best blood to such an extent 
 that it has not yet wholly recovered. An account of one epidemic of 
 typhus in Ireland is much like all others. Nothing to eat but potatoes ; 
 and an adult would devour ten or more pounds of these tubers each 
 day in the vain attempt to supply his body cells with the minimum 
 amount of protein demanded. Driven by hunger to sell the cow, fur- 
 niture, and even his clothing, the Irishman and his family huddled 
 together in rags and filth, while vermin fed on their bodies and simul- 
 taneously inoculated them with typhus. Murchison says : "In Dublin, 
 
TYPHUS FEVER 97 
 
 the servants of the upper classes were not allowed potatoes, and bread 
 was portioned out to them sparingly, few persons had more than a 
 quartern loaf in the week. The poor pawned their clothes, and even 
 their bedding for money to purchase food, and, as a natural conse- 
 quence, it was common for several members of one family to sleep in 
 the same bed." According to O'Connell, eighty thousand Irish died in 
 1740-1741 of famine and spotted fever and one-fifth the popula- 
 tion of Munster perished. Writing of a nineteenth century epidemic 
 of typhus in Ireland, Murchison says : 
 
 Extreme distress ensued. The four pound loaf was sold in Dublin in 1817 
 for Is, 9d; and the poor throughout Ireland are described as wandering about 
 the country gathering nettles, wild mustard, and other weeds, to satisfy the 
 cravings of hunger. . . . The probable population of Ireland at this time 
 was, in round numbers, six million, and the number of sick was estimated at 
 737,000, or at about one-eighth. In Dublin alone there were about 70,000 cases, 
 making about one-third of the inhabitants. 
 
 Of the same epidemic Carleton wrote: 
 
 People collected at the larger dairy farms waiting for the cattle to be blooded, 
 so that they might take home some of the blood to eat mixed with a little 
 oatmeal. The want .of fuel caused the pot to be set aside, windows and crevices 
 to be stopped, washing of clothes and person to cease, and the inmates of a 
 cabin to huddle together for warmth. This was far from the normal state of 
 the cottages or even of the cabins, but cold and hunger made their inmates 
 apathetic. Admitted later to the hospitals for fever, they were found bronzed 
 with dirt, their hair full of vermin, their ragged clothes so foul and rotten 
 that it was more economical to destroy them and replace them than to clean 
 them. 
 
 The roads were filled with infected vagrants and many a poor 
 cottier not only divided what he had in alms, but by giving shelter to 
 the wanderer introduced the infection into his humble home, while "the 
 dogs of the gentry kept all beggars from their gates." 
 
 The last great Irish famine (1845-1848) was the occasion for the 
 prevalence of relapsing fever and scurvy as well as typhus fever. This 
 scourge was foreseen in the development of the potato blight and was 
 mitigated somewhat by the repeal of the corn laws and by a change 
 in the navigation laws permitting the carrying of food supplies in other 
 than British bottoms. At that time Ireland lived almost exclusively 
 on milk and potatoes. Although it produced more than enough grain 
 
98 TYPHUS FEVER 
 
 to feed itself, even in these years of the potato blight, most of this had 
 to be sent to England to pay the rents. Years before both Malthus 
 and Cobbett had protested against a people trying to live so largely 
 on potatoes. The former wrote as follows: 
 
 When the common people of a country live principally on the dearest grain, 
 as they do in England, on wheat, they leave great resources in scarcity; and 
 barley, oats, rye and cheap soup and potatoes all present themselves as less 
 expensive, yet at the same time wholesome means of nourishment, but when 
 their habitual food is the lowest in the scale, they appear to be wholly without 
 resource except in the bark of trees like the poor Swedes ; and a great portion 
 of them must necessarily be starved. 
 
 After this famine the Irish ceased to rely so largely on the potato, 
 emigration to this country and Canada greatly increased, and "the 
 population has steadily declined and the well being of the people 
 steadily improved." 
 
 Before dismissing the subject of Irish typhus epidemics, I wish to 
 add a quotation from Creighton, showing that the case mortality in 
 this disease is higher among the robust and well fed than among the 
 weak and hungry. "There appeared to be a scale of malignity in the 
 fevers in an inverted order of the degree of misery. The most 
 wretched had the mildest fever, the artisan class or cottagers had 
 typhus fatal in the usual proportion, the classes living in comfort had 
 typhus of a very fatal kind. This experience, however strange it may 
 seem, was reported by medical observers everywhere with remarkable 
 unanimity. One says that six or seven of the rich died in every ten, 
 others say one in three. Forty-eight medical men died in 1847 in 
 Munster, most of them from fever; in Cavan County seven medical 
 men died from fever in twelve months and three more had a narrow 
 escape of death; two of the three physicians sent by the Board of 
 Health to the coast of Connemara died of fever. Many Catholic 
 priests died as well as some of the established Church Clergy; and 
 there were numerous fatalities of the resident gentry and among others 
 who administered the relief. Yet a case of fever in a good home did 
 not become a focus of contagion ; the contagion came from direct con- 
 tact with the crowds of starving poor, their clothes ragged and filthy, 
 their bodies unwashed, and many of them suffering from dysentery. 
 
TYPHUS FEVER 99 
 
 The greater fatality of fever among the richer classes (of course, 
 with a much smaller number of cases) has been a commonplace in 
 Ireland and is remarked by the best writers. 
 
 Creighton in his valuable "History of Epidemics in Britain" has 
 shown some interesting facts concerning typhus in England during the 
 eighteenth century. I will follow his facts but will draw my own 
 conclusions. During the half century from 1715 to 1765 England was 
 most prosperous financially. Monied men built up great fortunes and 
 the necessities of life were abundant and cheap. With two or three 
 exceptions the harvests were rich and grain was exported in great 
 quantity. Historians state that under the first two Georges there 
 was general prosperity. Even Adam Smith speaks of "the peculiarly 
 happy circumstances of the country during the reign of George II 
 (1726-1760)." Hallam speaks of this period "as the most prosperous 
 that England had ever experienced." Lecky says : 
 
 All the evidence we possess concurs in showing that during the first three- 
 quarters of the century the position of the poor agricultural classes in Eng- 
 land was singularly favorable. The price of wheat was both low and steady. 
 Wages, if they advanced slowly, appear to have commanded an increased pro- 
 portion of the necessaries of life, and there were all the signs of growing 
 material well-being. It was noticed that wheat bread, and that made of the 
 finest flour, which at the beginning of the period had been confined to the 
 upper and middle classes, had become before the close of it over the greater 
 part of England the universal food, and that the consumption of cheese and 
 butter in proportion to the population in many districts almost trebled. Beef 
 and mutton were eaten almost daily in the villages. 
 
 Johnson wrote: 
 
 There every bush with nature's music rings, 
 There every breeze bears health upon its wings. 
 
 However, there were even at this time some who saw beneath the 
 surface of abundance and prodigality. An economist, Rogers, pointed 
 out that the prosperity was all on the side of the ruling classes and the 
 capitalists, while the laborers were in "irremediable poverty and with- 
 out hope." Their wages were artificially fixed by the quarter sessions 
 and they were kept "in a condition wherein existence could just be 
 maintained." 
 
100 TYPHUS FEVER 
 
 Creighton writes : 
 
 But the Eighteenth Century, even the most prosperous part of it, from the 
 accession of George I to the beginning of the Industrial Revolution in the 
 last quarter or third of it, was none the less a most unwholesome period in 
 the history of England. The health of London was never worse than in those 
 years, and the vital stastistics of some other towns, such as Norwich, are little 
 more satisfactory. 
 
 In 1782, White wrote of the fever in London : 
 
 The annual deaths under the old regime exceeded by a good deal the 
 annual births; in the seven years, 1728-35, according to the figures in the parish 
 registers, the burials from all causes were 3,488 and the baptisms 2,803, an 
 annual excess of 98 deaths over the births in an estimated population of 10,800 
 (birth rate 37 per 1,000, death rate 46 per 1,000). 
 
 Creighton says: 
 
 The mean annual deaths were never higher in London, not even in plague 
 times over a series of years, the fever deaths keeping pace with the mortality 
 from all causes, and, in the great epidemic of typhus in 1741, making about a 
 fourth part of the whole. The populace lived in a bad atmosphere, physical 
 and moral. 
 
 It is stated that the consumption of alcohol in London amounted to 
 six gallons per head per annum. A duty of 20 shillings per gallon did 
 not prevent the poor from getting it, and large quantities of gin were 
 smuggled in from Holland. In 1726 the College of Physicians pre- 
 sented this matter to the House of Commons with the following state- 
 ment: 
 
 We have with concern observed for some years past the fatal effects of 
 the frequent use of several sorts of distilled spirituous liquor upon great num- 
 bers of both sexes, rendering them diseased, not fit for business, poor, a burthen 
 to themselves* and neighbors, and too often the cause of weak, feeble and dis- 
 tempered children, who must be, instead of an advantage and strength, a charge 
 to their country. 
 
 The poor in London were crowded into small quarters. In 1737 
 one house was found to contain eleven married couples and fifteen 
 single persons. A tax was levied on each window in a house and 
 each window in cellar, stairway and outhouse was counted and skylight 
 included. "No window or light shall be deemed to be stopped up 
 unless such window or light shall be stopped up effectually with stone 
 or brick or plaister on lath." 
 
TYPHUS FEVER 101 
 
 Debtors were thrown into prison where some remained for years 
 and if they had any comforts in the prison they had to pay for them. 
 Jailors grew rich out of the necessities of their wards. Those unable 
 to pay were crowded into unbelievably small quarters. The first com- 
 mission to inquire into these abuses reported: 
 
 George's ward, sixteen feet by fourteen and about eight feet high, had 
 never less than thirty-two in it all last year and sometimes forty; there was no 
 room for all to lie down, one-half the number sleeping over the others in ham- 
 mocks ; they were locked in from 9 p. m. to 5 a. m. in summer, longer in winter, 
 and as they were forced to ease nature within the room, the stench was 
 noisome beyond expression. 
 
 It is a matter of common knowledge that the work of prison reform 
 in England at the time of which we write was due largely to the efforts 
 of John Howard and his work was begun in 1773. 
 
 While the great land owners accumulated wealth, the poacher who 
 snared a rabbit was sent to jail or deported. The condition of the poor 
 was hopeless and the best blood of England flowed willingly or unwill- 
 ingly into the United States, Canada and Australia. However, typhus 
 often pursued the poor emigrant in his flight by sea and it is said that 
 one-third the immigrants to America in the eighteenth century died 
 during or soon after the voyage. It is well known that the fatality 
 from ship fever continued through the early part of the nineteenth 
 century. During the American War (1774-1780) the number of 
 British seamen raised was 175,990, the number of those who died of 
 disease was 18,545, and the number killed was 1,243. 
 
 It is interesting to 'note that during the eighteenth century English 
 physicians for the most part were not much concerned with the poor 
 and many of them saw but little typhus, while a colleague busy among 
 the poor saw much of it. A Dr. Moss, writing of diseases in Liver- 
 pool, said that typhus was rare at a time when Dr. Currie was seeing 
 more than 3,000 cases a year. In 1790 Liverpool was the second city 
 in England with a population of 56,000, while that of London was 
 estimated at 800,000. According to Currie 7,000 of the people of 
 Liverpool lived in cellars and 9,000 more in back houses with small 
 courts and with narrow passages to the streets. In ten years (1787- 
 1796) 31,243 cases of fever were registered, an average of 3,124 per 
 year. In the last quarter of the eighteenth century Chester was 
 
102 TYPHUS FEVER 
 
 regarded as the most desirable residence city in the kingdom. Within 
 the walls, it had a population of about 3,500 and from 1764-1773 the 
 death rate was only 17.2 per 1,000, but the poor lived outside the walls 
 and Haygarth describes the condition as follows : 
 
 The houses were small, close, crowded and dirty, ill supplied with water, 
 undrained, and built on ground that received the sewage from within the 
 walls. The people were ill-fed and they seldom changed or washed their 
 clothes; when they went abroad they were noisome and offensive to the smell. 
 ... In these poor habitations when one person was seized with the fever, 
 others of the same family are generally affected with the same fever in a 
 greater or lesser degree. 
 
 The second half of the eighteenth century saw the great manu- 
 facturing development of England by the employment of machinery. 
 Now the poor were exploited by the manufacturer. The houses occu- 
 pied by the operatives are said by Ferrier to have been dirty, without 
 ventilation, and with the beds almost touching. "As soon as one poor 
 creature dies or is driven out of his cell, he is replaced by another, 
 generally from the country, who soon feels in his turn the conse- 
 quences of breathing infected air." The only voices heard in behalf 
 of the poor were those of medical men, and in Manchester Ferrier 
 pleaded for them in strong language : 
 
 I have seen patients in agonies of despair on finding themselves over- 
 whelmed with filth and abandoned by everyone who could do them any service. 
 . . . The situation of the poor at present is extremely dangerous, and often 
 destructive to the middle and higher ranks of society. . . . The poor are 
 indeed the first sufferers, but the mischief does not always rest with them. By 
 secret avenues it reaches the most opulent and severely revenges their neglect 
 or insensibility to the wretchedness surrounding them. 
 
 It was the fact that typhus occasionally found its way into the 
 midst of the rich, and, when it did, killed so many and so quickly, 
 that they were compelled to recognize that the misfortunes of the poor 
 were of concern to themselves. Finally in a half-hearted way, urged 
 by physicians, growling about the wastefulness and improvidence of 
 the laboring classes, driven by the occasional deadly outbreaks in their 
 own ranks, the ruling classes began to provide special hospitals for the 
 isolation and care of cases of typhus. The London fever hospital 
 was established in 1802. 
 
TYPHUS FEVER 103 
 
 The epidemiologic history of Britain during the Napoleonic wars 
 presents many points of interest. Food prices were high. For a time 
 American markets were closed to British manufacturers. Still, the 
 period (1803-1816) was comparatively free from typhus, so far as 
 Britain was concerned. In peace the poor man's business is to serve 
 the rich, clothe himself in rags, rear his family in a stye and eat 
 nothing. In war he becomes a hero, the defender of his king and 
 country. He is well clothed, well fed and all that is asked of him is 
 that he die for his country if need be. The wife and children at 
 home must be cared for because more soldiers will be needed. 
 
 Immediately after the declaration of peace (1816) typhus began to 
 increase and within another year it took on epidemic proportions. 
 The condition of the London slums of the time is shown by a Par- 
 liament report as quoted by Creighton: 
 
 Calmel's Buildings, a small court near Portman Square, consisting of twenty- 
 four houses, in which lived seven hundred Irish in distress and profligacy, neg- 
 lected by the parish and shunned by everyone from fear of contagion. George 
 Yard, Whitechapel, consisting of forty houses in which lived two thousand 
 persons in a similar state of wretchedness. 
 
 In 1831 typhus became epidemic in England and continued its rav- 
 ages for more than ten years. The destitution and sickness among 
 the poor of Manchester in the latter part of this epidemic (1839-1841) 
 formed the basis of the story of Mary Barton written by Mrs. Gaskell. 
 The author dwells on the bitterness on the part of the poor. 
 
 The most deplorable and enduring evil that arose out of the period of com- 
 mercial depression to which I refer, was this feeling of alienation between the 
 different classes of society. It is so impossible to describe, or even faintly to 
 picture, the state of distress which prevailed in the town at that time, that I 
 will not attempt it; yet I think again that surely in a Christian land, it 
 was not known so feebly as words could tell it, or the more fortunate and 
 happy would have thronged with their sympathy and aid. In many instances 
 the sufferers wept first and then cursed. Their vindictive feelings exhibited 
 themselves in rabid politics. And when I hear, as I have heard, of the suffer- 
 ings and privations of the poor, of provision shops where ha'porths of tea, 
 sugar, butter and even flour were sold to accommodate the indigent of parents 
 sitting in their clothes by the fireside during the whole night for seven weeks 
 together, in order that their only bed and bedding might be reserved for the 
 use of their large family of others sleeping upon the cold hearth stone for 
 
104 TYPHUS FEVER 
 
 weeks in succession without adequate means of providing themselves with 
 food or fuel and this in the depth of winter of others being compelled 
 to fast for days together, uncheered by any hope of better fortune, living, more- 
 over, or rather starving in a crowded garret or damp cellar, and gradually 
 sinking under the pressure of want and despair into a premature grave; and 
 when this has been confirmed by the evidence of their careworn looks, their 
 excited feelings, and their desolated homes can I wonder that many of them, 
 in such times of misery, and destitution, spoke and acted with ferocious pre- 
 cipitation ? 
 
 In 1847-1848 there was a revival of typhus, under the name of 
 "Irish Fever," in England. The last epidemic in England occurred 
 in 1863-1864, and was in part due to the "cotton famine" resulting 
 from the Civil war in our own country. Since that time typhus has 
 gradually decreased in Britain, but has not entirely disappeared. 
 
 From the fact that I have dwelt on typhus in Britain, it must not 
 be inferred that it was unknown or was less prevalent on the conti- 
 nent of Europe during the seventeeth, eighteenth and nineteenth cen- 
 turies. It was constantly present and assumed epidemic proportions 
 of varying intensity in diverse places at different times. No European 
 nation has been wholly free from it and it has continued to develop 
 epidemics especially in Austria and Russia. The present war has 
 developed the conditions most favorable to its dissemination and I 
 shall not attempt to predict the part it may play in the savage struggle 
 now going on. 
 
 Taking Europe as a whole the period from about 1670 to about 
 1850 may be considered as the typhus age. This does not mean that 
 this disease did not exist before this period or that it ceased with the 
 close of it. Neither assumption would be true, but before that time 
 typhus was overshadowed for many centuries by the more deadly 
 plague. Still it is a question if even at that time typhus did not kill 
 more than the plague. The former was constantly present while the 
 latter lapsed from time to time apparently on account of lack of 
 susceptible material. Even during the typhus age other deadly infec- 
 tions, as smallpox, tuberculosis, diphtheria, etc., aided in rolling up 
 heavy mortality lists. A complete history of typhus would be a valu- 
 able contribution to human knowledge and should be studied by states- 
 men and all interested in the welfare of the race, as well as physicians. 
 
TYPHUS FEVER 105 
 
 There is certainly one great lesson which it teaches and that is that 
 the health conditions of the poor are of interest to all. No nation can 
 be great so long as its laboring classes live under unhygienic condi- 
 tions. Typhus impoverished Europe not only by its high mortality but 
 by the great emigration from its shores, leaving the degenerate to 
 beget its generations. 
 
 Before leaving the history of typhus in Europe, I wish to quote the 
 definition of the disease given by the greatest English authority of the 
 nineteenth century, Murchison: 
 
 A disease attacking persons of all ages generated by contagion, or by over- 
 crowding of human beings, with deficient ventilation, and prevailing in epidemic 
 form, in periods or under circumstances of famine and destitution. Its symp- 
 toms are : more or less sudden invasion marked by rigors or chilliness ; fre- 
 quent, compressible pulse; tongue furred and ultimately dry and brown; 
 bowels, in most cases, constipated ; skin warm and dry ; a rubeoloid rash appear- 
 ing between the fourth and seventh days, the spots never appearing in 
 successive crops, at first slightly elevated, and disappearing on pressure, 
 but, after the second day, persistent, and often becoming converted into true 
 petechiae ; great and early prostration; heavy flushed countenance; injected 
 conjunctivae; watchfulness and obtuseness of the mental faculties, followed 
 at the end of the first week by delirium, which is sometimes acute and noisy, 
 but oftener low and wandering; tendency to stupor and coma, tremors, sub- 
 sultus, and involuntary evacuations, with contracted pupils. Duration of the 
 fever from ten to twenty-one days, usually fourteen. In the dead body no spe- 
 cific lesion; but hyperemia of all the internal organs, softening of the heart, 
 hypostatic congestion of the lungs, atrophy of the brain, and edema of the 
 pia mater are common. 
 
 Typhus fever became epidemic in Mexico soon after the conquest 
 (1530) and has continued in endemic form with occasional severe 
 exacerbations to the present time. According to Liceaga the second 
 recorded epidemic occurred in 1545 and the third in 1575. In 1736- 
 1737 the disease is said to have killed 192,000. During the nineteenth 
 century there were many exacerbations, the most extensive of which 
 was in 1861. At the present time typhus is common in Mexico. 
 
 Importations of typhus by immigrants into this country have been 
 constant and it is probable that at no time have our large cities been 
 wholly free from it, but in most instances it has been limited to 
 recently arrived immigrants and those directly in contact with them. 
 
106 TYPHUS FEVER 
 
 Doty says: "Out of 439 cases of typhus fever which occurred in 
 New York during 1892-1893, 434 were removed from the poorer 
 tenement and lodging houses, principally the latter." 
 
 In the records of the civil war 1,723 cases with 572 deaths are 
 reported under this name, but the diagnosis of many of these were 
 questioned by the best medical officers, such as Woodward and Clymer. 
 No cases were reported by Confederate officers. It is certain that 
 typhus did not play any marked part in the mortality of that war. 
 
 THE TRANSMISSION OF TYPHUS 
 
 In 1909 Nicolle, stationed in Algiers, made two notable discoveries 
 concerning the transmission of typhus fever. In the first place, he 
 induced the disease in the chimpanzee by injecting the blood of patients 
 and in like manner he transferred the disease from the chimpanzee 
 to the macacus monkey. He was not able to transfer the disease in 
 this way directly from man to monkey, but could do so indirectly 
 through the chimpanzee. This suggests that the virus is increased in 
 intensity by passage through the chimpanzee. In the second place, 
 Nicolle succeeded in transmitting typhus from monkey to monkey 
 by the bite of the body louse. Typical eruptions were secured in the 
 chimpanzee constantly, but not uniformly in the monkey. 
 
 The fact that typhus is transferable by the bite of the body louse 
 has been confirmed by Anderson and Goldberger, Ricketts and others. 
 This renders it desirable for us to know as much as possible con- 
 cerning the life history of this parasite. Shipley of Cambridge, Eng- 
 land, has recently made studies along this line and I follow him 
 principally in the following statements : The body louse ( Pediculis 
 vestimenti) is somewhat larger than the head louse and carries longer 
 antennae. The male is about 3 mm. long and 1 mm. broad. The female 
 is about one-tenth larger. Its color is said to vary with that of the 
 people on whom it feeds, black, brown, and with different shades of 
 grayish white. It does not move about over the surface but is always 
 attached to the inner side of the underclothing. Even in feeding, it 
 remains attached by at least one of its six legs to the clothing. When 
 a lousy person is stripped, no lice can be found on him, but the inner 
 side of the underclothing may be alive with them. When grown for 
 the purpose of study, they must be permitted to attach themselves to 
 
TYPHUS FEVER 107 
 
 bits of flannel and these must be brought into contact with the skin 
 and the lice allowed to eat twice a day. They take hold promptly and 
 feed greedily but never detach themselves from the flannel. The 
 female after pairing begins to deposit eggs or nits at the rate of about 
 5 per day. These hatch after periods which vary markedly with 
 the temperature. Cold delays the hatching, but even freezing does not 
 destroy the nits. Under favorable conditions the larvae emerge about 
 the sixth day, and immediately begin to feed. Body lice seem not 
 to be hardy and soon die unless they have frequent opportunity of 
 feeding, but the clothing may carry the nits quite indefinitely and 
 these may hatch when the conditions become favorable. The newly 
 hatched do not survive more than thirty-six hours without food. 
 The lice are easily killed by gasoline or benzine or by turning the 
 underclothing inside out and carefully applying a hot iron. Special 
 attention should be given to the seams. Boiling quickly destroys 
 both the insects and their eggs. It will be seen that as simple as 
 these requirements are in ordinary life they are quite impracticable 
 to the soldier in the trenches, especially when he has no change of 
 underclothing. It is said that this parasite feeds only on dirty people 
 and that it will not Infest those who wear silk, but the soldier must 
 be dirty, sometimes at least, and he is not supplied with silk under- 
 wear. Gasoline and benzine cannot be used by the soldier on account 
 of their ready inflammability. A dilute solution of lysol or cresol 
 soap made into a lather is applied to the inside of the clothing and 
 left there to dry. Physicians and nurses in caring for typhus patients 
 are exposed to great danger and the death-rate among them has 
 always been high. In recent years more than one medical man has 
 contracted typhus in trying to solve its etiology and of the six Ameri- 
 can physicians who have recently studied typhus fever in Mexico 
 three have contracted the disease and two have died Conneff of the 
 State University of Ohio and Ricketts of the University of Chicago. 
 These are names now added to the martyr roll of science. Of 
 Ricketts, his teacher and friend, Hektoen, has deservingly said: 
 
 Those near him know that he fully understood the dangers to which he 
 would be exposed and the risks he would run. He decided he would take those 
 risks, meet the dangers with all possible means of prevention, and do the work 
 that would come to his hands. And so he made the great sacrifice and gave 
 all that a man can give to his fellow men. 
 
108 TYPHUS FEVER 
 
 Other American medical men and nurses have given their lives in 
 the combat with this disease in desolated Serbia and others still are 
 there and elsewhere in war-scourged Europe, seeking not to destroy 
 but to save lives, fighting under the great battle flag of humanity and 
 science. 
 
 Quite independently of the work of Nicolle, Anderson and Gold- 
 berger, Ricketts and Wilder, Conner! and others studied the etiology 
 of typhus in Mexico. They found that the disease could be trans- 
 mitted from man to the lower monkeys, without passage through a 
 chimpanzee, that the virus in the blood is removed by nitration through 
 porcelain, that one attack in the monkey gives immunity and that 
 Nicolle was right in his claim that the disease is transmitted by the 
 body louse. All attempts to transfer the disease by fleas and bed bugs 
 have failed, while those with the head louse (Pediculis capitis) have 
 not given uniform results. 
 
 For some years Brill has observed a peculiar disease in the wards 
 of Mount Sinai Hospital, New York, and up to the present time he 
 has records of about three hundred cases. Brill has described this 
 disease as follows: 
 
 An acute infectious disease of unknown origin and unknown pathology, 
 characterized by an incubation period of from four to five days, a period of 
 continuous fever, accompanied by intense headache, apathy, and prostration, a 
 profuse and extensive erythematous maculo-papular eruption, all of about two 
 weeks duration, whereupon the fever abruptly ceases either by crisis within 
 a few hours or by rapid lysis within three days. 
 
 Anderson and Goldberger have shown that Brill's disease is typhus 
 fever by injecting the blood of patients into monkeys and thereby 
 establishing immunity to typhus. 
 
 Nicolle has reduced typhus in Tunis from 838 cases in 1909 to 22 
 cases in 1912. The only measure employed consists in freeing the 
 people of lice. 
 
 THE ORGANISM 
 
 Plotz has isolated the organism and with Olitsky and Baeher has 
 shown by complement fixation and agglutination tests that he has, 
 most probably, found the infecting agent. In the agglutination tests 
 only positive reactions in dilutions 1 : 50 were considered. 
 
TYPHUS FEVER 109 
 
 Of twenty-four cases tested before the crisis all were negative except two 
 which were tested one day before the crisis, both of which had a titre of 1 : 100. 
 Of ten cases tested on the day of the crisis, three were positive and seven nega- 
 tive. After the crisis, thirty-eight cases were studied, 92.6 per cent, of which 
 were positive. Agglutinins have been demonstrated as late as five months 
 after the crisis. Of a very large series of control cases, no case gave a reac- 
 tion in a dilution above 1 : 50, except three cases in which the occurrence of 
 a previous attack of typhus fever could not be excluded. In these cases the 
 reactions varied from 1 :100 to 1 : 200. Control studies made by testing the 
 serum of typhus cases against various other organisms were negative. 
 
 The opsonic index increases at the crisis and remains high in the 
 convalescent stage. 
 
 The organism is a small gram-positive bacillus, from 0.9 to 1.93 microns 
 in length, the breadth being from one-fifth to three-fifths of the length. It is 
 not acid-fast, has no capsule, and polar bodies can be demonstrated by appro- 
 priate methods. When first isolated, it grows only anaerobically, but after a 
 time it can be grown aerobically. 
 
 Intraperitoneal inoculation of a pure culture of the organism into guinea- 
 pigs produces a rise of temperature in from twenty-four to forty-eight hours, 
 the temperature remaining high for four or five days, and then dropping by 
 crisis. This corresponds to the reaction seen in guinea-pigs after inoculation 
 with defibrinated blood from typhus fever patients, except that the incubation 
 period is shorter. Serum from a convalescing typhus patient has bactericidal 
 properties against the organism obtained from Brill's disease and typhus fever. 
 
CHAPTER XII 
 
 THE PLAGUE 
 
 History. According to Sticker the history of this disease can be 
 traced back to the time of the exodus of the Children of Israel from 
 Egypt. The Egyptians of the Pharaohs drained the land, built aque- 
 ducts, disposed of their dead hygienically, reared temples, maintained 
 law and order, developed the elements of literature and science and 
 devised and employed simple machinery. In speaking of the ancient 
 Egyptians, Diodorus says, "The whole manner of life was so evenly 
 ordered that it would appear as though it had been arranged by a 
 learned physician rather than by a lawgiver." Herodotus declared 
 ancient Egypt the healthiest of countries, but filled with physicians, 
 of whom "one treats only the diseases of the eye, another those of 
 the head, the teeth, the abdomen, or the internal organs." Writing of 
 a later time, Gibbon said "Ethiopia and Egypt have been stigmatized 
 in all ages as the source and seminary of the plague." It is evident 
 that in the time of its great civilization Egypt was salubrious ; coinci- 
 dent with the decline in the learning and wisdom of its people, it was 
 visited and desolated by pestilence. That Egypt had lost its salubrity 
 as early as the exodus of the Children of Israel is shown by many pas- 
 sages in the Bible in which the chosen people are threatened with the 
 diseases of Egypt if they neglect or violate the laws. Moses, "learned 
 in all the wisdom of the Egyptians" codified his sanitary rules and 
 regulations in the form of religious rites and ceremonies and thus 
 secured their observance among the faithful, even down to the present 
 time. 
 
 Sticker is quite confident that the pest among the Philistines 
 spoken of in the first book of Samuel, when the captured ark was 
 returned with five golden emerods and five golden mice, was the 
 bubonic plague. 
 
 Of the true nature of the Athenian plague described by Thucydides 
 there is some doubt. It is generally believed to have been the plague, 
 but the description is not sufficiently clear to justify a positive con- 
 
112 THE PLAGUE 
 
 elusion. It has been suggested that it might have been typhus fever, 
 but I think that the greatest probability is in favor of its having been 
 the pneumonic form of the plague. 
 
 The time of the earliest appearance of the plague in Italy is not 
 known. It was certainly quite well established there in the first cen- 
 tury of the Christian era and in all probability this was not the first 
 visitation. The historian, as a rule, confines his descriptions to martial 
 and political events and consequently gives a wholly erroneous idea 
 of true conditions. Gibbon says: "If a man were called upon to fix 
 the period in the history of the world, during which the condition of 
 the human race was most happy and prosperous, he would without 
 hesitation, name that which elapsed from the death of Domitian to 
 the accession of Commodus" (from 96 to 180 A. D.). Noah Webster, 
 in his work on epidemics and pestilence, quotes the preceding with the 
 following just comment: 
 
 It is certain that, at this time, the Roman Empire was in its glory, and 
 governed by a series of able and virtuous princes, who made the happiness of 
 their subjects their principal object. But the coloring given to the happiness 
 of this period is far too brilliant. The success of armies and the extent of 
 empire do not constitute exclusively the happiness of nations; and no historian 
 has a title to the character of fidelity, who does not comprehend, in his general 
 description of the state of mankind, moral and physical, as well as political 
 evils. 
 
 Let us make brief inquiry into the diseases of this "most happy 
 and prosperous" period. It was preceded by, it begun in, continued in, 
 and closed in pestilence. That the plague was endemic in Italy at that 
 time and that it developed in epidemic form with each increase in sus- 
 ceptible material there can be no doubt. Of the epidemic of 68 A. D. 
 Tacitus says : 
 
 Houses were filled with dead bodies and the streets with funerals; neither 
 age nor sex were exempt; slaves and plebians were suddenly taken off, amidst 
 the lamentations of their wives and children, who, while they assisted the sick, 
 or mourned the dead, were seized with the disease, and perishing, were burned 
 on the same funeral pyre. To the knights and senators the disease was less 
 mortal, though these also suffered in the common calamity. 
 
 About this time the plague appears to have spread over the whole 
 of Asia, northern Africa and Europe. According to Short, the deaths 
 
THE PLAGUE 113 
 
 from this disease in Scotland between 88 and 92 A. D. amounted to 
 not less than 150,000. This was probably not less than one-fourth, 
 possibly one-half, the population of Scotland at that time. 
 
 In the year 80 A. D. the deaths from the plague in Rome at the 
 height of the epidemic numbered 10,000 a day. It is estimated that the 
 population of Rome at that time was somewhat more than one million. 
 Rufus of Ephesus, who lived in the reign of Trajan (98-117 A. D.) 
 has left a description of the epidemic of his time which leaves no 
 doubt about its being the plague. "Pestilentes bubones, maxime letales 
 et acuti, qui maxime circa Lybiam, et Aegyptum et Syriam obser- 
 vantur." 
 
 Exacerbations of the disease in Rome are recorded for the years 
 102, 107 and 117 A. D. According to Short, 45,000 died of the plague 
 in Wales in 114 A. D. The year 167 A. D. is noted for an unusually 
 severe outbreak of the plague at Rome, where it continued for many 
 years. In the year 173 A. D., the Roman army was threatened 'with 
 extinction by disease, and special epidemics, or rather exacerbations 
 of the epidemic, prevailed in Rome in 175 and 178 A. D. That the 
 "happy and prosperous" period was followed by a continuation of the 
 plague is shown by the following quotation from Herodian : 
 
 A great pestilence raged throughout Italy at that time (about 187 A. D.) but 
 with most violence in the city, by reason of the great concourse of people assem- 
 bled from all parts of the earth. The mortality among men and cattle was 
 great. The emperor, by advice of physicians, retired to Laurentium, on account 
 of the coolness of the place, which was shaded with laurels. It was supposed 
 that the fragrance of the laurels acted as an antidote against the contagion. 
 The people in the city also, by the advice of physicians, filled their noses and 
 ears with sweet ointments and used perfumes, etc. 
 
 Under the spell of the historian we have been inclined to regard 
 the period when the great philosopher, Marcus Aurelius Antoninus, 
 sat on the throne of the world, as the golden age. Let us therefore 
 listen to a few words from his personal attendant, courtier and his- 
 torian, who writes: 
 
 Unless he, M. Antoninus, had been born at this juncture, the affairs of the 
 empire would have fallen into speedy ruin, for there was no respite from mili- 
 tary operations. War raged in the east, in Illyricum, in Italy and in Gaul. 
 Earthquakes with the destruction of cities, inundations of rivers, frequent 
 
114 THE PLAGUE 
 
 plagues, a species of locusts ravaging the fields; in short, every calamity that 
 can be conceived to afflict and torment man scourged the human race during 
 his administration. 
 
 The physician and historian, Procopius, in his account of the great 
 pestilence in the reign of Justinian "emulated the skill and diligence 
 of Thucydides in the description of the plague at Athens." Of this 
 epidemic Gibbon says: 
 
 In time its first malignancy was abated and dispersed; the disease alternately 
 languished and revived; but it was not till the end of a calamitous period of 
 fifty-two years, that mankind recovered their health, and the air resumed its 
 pure and salubrious quality. No facts have been preserved to sustain an account, 
 or even a conjecture, of the numbers that perished in this extraordinary mor- 
 tality. I only find that during three months, four and at length ten thousand 
 persons died each day at Constantinople, that many cities of the east were left 
 vacant, and that in several districts of Italy, the harvest and the vintage withered 
 on the ground. The triple scourge of war, pestilence and famine afflicted the 
 subjects of Justinian, and his reign is disgraced by a visible decrease of the 
 human species, which has never been replaced in some of the fairest countries 
 of the globe. 
 
 This epidemic spread over the whole of Europe and it took more 
 than a century to reach England, where "it fabled long after in prose 
 and verse as the great plague of Cadwalader's time." Then for quite 
 a thousand years it reaped its periodic harvests as often as immunity 
 was lost in new generations. 
 
 In the fourth century the seat of government was removed to 
 Byzantium. It is probable that this change was, in part at least, 
 determined by the insalubrity of Italy. Early in the fifth century 
 Rome was pillaged, but the real conquerors of Rome were not the 
 Goths and Vandals, but malaria and the plague. Disease continued 
 to devastate Italy. Creighton says : 
 
 About the year 668 the English archbishop-elect, Vighard, having come to 
 Rome to get his election confirmed by the pope, Vitalanius, was soon after his 
 arrival cut off by the pestilence with almost all who had gone with him. Twelve 
 years after, in 680, there was another severe pestilence in the months of July, 
 August and September, causing a great mortality at Rome and such a panic 
 at Pavia that the inhabitants fled to the mountains. In 746 a pestilence is said 
 to have advanced from Sicily and Calabria and to have made such devastation 
 in Rome that there were houses without a single inhabitant left. 
 
THE PLAGUE 115 
 
 From that time on the plague periodically spread over Italy until 
 the seventeenth century, while malaria has been in continuous posses- 
 sion down to our own time. We are told that the epidemic of 1348 
 reduced the inhabitants of the Eternal City to 20,000. 
 
 We are familiar with the graphic description of the plague in 
 Florence by Bocaccio, who wrote: 
 
 Such was the cruelty of Heaven and perhaps of men, that between March 
 and July following, it is supposed, and made pretty certain, that upwards of 
 a hundred thousand souls perished in the city only, whereas, before that calam- 
 ity, it was not supposed to have contained so many inhabitants. What mag- 
 nificent dwellings, what noble palaces were then depopulated to the last person, 
 what families extinct, what riches and vast possessions left, and no known heir 
 to inherit, what numbers of both sexes in the prime and vigor of youth whom 
 in the morning neither Galen, Hippocrates nor Esculapius himself, but would 
 have declared in perfect health after dining heartily with their friends here, 
 have supped with their departed friends in the other world. 
 
 It is worthy of note that Guy de Chauliac, body physician to 
 Clement VI (pope from 1342 to 1352) recognized the two forms of 
 the plague. He wrote : 
 
 Pestis habuit duos modos. Primus fuit per duos menses cum febre continua 
 et sputo sanguinis. Et isti moriebantur infra tres dies. Secundus fuit per 
 residuum temporis cum febre etiam continua et apostematibus et anthracibus 
 in exterioribus, potissime in subaxellis et inguinibus. Et moriebantur infra 
 quinque dies. Et fuit tantae contagiositatis, specialiter quae fuit cum sputo 
 sanguinis, quod non solum morando, sed etiam inspiciendo unus recipiebat ab 
 alio. 
 
 There are but few passages in literature so tragic as the short 
 record of the plague of the fourteenth century begun by the friar of 
 Kilkenny, but soon interrupted by his death : 
 
 I friar, John Clyn, of the order of Friars Minor and of the convent of Kil- 
 kenny, wrote in this book those notable things which happened in my times, 
 which I saw with my eyes, or which I learned from persons worthy of credit. 
 And lest these things worthy of remembrance should perish with time and fall 
 away from the memory of those who are to come after us, I, seeing these many 
 evils, and the whole world lying, as it were in the wicked one, among the dead, 
 awaiting death as I have truly heard and examined, so have I reduced these 
 things to writing; and lest the writing should perish with the writer, and the 
 work fail altogether with the workman, I leave parchment for continuing the 
 
116 THE PLAGUE 
 
 work, if haply any man survive, and any of the race of Adam escape this pesti- 
 lence and continue the work I have commenced. 
 
 It is estimated that during the dark ages the average of human 
 life was less than twenty years. A high birth-rate was necessary to 
 keep the race alive, but notwithstanding this, Europe was sparsely 
 inhabited. At the time of the Norman conquest the inhabitants of 
 England numbered between two and two and one-half million, prob- 
 ably nearer the former, for they had not reached the greater number 
 a hundred years later. Creighton says : "It would be within the mark 
 to say that less than one-tenth of the population was urban in any 
 distinctive sense of the term. After London, Norwich, York and 
 Lincoln, there were probably no towns with five thousand inhabitants." 
 Indeed, urban life, as we now know it, was quite impossible in this 
 age of pestilence and would soon become so again were the functions 
 of preventive medicine relaxed. 
 
 Most of the great epidemics of the middle ages were designated 
 as pestilentia or magna mortalitas. In the most deadly visitations the 
 bubonic plague is so accurately described that there can be no doubt 
 about its identity, but it must not be supposed that the people enjoyed 
 any high degree of health even in those periods when this contagion 
 languished on account of exhaustion of susceptible victims. Ergotism, 
 under the name of Saint Anthony's fire, was endemic in France and 
 adjacent territories; Normandy was filled with lepers, but Christ's 
 poor were not confined to that country. England was regarded as the 
 special home of hunger, but abundance was a stranger to the masses 
 in every land. The mysterious sweating sickness, apparently brought 
 to England with Henry Tudor in 1485, developed in five distinct epi- 
 demics which were characterized by the fact that the mortality was 
 greater among the rich than the poor. Typhus, known as morbus 
 pauperum, prevailed largely in the jails, on ships and among the 
 squalid inhabitants of the cities. Even the discovery of America car- 
 ried to Europe the scourge of syphilis, which was spread over Italy 
 by the soldiers of Charles VIII, and within a few years reached the 
 most distant parts of Europe. Smallpox appeared in England in the 
 sixteenth century, having journeyed, according to the most reliable 
 authority, all the way from the Orient. That tuberculosis, diphtheria, 
 dysentery and other diseases, still with us, prevailed during the middle 
 
THE PLAGUE 117 
 
 ages is shown by the records, but they were overshadowed by the 
 higher mortality of those mentioned above. Improved agriculture has 
 extinguished the fire of St. Anthony, except in the most benighted 
 provinces of Russia. The great fire in London in 1666 destroyed the 
 infected rats and relieved England of the bubonic plague, which had 
 been endemic in that country since 1349. Something more than one 
 hundred years later the discovery of Jenner robbed smallpox of its 
 horrors, wherever vaccination is properly enforced. The investiga- 
 tions of Howard improved the sanitation of jails and workhouses, and 
 did much to eradicate typhus. 
 
 Bacillus. This was discovered and isolated by Yersin and Kitasato 
 independently in the epidemic in Cochin China, and at Hongkong 
 (1893-94). Since the descriptions given by these investigators did 
 not agree in every detail, it was suggested that the organisms obtained 
 by them are not identical, but subsequent studies have shown that 
 they are only slightly different strains of the same bacterium. The 
 bacillus is a short, plump rod with rounded ends and stains more 
 deeply at the ends than in the middle bipolar staining. In length it 
 varies from 1.5 to 1.7 of a micron and its breadth is about one-third 
 its length. However, it manifests marked morphologic variability, 
 coccus-like forms and long rods being found in the same body, also 
 in the discharge from buboes and in the sputum. The polymorphic 
 growth of this bacillus must be held in mind in making a microscopic 
 diagnosis, which is easily done by an expert. It takes the basic stains, 
 such as methylene blue, quickly and deeply. Gaffky recommends that 
 the dried smear be washed with 0.5 per cent, of acetic acid before the 
 stain is applied. It is non-motile, non-liquefying and may show a 
 mucous capsule. However, this is often not recognizable, unless it 
 be brought out by special methods. In the first description of his find, 
 Kitasato made it a motile organism, but subsequently it was shown 
 that such motility as it may manifest is wholly passive. It is sporeless, 
 but may remain viable in culture for four years. Most pathogenic 
 bacteria have their optimum growth temperature at, or slightly above, 
 that of the animal body. This is not true of the plague bacillus. It 
 grows at the temperature of man's body; otherwise it could not be 
 pathogenic to man ; but in artificial cultures it grows much more rap- 
 
118 THE PLAGUE 
 
 idly and abundantly some degrees lower. It grows, but Mess rapidly 
 still, at febrile temperatures. It develops on neutral and feebly alka- 
 line media and is an aerobe. On gelatin plates at 22 C. (71.6 F.) 
 it develops within three days fairly characteristic colonies. The super- 
 ficial ones project above the surface, are coarsely granular and par- 
 tially transparent. They do not liquefy the gelatin and the deep 
 colonies are in no way characteristic. In gelatin stick cultures, this 
 bacillus grows slowly, but uniformly along the line. In undisturbed 
 bouillon, a deposit forms; later the surface is covered, and stalactites 
 and stalagmites may develop. However, these formations, although 
 striking, are not confined to cultures of the plague bacillus. Hankin 
 uses for diagnostic purposes an agar containing from 2.5 to 3.5 per 
 cent, of salt. On this medium well-marked involution forms develop. 
 Swollen, spindle-shaped, and ovoid forms appear instead of the normal 
 rods. Other investigators claim that other bacteria grown on this 
 medium develop similar forms and that this test should not be relied 
 on for diagnostic purposes. However, this is largely a matter of 
 expert training. Hankin in the midst of the plague in India has in 
 all probability acquired an expertness which a European laboratory 
 worker with only old cultures at hand is not likely to secure after a 
 short series of tests. The plague bacillus grows abundantly on coagu- 
 lated serum, but offers nothing distinctive in such growths. It multi- 
 plies slowly in sterilized milk without coagulation, although there is 
 a slight development of acid. In peptone solution and on potato its 
 growth is slow and non-distinctive. 
 
 The bacillus may retain both vitality and virulence for a long time 
 in men and rats recovered from the disease. The organism carried by 
 these hosts, however, is not always virulent. Moreover, as a rule, men 
 and animals, recovered from the disease, are free from the bacillus. 
 Strong found that avirulent bacilli injected subcutaneously in apes 
 are wholly destroyed within twenty-four hours. As has been said, 
 cultures protected from drying and from the light may remain viable 
 after four years and, indeed, they have been reported as still virulent. 
 Old subcultures after many years become quite inert. While complete 
 desiccation soon destroys the bacillus, so long as moisture persists, its 
 destruction within a reasonable time is improbable. From this we 
 may deduce two practical lessons. The first is that plague pus or 
 
THE PLAGUE 119 
 
 sputum deposited on clothing may retain its vitality for months. The 
 second is that air-borne infection does not play an important role in 
 the distribution of this disease. The last statement must not be taken 
 as denying the possibility or even the probability of droplet infection, 
 especially in pneumonic cases. Direct sunlight kills speedily, the 
 time varying with the thickness of the layer. Speaking generally, 
 hours are necessary. An agar culture exposed to direct sunlight con- 
 tains virulent bacilli after two hours and bubonic pus placed on glass 
 and exposed directly to sunlight is non-virulent after about six hours. 
 Bouillon cultures used for immunizing purposes are sterilized by heat- 
 ing for one hour at 58 C. (136.4 F.). Boiling kills in one minute. 
 Dry heat at 100 C. continued for one hour kills the bacillus. Ordinary 
 methods of disinfection suffice to destroy this organism. 
 
 The virulence of this bacillus is quite variable. It is probably true 
 that the bacterium from any animal dead of this disease is pathogenic 
 to the rat and guinea-pig, but some strains retain their virulence 
 through many generations when grown artificially, while others soon 
 lose it. The virulence is more quickly lost at incubator than at lower 
 temperature. In order to preserve the virulence of cultures, passage 
 through susceptible animals should be resorted to from time to time. 
 Repeated animal passage may revive a failing virulence. 
 
 All rodents are susceptible to the plague bacillus, but between the 
 different species of these there are wide variations. The most sus- 
 ceptible is the rat, which suffers extensively from epidemics of this 
 disease and responds to every form of artificial inoculation. When the 
 plague virus is rubbed into the shaved or clipped abdomen of this 
 animal the bacillus finds its way through the skin, apparently when 
 there is no injury, and causes a general infection. When the skin is 
 pricked with the finest infected needle, the nearest glands become 
 swollen and the neighboring tissue edematous, while the infection 
 extends to other glands and soon a general infection is established. 
 The spleen is enlarged, the lungs and liver become hyperemic and 
 after death the bacillus is found in every part of the body. When the 
 injection is made into the peritoneal cavity, the bacillus passes through 
 the peritoneal walls, which seem only somewhat more moist than nor- 
 mal, and reaches the various organs. Given by mouth, the first visible 
 
120 THE PLAGUE 
 
 effect may be an enlargement of the cervical glands, or the mucous 
 membrane of the stomach and small intestine may become inflamed and 
 hemorrhagic and the mesenteric and other glands may be enlarged. 
 Either form of the disease may develop and in any case the disease 
 terminates fatally. When a dilute culture is painted on the mucous 
 membrane of the nose carefully to avoid abrasion or dropped into the 
 conjunctival sac, general infection, the pneumonic or the bubonic form, 
 develops. 
 
 McCoy found that the ground squirrel and the rock squirrel of 
 California are quite as susceptible as the rat. Strong and others in the 
 study of the Manchurian outbreak place the Siberian marmot in the 
 same list. All these animals develop epidemics of the plague. 
 
 The guinea-pig is slightly less susceptible than the above named 
 animals to the plague bacillus on inoculation. No outbreak of the 
 plague in the guinea-pig in its native state is recorded, but there was 
 an epidemic among these animals in the Zoological Garden at Sydney 
 in 1902. Both gray and white mice are susceptible and may acquire 
 the disease by feeding on infected material. Rabbits are somewhat 
 less susceptible than guinea-pigs and mice. They are killed by sub- 
 cutaneous inoculations, but are not affected by feeding. Cats may 
 acquire the disease through eating infected mice or rats. Hunter 
 reports such cases from Hongkong. Ferrets, also used in destroying 
 rats, may succumb when the feeding is long continued. Hyenas, 
 jackals and dogs are only slightly susceptible, especially by way of the 
 mouth. According to Toyama, the Japanese bat is quite susceptible. 
 Wilson reports an epidemic among hogs in Hongkong. Cattle, sheep, 
 goats and horses are not susceptible. Subcutaneous inoculations in 
 these animals are followed by local reactions, but general infection 
 does not result. The testimony concerning the susceptibility of birds, 
 reptiles, amphibians and fish is conflicting, but it seems to be safe to 
 say that these animals play no part in the distribution of the disease. 
 
 In his early work, Yersin observed that an unusual number of the 
 flies in his workroom died and later Nuttall showed that the fly may 
 be infected, fatally to itself and may distribute the disease. The 
 plague bacillus has been found in ticks, ants and lice. The role played 
 by the flea in this disease will be discussed later. 
 
THE PLAGUE 121 
 
 Apes resemble man in their susceptibility to plague, developing 
 both the pneumonic and bubonic forms. Epidemics among these ani- 
 mals have been reported. 
 
 Modes of Infection. According to Dieudonne and Otto there are 
 five geographical foci where the plague is endemic and from which 
 it is spread to diverse parts of the earth. Four of these are in Asia 
 and one in Africa. The first lies in the Kwen-Fun mountains in the 
 Eastern Himalayas. From this place the plague extended in 1893 to 
 Cochin China and Hongkong. The second is in the southwestern foot- 
 hills of the Himalayas. From this place the disease spread over 
 India, reaching Bombay in 1896 and at the same time it traversed 
 Persia and reached the Black sea, invading Russia by way of Samar- 
 kand. This focus has a population of about one million, and English 
 physicians have reported thirty smaller or larger epidemics in this 
 region between 1823 and 1897. Many of these resembled the black 
 death of the middle ages and were certainly the pneumonic form of 
 the plague. These epidemics affected both men and rats. Among the 
 latter there exists a chronic plague which serves to keep the bacillus 
 alive and virulent. 
 
 The third region is the most extensive, covering northern Mongolia 
 and the Kirghiz Steppes. From this locality the plague in highly 
 virulent form spread over Manchuria in the winter of 1910-11. The 
 infection of this region was first investigated in 1895 by two Russian 
 physicians who discovered what has since been known as the "tara- 
 bagan" plague. The tarabagan or Siberian marmot is a small animal, 
 widely distributed in the mountains about Lake Baikal and over the 
 high table-land of Western Siberia. It lives in large families in 
 excavations which they make and which are several feet deep. They 
 leave their homes in great numbers in the fall in search of food. They 
 are valuable on account of their fur and many of them, being ill with 
 the plague, are easily captured. It has long been known that men 
 become infected with a highly fatal disease in skinning the animals. 
 The bacillus, having found a human host, is spread from man to man. 
 The crowded life in small huts during the winter favors the spread of 
 the infection. Whole communities are wiped out and in fear many 
 flee to adjacent territory, carrying the disease with them. The mar- 
 
122 THE PLAGUE 
 
 mots die in great numbers and are eaten by dogs and wolves. It is 
 not known whether these animals are infected from such food or not. 
 It is not supposed that they play an important role in the transmission 
 to man. In man the pneumonic form of the plague is most in evi- 
 dence, and the bacillus is disseminated by droplets in talking, sneez- 
 ing and coughing. The cervical glands are often involved, the inguinal 
 less frequently. The fourth Asiatic focus lies in the mountains on the 
 southwest coast of Arabia in the region of Assir on the Red Sea. 
 This region has not been closely studied. The African nursery is 
 found in Uganda near the source of the White Nile. It is supposed 
 that this region is the breeding place of the pestilence which has given 
 Egypt an evil reputation for so many centuries. 
 
 The distribution from these centers and from secondary foci fol- 
 lows lines of traffic, penetrating distant lands and traversing the widest 
 seas. 
 
 The infection in man may be transferred directly from one to the 
 other. This is the chief method of spread in the pneumonic form. 
 The sputum is full of the bacilli and in crowded families droplet infec- 
 tion is most common. Among the more civilized and the better housed 
 peoples, this method of transmission is rapidly becoming less potent. 
 In 1900 out of 276 cases in Sydney there were only ten houses in 
 which more than one case developed. While "carriers" play an unim- 
 portant role in the transmission of the plague, it is known that those 
 recovering from the pneumonic form may suffer from a more or less 
 chronic bronchitis in which the sputum remains infective. The 
 bubonic form does not favor direct transmission, but in this form the 
 transfer may be indirect, by soiled clothing and infected houses. It 
 has long been known that poverty and hunger favor the spread of 
 this disease. Undoubtedly ignorance and filthy habits are also impor- 
 tant factors. The figures from Bombay show the following distribu- 
 tion per million among the several classes : Low caste Hindoos, 53.7 ; 
 Brahmins, 20.7; Mohammedans, 13.7; Eurasians, 6.1; Jews, 5.2; 
 Parsees, 4.6 ; Europeans 0.8. 
 
 The rat has long been suspected as playing a part in the distribu- 
 tion of this disease. In the great epidemics of the middle ages it was 
 observed that rats come from their holes, lose all fear of man, become 
 uncertain in movement and die in great numbers. The most ignorant 
 
THE PLAGUE 123 
 
 came to regard deaths among rats as foretelling the coming of the 
 plague and fled from their homes, when confronted with this evidence. 
 The discovery of the bacillus and the study of its effects on the lower 
 animals, as well as on man, has at least partially cleared up the 
 mystery, although there are still unsolved problems. Rodents are the 
 most active distributors of this disease. They carry the infection from 
 house to house, from village to village, and from home ports to distant 
 lands. The first appearance of the disease in a country previously 
 free from the infection occurs in those occupied about the docks, 
 receiving grain and other commodities from infected lands. Generally 
 before a case has occurred in man the wharf rats are observed to 
 behave peculiarly and then to die in large numbers. An infected rat 
 has landed from the ship and has infected others. How does one rat 
 infect others ? The most probable answer to this question is that the 
 sick new arrivals, one or more, have died and the natives have fed 
 on the corpse and acquired the infection in this way. While a hungry 
 rat may feed on the dead of its own species, it seems to prefer other 
 food. Moreover, in a dead rat the bacilli of plague do not retain their 
 virulence for many days, the exact time varying with the temperature. 
 While a rat may be infected by feeding on a dead fellow, it is much 
 more susceptible to inoculation through the skin. The conclusion is 
 that while this method of transfer may and probably does occur, it is 
 not the sole or even the most important method, and we shall look 
 farther. 
 
 The urine and feces of the infected rat may be deposited on grain 
 or other kinds of food and eaten by the native animal. This is a 
 possibility easily submitted to experiment. It has been tried and has 
 failed in all cases. Corn and other grains have been mixed with the 
 urine and feces of infected rats and fed to sound ones with wholly 
 negative results. 
 
 Rats serve as hosts to several parasites, among which is the rat 
 flea (Pulex cheopis) and possibly this may serve in the transfer of the 
 bacillus from one rat to another. In the first place this flea is taken 
 from an infected rat, examined and found to contain the bacillus of 
 plague. This seems to be a step in the right direction. Such a flea 
 is crushed, a needle touched with the material is used to prick a 
 healthy rat and this animal becomes infected and dies of the plague. 
 
124 THE PLAGUE 
 
 Infected rats are kept in one side of a cage, uninfected ones in the 
 other side. So long as the two are separated by a flea-proof partition 
 the infection is not transmitted. Even when the partition is made of 
 tangle-foot which catches the flea when it tries to pass to the other 
 side, the sound rat remains sound. When such a partition is removed, 
 the sound rat becomes infected. Rat fleas are captured and fed on 
 cultures of the plague bacillus and then freed in a cage occupied by 
 healthy rats which soon become infected. Infected rats are stripped 
 of all their fleas and then placed in cages with healthy ones, which 
 remain uninfected. Infected rats carrying their fleas are caged with 
 guinea-pigs, and the latter become infected. 
 
 These with many other variations on the experiment have been 
 made, and show conclusively that the plague is transferred from rat 
 to rat or from rat to guinea-pig by the bite of the rat flea. This 
 question is satisfactorily answered. 
 
 How is the plague transferred from rat to man? Evidently 
 experiment along this line might be open to serious criticism and we 
 must depend on observation, which is never so thoroughly convincing 
 as experiment. Will the rat flea bite man and if it does will such a 
 flea bearing the plague bacillus infect man? While we cannot use 
 man in this experiment, we may employ his nearest relative, the ape. 
 The rat flea does bite the ape, and if the flea is infected with the 
 plague bacillus its bite induces this disease in the ape. It is the testi- 
 mony of several observers that uninfected rat fleas, while preferring 
 their own host, will in its absence feed on man. 
 
 Liston reports that in a certain house in India on April 6, 1904, 
 many rats were found dead; on April 11 the house was so infested 
 with fleas that the occupants sought sleep on the veranda. On April 
 17, two of these people were stricken with the plague. On April 20, 
 thirty fleas were captured in this house and of these fourteen were 
 rat fleas, while of 246 fleas captured in uninfected houses, not one was 
 a rat flea. Tidswell of Sydney states that on a wharf where many 
 rats were dead he was violently attacked by fleas. 
 
 It has happened that in some localities rats die of the plague, while 
 there is no infection among men. This is explained by the absence 
 of the flea, which, while widely distributed, is not found on all rats 
 at all times. However, there is another factor which needs considera- 
 
THE PLAGUE 125 
 
 tion. In the transmission of the plague from rats to man by the flea 
 there is a time of variable length during which the flea is on neither 
 rat nor man. The duration and conditions of this interval are widely 
 variable and not equally favorable to the transmission of the disease. 
 In a hot, dry climate rat fleas soon die when detached from their hosts. 
 Local conditions may play an important role in the transfer of the 
 infected flea from rat to man. 
 
 I think that it must be admitted that the evidence in favor of the 
 possibility of the transfer of the plague from rat to man through the 
 flea is strongly positive. Whether this is accomplished through other 
 agencies or not is an open question. 
 
CHAPTER XIII 
 
 SYMPTOMATIC ANTHRAX 
 
 History. Under various names, such as "blackleg," "quarter evil" 
 in English ; "Charbon Symptomatique" in French ; and "rauschbrand" 
 in German, this disease has been a cattle scourge for centuries. We 
 owe our first and most valuable knowledge concerning it to French 
 investigators. As early as the eighteenth century it was shown by the 
 studies of Chabert and Boutrolle to be a specific disease. The most 
 thorough studies of the nineteenth century were made by Arloing, 
 Cornevin and Thomas of Lyons. As early as 1879 these men recog- 
 nized the infectious nature of the disease and began their work on the 
 bacillus, the pathology and the immunology of this pest. It is con- 
 fined to cattle and no case of infection in man has been observed. 
 
 The Bacillus. This organism is generally known as Bacillus 
 chauvei, from the distinguished French veterinarian Chaveau. It is 
 a large, spore-forming anaerobic bacillus, sometimes growing in chains, 
 but usually in separate rods. The diameter of the spores being much 
 greater than the breadth of the rod and the location being at or near 
 the middle, the spore-bearing rod has a peculiar appearance well 
 designated as "snowshoe" or "whetstone." In old cultures free spores 
 may be seen and sometimes are numerous. The spores are highly 
 resistant to heat and chemical disinfectants, and when a locality 
 becomes infected eradication of the disease is not easy. This organism is 
 is not nearly so virulent as the anthrax bacillus, one rod of which suffices 
 to infect a guinea-pig fatally, while many hundred rods of the symptom- 
 atic anthrax bacillus may fail to induce a like result. Infection fol- 
 lows subcutaneous and intramuscular injections. In guinea-pigs the 
 period of incubation after artificial inoculation runs from twelve to 
 twenty-four hours, depending on the amount and virulence of the cul- 
 ture employed. The animal ceases to feed and soon begins to develop 
 an edematous area about the point of inoculation. However, if this 
 be directly on the back, the edema is more marked on the sides than 
 
128 SYMPTOMATIC ANTHRAX 
 
 directly about the site of injection. At first the edematous areas are 
 soft and pasty ; later gas accumulates and they become crepitant. This 
 continues for from twenty-four to forty-eight hours, when the ani- 
 mal shows agonal breathing and dies either in convulsions or coma. 
 In certain instances the development of the infection is atypical. It 
 proceeds less rapidly, leads to the formation of an abscess and ulti- 
 mately ends in recovery. On necropsy the subcutaneous tissue is found 
 impregnated with bloody fluid and distended with gas. In the serous 
 cavities, pleura, peritoneum and pericardium, there are exudates, more 
 or less stained with blood and often coagulated. The heart is soft and 
 distended ; the liver and kidneys hyperemic ; the lungs anemic ; and the 
 spleen normal in size. This is practically the symptomatology of the 
 disease in cattle. Young animals are most susceptible and die within 
 a few hours after the first indication of being ill. The disease is widely 
 distributed and has been the cause of great commercial loss. It is most 
 prevalent during the summer and early fall and in low-lying meadows 
 and along water courses. Just how animals become infected is not 
 known, but it is generally supposed that the virus finds entrance 
 through some accidental wound. To one who has seen herds of calves 
 die within a few days from this disease, this explanation is not wholly 
 satisfying. It is not probable that all the animals in the herd, or even 
 a large percentage of them, carried accidental wounds at the same 
 time. No insect has been convicted of this crime up to the present 
 time. The infection is not transmitted by feeding and, strange to say, 
 animals bear without infection large intravenous injections of pure 
 cultures, provided that none of the fluid finds its way into the sub- 
 cutaneous tissues. 
 
 While epidemics have been observed only in cattle, possibly a few 
 in hogs, many animals are susceptible to direct inoculation into the 
 subcutaneous or muscular tissue. Rabbits, white rats, and mice are 
 refractory, but may succumb to large inoculations. 
 
 The bacillus grows best on a medium containing an emulsion of 
 brain tissue. As has been stated, it does not grow in the presence of 
 oxygen and deep intramuscular injections are more certainly fatal 
 than subcutaneous ones. Injections into serous cavities are generally 
 without effect. Bacilli introduced into these cavities are speedily 
 devoured by the phagocytes. When injected with lactic acid, which 
 
SYMPTOMATIC ANTHRAX 129 
 
 repels the phagocytes, the bacilli develop. Inoculations on the ears or 
 the tail induce only local reactions and cause a degree of immunity. 
 The farther from the root of the tail the less marked is the effect. 
 When an inoculation into the tail has been made and the site kept 
 covered with an ice bag, the area of involvement is restricted and may 
 escape detection. On the other hand, if the site of inoculation on 
 the tail be kept covered with warm poultices the area involved is more 
 extensive and a general infection may result. 
 
 Much has been done in the immunization of animals to this dis- 
 ease, although an ideal process has not been developed. The funda- 
 mental facts have been supplied by French investigators. At first they 
 employed intravenous injections of fully virulent, even spore-bearing 
 cultures. Cattle bear up to 6 c.c. of such cultures administered in 
 this way. A slight febrile reaction follows and after this the animal 
 is immune. As a laboratory method and in skilled hands this method 
 works, but it fails in unskilled hands in the field, because some of the 
 fluid is injected, not directly into the blood current but into the tis- 
 sues, and fatal infection follows. The second method consisted in the 
 subcutaneous inoculation of virulent cultures in the tail. In this local- 
 ity the organism develops slowly and the phagocytes finally destroy 
 them. A small pledget of cotton which has been moistened in a culture 
 is introduced under the skin on the tail. This method has been used 
 widely and successfully in Alsace-Lorraine and in Holland. A third 
 method consists in the employment of two vaccines. The first is a 
 culture heated for six hours at 100 to 104 C. ; the second is heated 
 for the same time at 90 to 95 C. These are dried, ground and dis- 
 tributed in packages bearing directions. The first vaccine is intro- 
 duced under the skin of the tail three hand's breadths from the root 
 and the second, ten to fourteen days later one hand's breadth from 
 the root of the tail. On account of the time required to make two 
 inoculations this method has been cut down to the use of one vac- 
 cine heated to from 95 to 100 C. and the inoculation is made on the 
 shoulder. 
 
 The method of Norgaard is followed by the Bureau of Animal 
 Industry in this country. The tissue of a fresh tumor is pulverized, 
 extracted with water and strained through cloth. The filtrate is dried 
 to a brown scale, which is sent out in packages with directions for 
 
130 SYMPTOMATIC ANTHRAX 
 
 using. The powder is dissolved in water, heated for six hours at 
 from 95 to 100 C, and injected into the animal. The number of 
 doses of this vaccine used annually in this country amounts to more 
 than a million and a quarter. This has greatly decreased the loss from 
 this disease. 
 
 In 1911 Foth announced the preparation of a superior vaccine for 
 symptomatic anthrax. Massive cultures are filtered through a hard 
 paper and the filtrate precipitated with alcohol. This precipitate pro- 
 tects both cattle and guinea-pigs, and its strength can be more accur- 
 ately determined than the older vaccines. However, its practical use 
 on a large scale has not yet been demonstrated. 
 
CHAPTER XIV 
 
 MALIGNANT EDEMA 
 
 History. This is a rare disease and it is impossible to secure any 
 exact information concerning its prevalence in past ages. In 1877 
 Pasteur introduced bits of putrid flesh under the skin of guinea-pigs 
 and rabbits, and thus induced a rapidly progressive disease character- 
 ized by the accumulation of fluid in the subcutaneous tissue. He was 
 able to transfer the disease from one animal to another and found 
 that it was due to a rod-shaped, spore-bearing organism which he 
 designated as Vibrion septique. In 1881 Koch continued this work 
 and since that time the disease has been known as malignant edema. 
 
 The Bacillus. It is still a question whether there is only one or 
 several closely related organisms capable of inducing this pathologic 
 condition. Even when the same strain is employed in experimental 
 inoculation, the effects are not always exactly the same. The fluid 
 which collects in the subcutaneous tissue may be only slightly, or 
 markedly, bloody and the infiltration may be accompanied by the 
 evolution of more or less gas. The typical bacillus is a rod with 
 rounded ends, slightly motile, growing in the absence of air, and 
 developing spores. It liquefies gelatin and blood serum, coagulates 
 milk and then digests the coagulum. It produces abundant gas in 
 media containing glucose and traces of gas in media practically 
 free from carbohydrates. Horses, cattle, hogs, and sheep are sus- 
 ceptible, but infection probably never occurs except through a wound 
 either on the skin or the mucous membrane. It is one of the sequelae 
 of castration in males and of birth in females among our domestic 
 animals, although even in these conditions it is quite rare. When 
 infected matter is taken into the alimentary canal it passes through 
 without doing harm unless there be some break in the mucous mem- 
 brane. When it infects man and the larger animals, the bacillus is 
 found abundantly in the edematous fluid, but seldom widely dis- 
 tributed through the body. This indicates that it kills by the elabora- 
 
132 MALIGNANT EDEMA GAS PHLEGMON 
 
 tion of a soluble toxin. In smaller animals, such as mice and guinea- 
 pigs, a general, systemic infection may develop. In some instances 
 the diseased condition becomes evident within a few hours after inocu- 
 lation. The tissue around the point of introduction becomes edema- 
 tous and the involved area rapidly extends and death may follow 
 within twenty-four hours. Outside of putrid flesh, the bacillus has 
 been found in polluted soil, in which the spores may retain both vital- 
 ity and virulence for a long time. The spores generally develop in the 
 middle of the rod, making it spindle-shaped. 
 
 GAS PHLEGMON 
 
 There are many related bacteria which when introduced through 
 wounds cause death of tissue with the evolution of gas. The best 
 known of these organisms are the following: 
 
 1. The Welch bacillus, discovered in 1891 and known as Bacillus 
 aerogenes capsulatus. 
 
 2. The Ghon-Sachs bacillus, isolated in 1903 from a patient in a 
 case of gaseous gangrene. 
 
 3. The Novy bacillus, found in milk in 1894 and described under 
 the name of Bacillus edematis maligni II. 
 
 4. Hibier's bacillus, found in 1894 in a case of gaseous gangrene, 
 developing after a complicated fracture in which the wound was 
 polluted with earth. 
 
 5. The Klein bacillus, found in the stool of a person suffering 
 from acute enteritis. 
 
 6. The Stolz bacillus, found in a case of gas phlegmon following 
 a fracture. 
 
 Besides the above and other related organisms, the colon and 
 proteus may develop gas phlegmon with rapidly progressive and 
 destructive changes under certain conditions, as for instance, in those 
 debilitated by diabetes. All of these, with the exception of the two 
 last mentioned, are spore-bearing, anaerobic organisms, which are 
 found in polluted soil and become infective only through wounds. The 
 mortality among the infected is high. 
 
CHAPTER XV 
 
 GLANDERS 
 
 History. As early as the fourth century the infective nature of 
 this disease was held by a few observing men. In the seventeenth 
 century Solleysel taught that glanders is highly infectious, may extend 
 from stall to stall, and that the air becomes impregnated with the 
 infection. In the next century certain French veterinarians recom- 
 mended that diseased horses should be isolated, observed, and if found 
 to have glanders should be killed. In the last decennium of the eight- 
 eenth century a Danish veterinarian, Viborg, inoculated sound horses 
 with pus, blood, nasal secretions, saliva, urine and perspiration from 
 glandered animals, and succeeded in transmitting the disease. He 
 showed that heat destroys the infective agent. Later it was shown 
 that donkeys, goats, sheep, dogs, cats, rabbits and guinea-pigs are 
 susceptible. This work led to experiments with the view of disinfecting 
 the discharges and stalls which had been occupied by diseased ani- 
 mals. Chaveau showed that the infection is carried, for the most 
 part at least, in the corpuscular elements of the discharges. In 1881 
 Babes and Havas of Roumania found bacilli in the pus from an abscess 
 on a man who had the disease. Bouchard and others saw the organ- 
 ism, but its isolation and identification resulted from the work of 
 Loffler and Schutz (1882). Certain cases of glanders remained diffi- 
 cult of diagnosis because of the organs involved, there being no avail- 
 able discharge. The discovery of mallein by two Russian physicians 
 in 1890 and the demonstration that this is a valuable diagnostic agent, 
 as tuberculin is in tuberculosis, made the recognition of these occult 
 cases possible and aided greatly in the restriction of the disease. Acute 
 glanders, which is seen both in men and horses, is a rapidly fatal dis- 
 ease. After a short (from two to five days) incubation period the 
 temperature often becomes very high (106-107 F.), there is marked 
 prostration and great pain in the joints and limbs. Local ulceration 
 deepens rapidly and boils and abscesses appear on various parts of 
 
134 GLANDERS 
 
 the body and rapidly destroy skin, subcutaneous tissue and muscle, 
 exposing blood vessels, tendons and bones. Death usually occurs in 
 from one to three weeks. The most frequent primary lesion is in the 
 nose, though it may occur in the larynx, lungs or from a wound on 
 any part of the body. In about 90 per cent, of the cases, the course 
 is chronic and may continue for years. The chronic form in man is 
 by no means always fatal, the percentage of recovery given by 
 Bellinger being as high as 50 ; but no one else agrees with this estimate. 
 
 The Bacillus. Bacillus mallei is a slightly bent rod with rounded 
 ends, whose length varies from one to two-thirds the diameter of red 
 blood corpuscles. It is sporeless, non-motile and non-liquefying. It 
 takes the ordinary basic stains, as methylene blue and gentian violet, 
 fairly well, but when intensive coloring is desired it is better to select 
 a stain containing a mordant, such as carbol-fuchsin. The stain is 
 easily removed with dilute mineral acid. This bacillus grows on all 
 ordinary culture media without characteristic appearances except 
 on potato. On the second day a typical potato culture shows a hard, 
 yellowish, transparent growth. This general appearance, which has 
 been likened to that of a layer of liquid honey, continues until from 
 the sixth to eighth day, when the transparence gradually disappears 
 and the color takes on a red tint resembling that of cuprous oxid. 
 The boundaries of the growth show a slightly greenish tint, while the 
 uncovered surface of the potato is grayish white. While the growth 
 on potato is quite unusual, it is not sufficiently characteristic to form 
 the sole basis in identification. For a sporeless organism, it may, when 
 protected from the light, retain its vitality for an unusually long time. 
 Wladmiroff states that the organisms from glycerin-bouillon tubes, 
 with the ordinary cotton plug, were found viable after four years. 
 Direct sunlight destroys this organism within from a few hours to a 
 few days depending on the thickness of the layer and the intensity of 
 the light. Bacillus mallei is rather resistant to mercuric chlorid, but is 
 easily destroyed by phenol (2 per cent.), zinc chlorid (2 per cent.), 
 and lime water (saturated solution). The disinfection of stables with 
 gaseous agents is, as a rule, not feasible on account of the openness of 
 barns. Saturated lime water is the best thing to use. 
 
 Avenues of Infection. Many experiments have tested the possi- 
 bility of glanders infection through the unbroken skin, and while the 
 
GLANDERS 135 
 
 results are negative so long as the skin remains without a break, a 
 minute lesion, enough to offer an atrium to a bacillus, is easily made. 
 Babes and Cornil rubbed an ointment containing the bacilli on the 
 shorn abdomen of guinea-pigs and succeeded in infecting them, prob- 
 ably through the hair follicles or some lesion not recognizable. It 
 seems also probable that the unbroken mucous membranes of the nasal 
 cavities exclude the bacilli, but in neither man nor horse is this struc- 
 ture likely to remain without microscopic lesions for any great length 
 of time. This is especially true of the horse, on account of the char- 
 acter of its food. Beards and husks and dust are constantly being 
 inhaled while the animal eats, and injury of the mucous membrane 
 of the upper air passages is a frequent occurrence. The mucous mem- 
 brane of the mouth is scarcely less exposed to slight but frequent 
 insult. That the glanders bacillus may find its way through the intes- 
 tinal walls, leaving no recognizable lesion, and first manifest itself 
 in the lungs has been demonstrated by the researches of Nocard. 
 Although LofHer reports a case of human infection through milk, the 
 instance is questioned because other sources of infection were not 
 excluded. Under Viborg's efforts one hundred army horses, found 
 to be infected, were slaughtered in Copenhagen and their flesh used as 
 food without ill effects. Similar instances on a smaller scale have 
 been reported elsewhere. The possibility of intr^-uterine infection in 
 case of a diseased mother is recognized and, indeed, such cases have 
 been reported in both France and Italy. Of all domestic and men- 
 agerie animals, cows and the house rat are the only ones that are 
 known to be immune to glanders, although others differ much in 
 degree of susceptibility. 
 
CHAPTER XVI 
 
 BOTULISM SAUSAGE POISONING 
 
 History. In certain parts of Germany, especially in Wurtemburg 
 and neighboring sections of Baden and Bavaria, where sausage, a 
 favorite article of diet, is imperfectly cured and eaten raw, poisoning 
 from this article of diet has long been known. Other foods, as meats, 
 especially pork and fish, and vegetable preparations sometimes pro- 
 duce alarming and even fatal illness. As a rule, the foods which prove 
 harmful are those which have been prepared for a relatively long 
 time before they are eaten. The term "botulism," as here used, does 
 not cover every form of food poisoning, but only those in which the 
 poisonous substance is the product of a certain organism. In 1895 
 some thirty cases of food poisoning occurred in a small Belgian village 
 and were investigated by Van Ermengem of Ghent. The food in this 
 case was a ham which had been kept in a dilute brine. It was from 
 a sound animal, a part of which had been eaten in the fresh state 
 without harm. In fact, the companion ham from the same brine had 
 been eaten without disturbing those who partook of it. The sound 
 piece lay near the surface and was not fully covered by the brine. 
 The faulty ham was on the bottom of the vat and completely excluded 
 from the air. It was not noticeably decomposed, but was marked by 
 soft, colored spots and the odor of butyric acid. In it the Bacillus 
 botulinus was found. A watery extract from the meat was injected 
 into various animals and found to be intensely poisonous. In cats, 
 it caused dilatation of the pupils, an abundant mucus secretion in 
 the mouth and pharynx, prolapse of the tongue, roughness of the voice 
 followed by complete aphonia, difficulty in swallowing and paralytic 
 symptoms, followed by death in from four to eight days. Mice, 
 guinea-pigs, rabbits and apes were affected in much the same way. The 
 last-mentioned animals were found to be equally susceptible when 
 fed with the meat or its extract, while cats, rats, dogs and chickens 
 were not susceptible by the mouth. Some five years later, another 
 ham kept under similar conditions had a like effect and contained the 
 
138 BOTULISM 
 
 same organism. Later still, other small outbreaks have been studied 
 and the bacillus botulinus found in all. 
 
 The Bacillus. This is a rod (from 4 to 6 microns long by 0.9 to 
 1.2 of a micron broad) with imperfectly rounded ends. It often 
 appears in chains formed of two or more rods, attached end to end. 
 It is slightly motile, carrying from four to eight flagellae. It forms 
 spores, which for the most part are terminal, rarely central. It takes 
 ordinary stains easily and is strictly anaerobic. In pure cultures it 
 will not grow in the presence of air, but in mixed cultures it may 
 do so, the other organisms consuming the oxygen. It develops gas, 
 especially in media containing grape-sugar or other carbohydrate. 
 It grows only feebly at the temperature of the animal body. Special 
 interest attaches to this bacillus because it is not a pathogenic, but 
 is a toxicogenic organism. When grown outside the body as in the 
 ham, it elaborates a poison or toxin and it is to this that its harmful 
 effects are due. It causes not an infection, but an intoxication. When 
 all the bacilli have been removed by filtration through porcelain, the 
 clear filtrate is just as poisonous as the original culture. Indeed, the 
 bacillus does not multiply in the animal body, or does so only to a 
 slight extent. Another very striking fact is that the soluble poison 
 affects many animals when taken by the mouth. Most toxins and 
 venoms are harmless when introduced into the alimentary canal, but 
 this is not. One one-thousandth of a cubic centimeter, and even a 
 smaller dose, of germ-free filtrate kills a rabbit. An effective anti- 
 toxin has been prepared and used. 
 
 It is to be remembered that it is not this organism which causes 
 most instances of food poisoning, in which nausea, vomiting, and 
 purging are prominent symptoms. Bacillus botulinus apparently is 
 not widely distributed. So far it has been found only once except in 
 food, and that was in the feces of hogs. As has been stated, it grows 
 only in the absence of air and it has been found in canned foods. In 
 such, it produces gas which bulges the ends of the can. In brine of 
 more than 10 per cent, strength it will not grow. It is of especial 
 interest because it is essentially a saprophytic organism, producing in 
 food, in the absence of air, a most potent poison which affects man 
 when taken into the stomach. 
 
CHAPTER XVII 
 
 MALTA FEVER 
 
 History. It has long been known that a fever prevalent on the 
 shores and islands of the Mediterranean differs from those of other 
 regions. It is not malarial, nor typhoid, nor typhus. It is a low, long- 
 continued fever with a low mortality and characterized by a chronic 
 course accompanied by slow but progressive emaciation. It has been 
 given many names, such as Malta, Mediterranean, Cyprus, Gibraltar 
 and Neapolitan fever. It has prevailed extensively on the island of 
 Malta and has afforded a field of research for English physicians sta- 
 tioned there. There have been some differences of opinion as to 
 whether or not it is included among the diseases described by Hippo- 
 crates. Since the means for its positive identification have been placed 
 in the hands of the profession, its distribution has been found to be 
 much wider than was formerly supposed. Besides the Mediterranean 
 shores, it has been found in India, China, the West Indies, South 
 America, the Philippines, and in Texas. Cases are reported in most of 
 the great ports of the world among those who have visited infected 
 regions. The specific cause was discovered by Bruce in 1887 in the 
 spleen of a man who died of the disease at Malta. 
 
 The Organism. This is known as Micrococcus melitensis and is 
 one of the smallest of the bacteria, having a diameter of about 0.4 of a 
 micron. It may be seen as isolated bodies, in twos, and in chains. On 
 certain media it is more ovoid than spherical and in this form it 
 is regarded as a bacillus. It is non-motile, save the molecular oscilla- 
 tions seen in all small suspended bodies, and takes the ordinary basic 
 aniline stains readily and deeply. On artificial culture media it 
 grows slowly with the temperature of the animal body as its optimum. 
 Under 6 and above 45 C. it does not multiply. It does not liquefy 
 gelatin and develops very slowly in this medium, requiring about five 
 days at 22 to show recognizable colonies. On agar plates the colonies 
 are not always visible to the unaided eye and when seen through a 
 
140 MALTA FEVER 
 
 low power appear much like minute drops of water. It is destroyed 
 by moist heat in about five minutes at 60 C. (140 F.), with dry heat 
 at 95 C. (203 F.) and by direct sunlight within from a few minutes 
 to an hour depending on the thickness of the layer and the intensity 
 of the light. It is quite highly susceptible to the usually employed 
 chemical disinfectants. However, in old cultures kept in the dark it 
 may retain its vitality for more than a year, especially when complete 
 desiccation is prevented by a rubber cap. In laboratory animals both 
 acute and chronic infections can be induced. For the production of 
 the former a relatively large inoculation is necessary. The weight 
 begins to fall in a few hours, then the temperature falls and rises. The 
 animal becomes weaker, develops general tonic convulsions and at last 
 falls into coma with low temperature, and dies. Necropsy shows a 
 general septicemia with frequent acute inflammation of the mucous 
 membrane of the urinary organs. 
 
 The chronic form, after an incubation of from two to three days 
 develops a remittent or intermittent low fever with slow progressive 
 emaciation. For months the animal may seem quite well, save for the 
 slow, continued wasting, when it dies suddenly. After death most of 
 the organs are found to be sterile, but usually the coccus in small 
 numbers will be found in the bone marrow or the kidneys, or in both. 
 Usually it is abundant in the urine during the whole course of the 
 disease. The spleen is generally found to be markedly enlarged, like- 
 wise some of the lymphatic glands. 
 
 Horses, donkeys, cattle, sheep and goats are susceptible to inocu- 
 lation. The study of this infection in goats is of special interest. In 
 these animals the disease is exceedingly chronic and seems to disturb 
 the animal but little. The temperature is not altered and there is not 
 always a decrease in weight. Frequently there is a dry cough. From 
 the end of the first to that of the third week the blood serum of the 
 animal promptly agglutinates the micrococcus. Indeed, this is the only 
 way in which Malta fever can be positively diagnosed in either man or 
 animals. In 1906 an English commission found one-third of the goats 
 on the island of Malta infected with this disease and the micro- 
 organism in the milk of one-tenth. The question of how the goats 
 become infected naturally is an interesting one. Experimentally this 
 is easily done through an abrasion and it is supposed that naturally 
 
MALTA FEVER 141 
 
 it occurs in the same way. The hands of the milker, moist with the 
 infected milk of one animal may easily transfer it to another. The 
 udders of Malta goats are unusually large and in some drag on the 
 ground. They generally show slight wounds, and through these the 
 virus may easily find its way from the hands of the milker. Biting 
 flies have been suspected and have been examined with negative 
 results. 
 
 Man and apes are easily infected by feeding. Of twenty-eight apes 
 fed with infected milk, twenty-six developed the disease. The course 
 is shorter and the fever higher in apes than in man. The milk of 
 infected goats is often a pure culture of the coccus and it may be that 
 man occasionally receives the virus through minute wounds ; the great 
 source of infection is the drinking of milk. There are several illus- 
 trations of infection from drinking milk. In 1905 the Nicholson sailed 
 from Malta with sixty-five milk goats. The first destination was 
 Antwerp. Of the ten men who drank the raw milk from the goats on 
 this voyage, eight developed Malta fever within from eighteen to 
 thirty-four days after leaving Malta. From Antwerp the Nicholson 
 proceeded to New York. The captain and crew used the goats' milk 
 on this trip and subsequently many of them developed the disease. 
 Five of the goats died between Malta and New York, and of the sixty 
 placed in quarantine, thirty-two were shown to have Malta fever by 
 the agglutination test and the coccus was found in the milk of several. 
 In 1910 an epidemic of Malta fever appeared in the valley of Cavenne 
 following the importation of goats from the island and the use of 
 their milk. Malta fever, formerly frequent among English soldiers 
 and sailors stationed at Malta, has disappeared on the discontinuance 
 of the use of uncooked milk from goats, while it has continued among 
 the natives who still use the raw milk. 
 
CHAPTER XVIII 
 
 PNEUMONIA 
 
 History. As early as 1878 Klebs observed and briefly described 
 an organism found in the bronchial content after death from pneu- 
 monia. In 1880 Pasteur experimented with a micrococcus found in 
 the saliva of a boy under treatment for hydrophobia, found it to be 
 highly pathogenic to rabbits and designated it microbe septicemique 
 du salive. About the same time Sternberg gave an accurate descrip- 
 tion of the morphology and pathogenicity of an organism found in 
 the saliva of healthy persons. In 1882-83 Friedlander studied the 
 sputum during life and the bronchial and alveolar contents after death 
 from pneumonia and found the same organism that had been seen 
 by others, and for a time it was known as the capsule bacillus or 
 Bacillus Friedlander. Simultaneously with Friedlander, Talamon not 
 only observed the lanceolate bacillus, but grew it in artificial media. 
 In 1884 A. Frankel reported the rinding of this organism in the sputum 
 of normal persons and in that of those suffering from pneumonia. 
 He observed the great differences in virulence of the strains obtained 
 from these sources, demonstrated their effects on rabbits and mice, 
 and, in fact, gave the most complete report made up to that time on 
 the organism now known as "Frankel's bacillus" or the pneumococcus. 
 Frankel in his early papers held that the pneumococcus is the sole 
 cause of pneumonia. Possibly it was this positive, but erroneous, 
 statement which succeeded in fastening the name of Frankel to the 
 bacillus. Certainly he was not the first to see it, or grow it, or to 
 demonstrate its effects on animals ; and he was in error in his claim 
 that it is the sole cause of pneumonia. Indeed the work done by 
 Weichselbaum about the same time was more thorough and, as subse- 
 quent studies have shown, more accurate. The last mentioned 
 observer held that while pneumonia is usually caused by the pneumo- 
 coccus, it may result from infection with streptococci and other bac- 
 teria. This is now generally recognized. 
 
144 PNEUMONIA 
 
 The Bacillus. The pneumococcus, known also as Diplococcus 
 lanceolatus, and Diplococcus pneumoniae, is a small lanceolate organ- 
 ism, often with spherical and ovoid individuals. It presents marked 
 variations in shape and size, but as a rule the number of typical indi- 
 viduals renders indentification easy. It is non-motile and takes the 
 ordinary stains easily. It is a capsulated bacillus and when in diplo- 
 coccus forms, both individuals are enclosed by the same capsule. In 
 chain forms, not commonly seen, several links in the chain may be 
 covered by the same capsule. The formation of the capsule is depend- 
 ent on conditions. Highly virulent organisms taken from the animal 
 are capsulated. On the other hand, subcultures grown on artificial 
 media through many generations have no capsules or show imper- 
 fect ones. Growth in blood serum seems to favor capsular develop- 
 ment. It seems most probable that the formation of the capsules is 
 a protective function. The pneumococcus grows on ordinary culture 
 media, but not abundantly, and is highly susceptible to slight modi- 
 fications in composition and reaction. Fresh cultures do not develop 
 on gelatin below 24 C, but old subcultures grow at temperatures as 
 low as 20 C. There is no liquefaction. After twenty-four hours in 
 the incubator, bouillon tubes are slightly cloudy and may show a 
 flocculent deposit. As a result of the autolysis of the cells the bouillon 
 may partially clear up after some days. On account of the low spe- 
 cific gravity of the cells a high speed is necessary to completely deposit 
 the organism in a centrifuge. On potatoes there is often no growth, 
 sometimes a slight, scarcely visible coat. In milk this bacterium 
 develops with a scanty production of acid which may suffice to 
 coagulate. Media containing from 4 to 6 per cent, of glycerin and 
 those containing blood or serum furnish richer growths. Old sub- 
 cultures develop on artificial media more rapidly and abundantly 
 than fresh, virulent cultures. Air supply has no marked effect, one 
 way or the other, on the growth of this organism. It needs frequent 
 transplantation in order to preserve both viability and virulence. It 
 is easily destroyed by the ordinary disinfectants, both liquid and 
 gaseous. 
 
 There is probably no other pathogenic bacterium of such diver- 
 gent virulence as this. I have worked with two strains, one of which 
 is fatal to guinea-pigs after intraperitoneal injection only in doses of 
 
PNEUMONIA 145 
 
 1 c.c. or more of a twenty-four-hour bouillon culture, while 
 0.0000001 of this amount of the other kills in the same time. 
 The virulence may be intensified by repeated passage through animals, 
 but there is great difference in the degree with which different strains 
 hold their virulence. Some of high power rapidly lose from gen- 
 eration to generation, while others remain fairly steadfast through 
 many successive generations. The difference between strains of low 
 and high virulence seems to be in rate of multiplication. Two guinea- 
 pigs are treated at the same time with the two strains mentioned 
 above. The size of one dose is 0.0000001 that of the other, 
 and still the animals die at the same time and the growth in one is 
 found after death to be as great as that in the other. It seems from 
 this that the more virulent strain has multiplied much more rapidly 
 than the other. Moreover, when large amounts of the cellular sub- 
 stance of both are obtained and split up chemically, the yield of poison 
 by the two, per gram, is the same. This certainly is strong evidence 
 that difference in virulence is determined by rate of growth. 
 
 While the pneumococcus is quite labile in structure, under certain 
 conditions, it easily undergoes autolysis and is destroyed quickly by dis- 
 infectants. Samples of sputum have been found to retain virulent 
 cocci for months. All sputum should be burned or otherwise destroyed. 
 Floors and sidewalks are not proper receptacles for expectoration from 
 either the well or the sick. 
 
 It is a matter of scientific interest that bile not only destroys but 
 dissolves living, virulent pneumococci. On dead and non-virulent 
 cultures bile has no such action. This solvent effect has been found 
 to be due to the bile acids. Since most other pathogenic bacteria 
 easily multiply in undiluted bile, this effect on pneumococci is striking 
 and interesting, although it is not known to be of any practical 
 importance. 
 
 The laboratory animals most susceptible to the pneumococcus are 
 the rabbit and the mouse. Fresh cultures in bouillon containing 10 
 per cent, of ox serum kill these animals on subcutaneous or intraperi- 
 toneal inoculation in doses as small as 0.0000001 c.c. However, animals 
 thus treated do not develop pneumonia, but die of general septicemia. 
 It has been found by examination of the sputum and by lung puncture 
 that the virulence of the coccus abates day by day as the disease 
 
146 PNEUMONIA 
 
 develops. Pulmonary hepatization has been induced in rabbits by 
 tracheal, intrapleural and intrapulmonary inoculations with less viru- 
 lent cultures. Rats are but little less susceptible than rabbits and 
 mice, then follow guinea-pigs, dogs, cats and sheep. In the less sus- 
 ceptible animals local lesions are more common than in the more 
 highly susceptible. This raises the question of the relative susceptibility 
 of man. It is reasonable to suppose that man is quite refractory, com- 
 pared with rabbits and mice, to the pneumococcus. He generally carries 
 the organism in his mouth, but becomes infected with it only under 
 certain conditions. It does not induce a general septicemia in man. 
 Klemperer has shown that a culture highly virulent to rabbits is fol- 
 lowed by only a local reaction when injected subcutaneously in man. 
 Spontaneous and epidemic pneumonia has been observed in guinea- 
 pigs and the disease has been induced in these animals by inhalation 
 and by intratracheal and intrapulmonary inoculations. The pneumonia 
 thus induced may be either acute or chronic. It often involves several 
 lobes and presents the anatomic characteristics of a catarrhal rather 
 than a croupous process. It is generally fatal. 
 
 The question of the production of a toxin by the pneumococcus has 
 been the basis of much experimental work. The evidence supplied by 
 these experiments seems to show quite conclusively that this organism 
 elaborates or secretes no true toxin like that of the diphtheria bacillus, 
 but like all bacterial proteins it does yield a poison when properly 
 disrupted. When suspended in salt solution the cells easily and quickly 
 undergo autolytic changes whereby a poison is liberated. This has 
 been conclusively demonstrated by the work of Rosenow and others. 
 
 That a certain degree of active immunity to this organism can be 
 established in rabbits and other animals seems to have been demon- 
 strated. For this purpose, heated sputum, heated cultures, cultures 
 attenuated by phenol, cocci dissolved in bile, and the residue left after 
 autolysis have been employed. One attack of the disease in man 
 confers at least no lasting immunity, and often appears to render the 
 individual more susceptible. That the sera of immunized animals 
 have some protection and even some curative value in the disease in 
 both man and animals seems to be demonstrated, but that such sera 
 have true antitoxic values is certainly not demonstrated. Some claim 
 that the sera of immunized animals have a bactericidal action, 
 
PNEUMONIA 147 
 
 while others think that they only render phagocytic action more effec- 
 tive. The best pneumococci sera either in the fresh state or after 
 the addition of complement do not destroy the organism. They may 
 possibly stimulate the phagocytes or they may render the cocci more 
 susceptible to the phagocytes. In order to be of service either in 
 prevention or treatment, a relatively large amount of the immune 
 serum must be used. In other words, a certain degree of concentra- 
 tion must be reached. The law of multiple proportions which holds 
 good between diphtheria toxin and antitoxin fails here. Some have 
 found that the immune sera which they have studied are effective 
 only against those strains used in immunizing the animals and this 
 view has induced attempts to secure polyvalent sera, but up to 
 the present time these cannot be pronounced successful. 
 
 Neufeld and Handel, in a discussion of the value of pneumococci 
 sera, conclude that experiments on animals have shown that such 
 have not only a protective but a curative effect on both septicemic 
 processes and pneumonia, but not until the dose is large enough to 
 reach a certain concentration in the body. 
 
 Some of the strongest opponents of the phagocytic theory admit 
 that natural immunity to this disease is due to phagocytic action and 
 that extracellular destruction of the pneumococcus has not been dem- 
 onstrated. Furthermore, they state that even normal serum in large 
 doses protects animals against this infection. 
 
 Inasmuch as a large proportion of healthy people carry the pneumo- 
 coccus in their mouths and throats, the question of what happens when 
 one develops the disease, becomes one of both practical and scientific 
 interest. Several possibilities suggest themselves. In the first place, 
 while this organism is found in most cases of lobar pneumonia, it is 
 not found in all instances. Moreover, while frequently present in 
 other forms of pneumonia, it is not so constantly present in these. 
 The best of evidence exists for the statement that true croupous 
 pneumonia may be due to other bacteria, such as the pneumobacillus, 
 Streptococcus pyogenes and Streptococcus mucosus. These facts have 
 led some to believe that pneumonia may be due to the conjoint activity 
 of two or more organisms, but no two of these are constantly found 
 and there seems to be no substantial basis for this idea. A second 
 possibility is that the pneumococcus normally present in the saliva 
 
148 PNEUMONIA 
 
 does not cause pneumonia and that the disease results only when one 
 harbors a more virulent strain. Those who hold to this theory insist 
 that disinfection of all pneumonia sputum and the isolation of those 
 suffering from this disease should be rigidly enforced. Opponents of 
 this theory point out that such measures do not lead to a decrease in 
 the prevalence of this disease. They say that while isolation and dis- 
 infection are followed by a decrease in other infectious diseases, they 
 have had no such effect on pneumonia. A third possibility is that 
 the pneumococcus so constantly the guest of man, becomes virulent 
 when for any reason the vitality of the individual is lowered. To-day 
 this is the prevalent belief and it must be added that it has much sup- 
 port. The frequency with which pneumonia develops after exposure 
 to cold is generally admitted. That form of pneumonia which follows 
 injury to the lung tissue, known as traumatic pneumonia, and the fre- 
 quency and the great fatality of this disease among chronic alcoholics 
 and in the general enfeeblement of old age are illustrations. The safest 
 plan is to isolate the pneumonia patient, to disinfect his expectoration, 
 and to avoid all conditions which render the body more susceptible to 
 this and other bacteria, which may cause this disease. However, it 
 must be added that the epidemic character frequently exhibited by 
 pneumonia leaves no doubt in my mind that exposure to an unusually 
 virulent strain of the pneumococcus is an important factor in the 
 distribution of this disease. 
 
CHAPTER XIX 
 
 TETANUS 
 
 History. A disease with such striking, distressing and fatal symp- 
 toms, as those characteristic of lockjaw, could scarcely escape observa- 
 tion and comment whenever seen. It is not, therefore, surprising that 
 the medical records of Greece and Rome supply details of the symptoms 
 and notes of the great fatality of this disease. However, in all ages 
 it has been relatively rare except in certain restricted localities. It was 
 a matter of early record that tetanus was in some way connected 
 with wounds. It was seen to be more common in military than in 
 civil life and in the latter it most frequently follows injury. Before 
 the development of experimental medicine, theories concerning the 
 causation of this disease were many and diversified. It was soon 
 seen that while it generally followed injuries, it did not follow all, and 
 that there was no relation between the severity and extent of the injury 
 and the development of tetanus. The infectious nature of the disease 
 was first emphasized by French physicians, especially Verneuil. How- 
 ever, the first positive demonstration of its infective character was 
 made in 1884 by two Italian physicians, Carle and Rattone, who inocu- 
 lated twelve rabbits with matter taken from an acne pustule on a man 
 with tetanus. Within two or three days, eleven of the animals thus 
 treated developed the disease. Furthermore, they succeeded in trans- 
 ferring the infection to other animals. Soon thereafter, Nicolaier 
 induced tetanus in rabbits, guinea-pigs and mice by inserting bits of 
 earth under the skin. He also found the specific bacillus and grew it 
 in mixed cultures, but failed to separate it from associated bacteria. 
 This was done by Kitasato. 
 
 The Bacillus. Kitasato found that the tetanus bacillus grows only 
 when the air is excluded and that it forms spores which are markedly 
 resistant to high temperature. He smeared the infected material on 
 agar, kept the tubes at incubator temperature for two days, the time 
 required for the bacilli to develop spores abundantly, and then heated 
 
150 TETANUS 
 
 at 80 C. for one hour and allowed the spores which had withstood 
 this temperature to develop in an atmosphere of hydrogen. The high 
 temperature killed all the bacilli, both those of tetanus and other kinds 
 present, but did not destroy the tetanus spores. The bacillus is a 
 rod, from 2 to 4 microns long and from 0.3 to 0.5 of a micron broad. 
 It is feebly motile, carrying numerous flagellae and is often found 
 in chains. The bacilli develop terminal spores, spherical or oval bodies, 
 with a diameter larger than the breadth of the bacillus. This gives 
 to the spore-bearing orgainsm a drum-stick appearance. It is a 
 liquefying organism and takes the ordinary stains easily and distinctly. 
 It is strictly anaerobic, which accounts for the fact that the disease 
 develops most frequently in deep wounds with closed openings and 
 rarely in those in which the infecting material is freely exposed to 
 the air. Tetanus spores are among the most resistant forms of bac- 
 terial life. A splinter of wood bearing infected material may remain 
 a source of danger for many years. Direct sunlight kills the spores 
 within from two hours to many days, depending on the thickness of 
 the layer and the intensity of the light. They are destroyed by live 
 steam within five minutes; by 5 per cent, phenol after fifteen hours; 
 by mercury chlorid (1 : 1000) after three hours. 
 
 Tetanus spores are widely and unevenly distributed over the earth. 
 In some localities 100 per cent, of animals inoculated with earth 
 develop the disease, while in other places such inoculations wholly 
 fail. As a rule the spores are most abundant in filthy soil, especially 
 that impregnated with manure. Before the days of aseptic surgery, 
 tetanus was especially prone to follow operative procedures as was 
 noted by Larrey, Napoleon's great surgeon, and many other operators 
 both in the field and in the hospital. Among certain primitive and dirty 
 people tetanus of the newly born is frequent on account of the methods 
 of cutting and dressing the cord. On certain islands, as Reunion and 
 Cayenne, the infantile death-rate from this cause has in some years 
 been as high as 50 per cent. In other localities tetanus works havoc 
 among women in the puerperal state. Some savage tribes smear 
 their arrowheads with mud rich in tetanus spores. The marked mortal- 
 ity from Fourth of July celebrations in this country a few years ago 
 was due to tetanus infection. Fortunately, the barbaric rites with 
 which we were accustomed to celebrate the birthday of our nation 
 
TETANUS 151 
 
 have been beneficially modified, largely through the knowledge spread 
 by The Journal of the American Medical Association. The parts of 
 our country most abundantly infected with this virus seem to be the 
 Atlantic States, Long Island and the valley of the Hudson. Commer- 
 cial gelatin and catgut used by surgeons, have been the bearers of 
 this infection and most thorough sterilization is necessary in order 
 to destroy the spores. Formerly, we spoke of idiopathic and traumatic 
 tetanus. Now, we are quite sure that the former does not exist. 
 The wound may be so trivial that it has healed before symptoms of 
 tetanus develop. In other cases the wound may be not on the skin 
 but on a mucous membrane as in the mouth, nose or throat. I saw a 
 case in which the virus had entered through the gum from which a 
 tooth had been extracted. Some have claimed that tetanus is more 
 prevalent in black and mixed races than among whites and have 
 endeavored to show the existence of racial susceptibility. The truth 
 is that filthiness is the predisposing agent rather than a racial difference. 
 The simple custom of drying the wash by spreading the clothes on the 
 ground has been found to play a part in the prevalence of this disease. 
 
 The distribution of the tetanus virus seems to be world wide. It has 
 been found in every land and in many waters, such as those of Lake 
 Geneva and the Dead Sea. It may be present in bilge water and 
 ships may be generally infected. On one English ship, after a naval 
 battle, sixteen of the wounded died of tetanus. It may be carried 
 into wounds with bits of infected clothing, and it has been found on 
 nearly every article worn by soldiers from the shoes to collars. Virgin 
 forest soil has generally been found free from this virus, but the 
 sweepings from the streets, stables, houses, boats and cars frequently 
 produce tetanus when introduced under the skin of animals. 
 
 Of our domestic animals, the horse is the most susceptible and 
 is a frequent victim. The ox comes next on the list, followed closely 
 by sheep and goats. Dogs and cats are not easily infected, but do 
 succumb to inoculations. 
 
 When swallowed the tetanus bacillus has no effect .unless there be 
 some break in the mucous membrane, and it is eliminated with the 
 feces unchanged. In this way the fecal matter of man and animals 
 pollutes the soil. The tetanus bacillus produces a soluble toxin which 
 is one of the most potent poisons known. Injected into an animal, 
 
152 TETANUS 
 
 even in a dose of a fraction of a milligram, it develops tetanus after a 
 period of incubation of a few days. Great care should be used in the 
 employment of vaccines and sera for fear of inoculation with 
 tetanus. The vaccine may carry the infection or it may be introduced 
 later through the vaccine lesion. Such an accident occurred at Camden, 
 New Jersey, in 1901, when several children vaccinated against small- 
 pox developed tetanus and died. A similar misfortune was reported 
 from India in 1902. Out of a group of 107 persons vaccinated against 
 plague, nineteen died of tetanus. In St. Louis, diphtheria antitoxin 
 was drawn from a horse which was apparently well, but which devel- 
 oped tetanus a fe wdays later. Some of the children treated for 
 diphtheria with this serum died of tetanus. 
 
CHAPTER XX 
 
 STREPTOCOCCIC INFECTION 
 
 History. The streptococcus probably has a much longer ancestry 
 than man and began its assaults on the animal kingdom long before 
 there was any indication of the development of homo sapiens. The 
 unicellular has been the companion of the multicellular through all the 
 evolutionary forms of the latter. Man came into existence as a host 
 to the streptococcus and the victims of the microscopic parasite are as 
 innumerable as the sands of the seashore. Borne on the surface and 
 in the cavities of the greater, the smaller has always been ready to 
 find its way into the vitals of its host and to feed on blood and tissue 
 until the whole became its prey. In peace and in war, among the 
 good and the bad, the wise and the foolish, the streptococcus has always 
 been a factor in determining the mortality rates. As a primary infec- 
 tion there is no part of man's anatomy immune to the invasion of this 
 organism. As a secondary infection, it profits by the lesions induced 
 by other pathogenic bacteria. As a terminal infection, it swarms over 
 every part of dying man, and secures the greater part of the booty of 
 every war, whether waged by itself as principal, as ally or as guerilla. 
 In the earliest medical records wound infection is described. It became 
 the scourge of armies and the military hospital was often more dreaded 
 and more deadly than the field of battle. Indeed, there was a time 
 when all hospitals, both military and civil, became great incubators 
 for the growth and dissemination of pus germs. In the old Hotel Dieu 
 at Paris, the simplest amputations were followed by infection and in 
 a large number this terminated only in death. Even after the dis- 
 covery of surgical anesthesia, when operations were no longer forms 
 of torture, wound infection remained the horrid nightmare of the 
 surgeon. Happily the science of Pasteur and its application to surgery 
 by Lister, opened a new era in the history of surgery. In the first half 
 of the nineteenth century, Gaspard, Leurent and others taught that 
 wounds become infected with invisible organisms, but this was only 
 
154 STREPTOCOCCIC INFECTION 
 
 theory and at that time impossible to demonstrate. Pasteur undoubt- 
 edly in some of his early work saw pus organisms, but the credit of 
 identifying and describing them belongs to Ogston, who found that 
 some are spherical bodies arranged in chains while others are clustered 
 like grapes in a bunch. The former he designated streptococci and the 
 latter staphylococci. 
 
 The Organism. Streptococci are spherical or oval bodies, from 
 0.5 to 1.5 of a micron in diameter, arranged in chains of variable length. 
 Some strains show only short, and others only long, chains. Some 
 investigators regard these as different species, while others consider 
 them as only varieties. It seems most reasonable to look on the 
 streptococci as a great family with many subfamilies, and these may 
 show marked differences in form, in cultural characteristics, and in 
 virulence. All are non-motile and sporeless. Inasmuch as these organ- 
 isms induce suppuration, they are often designated as Streptococci 
 pyogenes, to which we may add longus or brevis, as the case may be. 
 Some authors divide them according to the tenacity with which they 
 cling together or the amount of mucus formed, thus providing a type 
 known as 5. mucosus. In the animal body the chains are generally 
 short, often being reduced to diplococci. In artificial cultures the 
 chains are often long and coiled in groups forming felt-like masses. 
 Cultures rich in peptone (as high as 5 per cent.) give the most 
 abundant growths. The presence of grape-sugar (from 0.2 to 2 per 
 cent.) favors growth, but the development of too much acid may prove 
 detrimental. Blood serum, either alone or in bouillon, is an excellent 
 medium, and strains obtained from man grow best on human serum, 
 and the same holds good for other species. The streptococcus does not 
 grow abundantly on ordinary solid media. The optimum temper- 
 ature is that of the animal body, but growth proceeds slowly at as low 
 as 15 and as high as 42 C. The streptococcus is a facultative anaerobe, 
 but different strains show wide variations under diverse air supply. 
 In general, however, in the presence of air this organism loses in both 
 viability and virulence. Different strains act differently on carbo- 
 hydrates and attempts at classification have been made on this basis, 
 but have led to no practical results. These are varieties which decom- 
 pose lactose and coagulate milk. A striking action is the hemolytic effect 
 
STREPTOCOCCIC INFECTION 155 
 
 of streptococci cultures. The capability of dissolving red corpuscles 
 was first noted by Marmorek in 1895, and has been the subject of 
 much study since that time. If a tube of bouillon to which 0.5 c.c. of 
 blood has been added be inoculated with the streptococcus and incu- 
 bated, in a few hours the corpuscles are completely dissolved, coloring 
 the whole fluid. On prolonged standing, the color becomes brown, 
 owing to the conversion of oxyhemoglobin into methemoglobin. It was 
 at first thought that the hemolytic action is due directly to the living 
 organism, but Besredka showed that germ-free filtrates of highly 
 active cultures are hemolytic. The hemolytic substance is highly labile 
 and is destroyed by a temperature of 60 C. It must be classed as a 
 ferment. Indeed, it seems that there are two ferments, one of which 
 dissolves the corpuscles, while the other converts the soluble oxyhemo- 
 globin into methemoglobin. Although this organism is sporeless, it 
 may not only live but retain its virulence for many months in cool, 
 dark places. Before the days of aseptic surgery, certain wards in 
 hospitals became infected with erysipelas and retained the infection 
 through long periods. Puerperal fever followed, or rather, accom- 
 panied, certain midwives and obstetricians from house to house until 
 they came to believe that some dreadful fate hung over them and in 
 despair fled from those who sought their services. Holmes collected 
 cases of this kind and concluded that puerperal fever and other forms 
 of sepsis are due to a contagium. The experiences of Semmelweis in 
 the old lying-in wards at Prague led him to the same conclusion, and he 
 pointed out that the obstetrician could not, with safety to those under 
 his charge, go from the dead room to the woman in labor without first 
 making himself clean. Moreover, he demonstrated in his own work 
 that cleanliness on the part of the accoucheur resulted in the reduction 
 of the number of cases of puerperal fever. 
 
 The streptococcus freshly taken from an infected man is not highly 
 pathogenic to laboratory animals. Large doses are necessary to fatal 
 infection and subcutaneous inoculations usually induce, at most, local 
 abscesses. When mice are inoculated at the root of the tail, the organ- 
 ism multiplies at the point, spreads through the connective tissue and 
 finally is carried by lymph and blood to various organs, and death may 
 result in three or four days, earlier with the most virulent strains. 
 With less virulent cultures a local abscess may develop and continue 
 
156 STREPTOCOCCIC INFECTION 
 
 active for weeks, during which time there is a slowly progressive 
 emaciation. Intraperitoneal injections induce fatal peritonitis. Ani- 
 mals have been infected by feeding experiments. In such cases the 
 primary infection develops in the small intestine, causing an acute 
 enteritis and followed by systemic infection and death. Repeated 
 passage through animals rapidly increases the virulence and in this 
 way cultures have been obtained which kill rabbits in doses of 
 0.0000001 c.c. However, not all strains can be developed to this 
 extent. Association with certain other bacteria, such as the proteus 
 and colon bacillus, is favorable to an increase in virulence. The pres- 
 ence of bile seems to have a like effect. The condition of the animal 
 influences the rate of increase in virulence. Starvation, overexertion, 
 and other depressing influences render the animal more susceptible. 
 The same is true of the condition of the infected tissue. Extensive 
 bruises, lacerations, and other injuries favor the growth of the strepto- 
 coccus. When implanted on a mucous membrane already irritated 
 by chronic catarrh, scarlet fever, or diphtheria, this micro-organism 
 multiplies with unusual rapidity and develops marked virulence. Each 
 species of animal seems to have its own strain of streptococcus. The 
 bacterium accommodates itself to its peculiar host and thrives best 
 on that species. Those strains found on man are more pathogenic to 
 man than those found on other animals, and when the virulence of 
 any strain is increased by repeated passage through a certain animal, 
 it is more pathogenic to that than to other species. 
 
 There is no tissue or organ of the human body immune to invasion 
 by this organism. When a virulent strain of the streptococcus finds its 
 way into the lymph vessels of the skin, erysipelas results. There is 
 marked migration of leukocytes to the infected area, which becomes 
 red and swollen and extends more or less rapidly. When experi- 
 mentally induced, the period of incubation varies from ten to sixty 
 hours. The injury done depends on the virulence of the infecting 
 strain and may be slight and superficial or it may be widely destructive 
 and fatal. The infection may extend to mucous surfaces, to internal 
 organs and to the brain and its membranes. A case of erysipelas does 
 not necessarily come from a preceding case of the same disease, for 
 the infection may be transferred from any pyemic or septic source 
 to the skin. Erysipelas may be acquired from puerperal fever or 
 
STREPTOCOCCIC INFECTION 157 
 
 the reverse may be true. This was suspected long before we had any 
 definite knowledge of bacteria. The village doctor of that time knew 
 that it was not a wise thing to attend a childbirth while he had patients 
 with erysipelas or scarlet fever, or while he was dressing infected 
 wounds. This indefinite knowledge of that time has been defined 
 by experiments. Erysipelas has been induced experimentally with 
 matter taken from wounds, from throats in angina, and from the 
 uterus in puerperal fever. All these and many other diseases are due 
 to the same organism and are mutually convertible one into another. 
 
 When the infection lies deeper and in the subcutaneous tissue, 
 diffuse phlegmon and widely extended abscesses with extensive 
 destructive changes result. With the infection in the larger lymph 
 vessels, lymphangitis and lymphadenitis occur. In these either the 
 streptococcus or the staphylococcus, or both, may be found. Other 
 skin affections due to the pus bacteria are acne, impetigo, erythema 
 and infectious purpura. From infected wounds a scarlatinous rash 
 may extend over the greater part of the body, and may lead to arthritis 
 and nephritis. 
 
 The streptococcus is frequently found in every part of the respira- 
 tory passages and it seems to play an important role in various inflam- 
 matory diseases of these parts. Whether the normal residents of these 
 surfaces become suddenly virulent or more virulent strains are intro- 
 duced, is not always easily determined. The streptococcic sore throat, 
 which has in recent years occurred in epidemic form and proved so 
 highly fatal, is believed to be due to the use of milk containing highly 
 virulent strains. There are reasons for believing that the essential, if 
 not the sole, causal factor in scarlet fever is a streptococcus. This 
 organism is found constantly in otitis media. Malignant endocarditis 
 and polyarthritis are due to virulent strains of the streptococcus. 
 Streptococcic pneumonia is recognized and may run either an acute or 
 a chronic course. The latter may resemble typhoid fever and the 
 intensity of the general symptoms may be out of proportion to the 
 physical, local findings. Purulent pleurisy is not rare. The part taken 
 by the streptococcus in the etiology of the summer diarrheas of infancy 
 seems to be important and market milk often contains virulent strains 
 of this organism. In inflammatory diseases of the udders of cows, 
 highly active strains of the streptococcus find their way into the milk. 
 
158 STREPTOCOCCIC INFECTION 
 
 In other cases the organism in the tonsils of the child may pass into 
 the intestine and induce a serious enteritis. From the intestine the 
 organism may pass into the blood and a systemic infection may result. 
 In such cases the streptococcus has been found not only in the stools, 
 but in the blood and urine also. 
 
 The secretions of the vagina, in both pregnant and non-pregnant 
 women, often contain streptococci, but for the most part, at least, these 
 are not numerous and are non-virulent. This is due to the fact that 
 under normal conditions the vaginal tract is self-cleaning and its 
 secretions are bactericidal. In the puerperal state, when bits of pla- 
 centa or membrane are left in the uterus, the streptococci normally 
 present may become virulent and may lead to a septic condition. It 
 is possible, therefore, for puerperal fever to develop without extrane- 
 ous infection. That this is not the usual way in which puerperal fever 
 originates is quite certain. A virulent strain is introduced shortly 
 before, during or after labor. It may happen before labor by vaginal 
 examination, by improper douches or by coitus. It may happen during 
 labor by some fault of the accoucheur. It may happen after labor by 
 improper douches or handling the parts. The obstetrician must guard 
 against both autogenous and exogenous infection. He must avoid 
 those conditions which tend to increase the virulence of organisms 
 normally present and he must prevent the introduction of virulent 
 cocci. Puerperal fever is not confined to the human species, but 
 occurs in cows and other domestic animals. Contagious coryza, the 
 pleuropneumonia of horses, and certain inflammatory diseases of the 
 udders of cows, are results of streptococcic infection. Moreover, 
 wound infection and sepsis are -frequent causes of death among all the 
 higher animals. 
 
 The streptococcus does not produce a soluble toxin in the sense 
 of that elaborated by the diphtheria bacillus. Its hemolytic product 
 is a soluble toxin, but the poisonous agent in the cellular substance of 
 streptococci is the protein poison. Filtrates from old cultures in large 
 doses kill animals, but there is nothing specific in this. Marmorek grew 
 cultures in blood serum for three months and found that the filtrate 
 killed animals, but the same result may be accomplished with many 
 non-pathogenic organisms. Baginsky and Sommerf eld grew the organ- 
 ism in strongly alkaline bouillon cultures for many weeks and found 
 
STREPTOCOCCIC INFECTION 159 
 
 that the filtrate, in doses of 5 c.c. intravenously, killed rabbits, but the 
 poison was not destroyed by boiling and, therefore, could not have 
 been a toxin. Moreover, the poison from egg white is quite as potent 
 as this. The poison in the streptococcus is that common to all proteins 
 and it is probable that when it is isolated the yield from the protein 
 substance of this organism will be less than the average from proteins 
 in general. In other words, the streptococcus is probably not rich in 
 poison. If it were otherwise, recoveries from streptococcic infection 
 would be less rare than they are. It is true that immune sera have 
 been prepared, their protective value demonstrated on animals and 
 their beneficial effects in man shown, but they do not act like anti- 
 toxins. They do not fulfil the law of multiple proportions. Their 
 beneficial effects, so far as they have any, are due to favoring phago- 
 cytosis and not to neutralizing a toxin. The immune sera are 
 obtained by treating animals with strains the virulence of which has 
 been greatly increased by passage through animals, and while certain 
 amounts of the serum are protective against certain doses of the 
 culture, when the latter remains small, multiple amounts of the serum 
 fail to protect against like amounts of the culture. Much credit is due 
 Marmorek, Tavel, Aronson, Menzer and others for the most careful 
 and scientific work in attempts to prepare curative sera against 
 streptococcic infection. Success in this would bring to medicine a 
 great triumph and to humanity a greater blessing, but it must be 
 admitted that, up to the present time, the problem remains without 
 practical solution, and prevention rather than cure must demand our 
 best efforts. 
 
CHAPTER XXI 
 
 STAPHYLOCOCCIC INFECTION 
 
 The Organism. In his study of wound infection, Ogston recog- 
 nized two groups of bacteria with different morphologic characteristics. 
 In one the cocci are arranged in chains, in the other they are in bunches. 
 The former he designated as streptococci and the latter as staphylo- 
 cocci. Of the staphylococci one group is chromogenic and the other 
 is not. The former is known as Staphylo coccus pyogenes aureus, and 
 the latter as albus. The staphylococci constitute a large group with 
 many varieties, differing more or less widely in cultural, tinctorial and 
 pathogenic properties. 
 
 The individual cocci are quite variable in size, which seems to be 
 influenced by food, age and temperature. They take the basic anilin 
 stains easily, also certain acid stains, and are slightly colored by hemo- 
 toxylin. The readiness with which such a variety of stains may be 
 employed has favored attempts to ascertain the finer structures of 
 these organisms. Some are convinced that the cocci consist of a distinct 
 membrane with protoplasmic content, while others find evidence of 
 well-defined nuclei. However, all of this work needs more extended 
 study before the conclusions reached by different observers can be 
 correlated and accepted. 
 
 The optimum growth temperature is that of the animal body, 
 though multiplication continues at temperatures as high as 43 C. and 
 as low as 10 C. Free oxygen is not essential and growth will proceed 
 in proper media in an atmosphere of hydrogen, but not in carbonic 
 acid, nitrogen or illuminating gas. It does not grow abundantly in 
 media containing no protein, but it may obtain its nitrogen from 
 ammonia salts, kreatin or asparagin. It develops abundantly in pep- 
 tone solutions, but this is not an essential constituent of nutritive 
 media. A feebly alkaline reaction is most favorable, but feeble 
 acid does not prevent growth. In bouillon at incubator temperature 
 multiplication proceeds with great rapidity ; one loop of such a culture 
 
162 . STAPHYLOCOCCIC INFECTION 
 
 twenty-four hours old may contain millions of living cocci. In milk 
 there is a slow evolution of acid and coagulation results after about 
 one week. It slowly liquefies gelatin by the formation of a peptonizing 
 ferment This ferment converts proteins into albumoses, peptones, 
 amins and ammonia. 
 
 A temperature of 70 C. (158 F.) continued for five minutes suffices 
 to destroy the organism, and immediate sterilization is secured by 
 boiling. The staphylococcus is highly resistant to drying. Dried pus 
 may contain viable organisms after many months and dust may harbor 
 them and aid in their distribution. Mercuric chlorid in dilution as 
 great as 1 : 10,000 may inhibit growth but does not kill these bacteria. 
 Indeed, they are rather resistant to this germicide, 1 : 1,000 requiring 
 several hours and even 1 : 100 needing from five to ten minutes. 
 Absolute alcohol is without effect but 50 per cent, alcohol is quite 
 efficient in ten minutes. Phenol, from 3 to 5 per cent., kills within 
 five minutes. For disinfecting the hands lysol followed by dilute alco- 
 hol is recommended. 
 
 The staphylococcus is usually found on the skin, the albus most 
 frequently, but the aureus not seldom. It is also present in normal 
 saliva, on the tonsils and walls of the pharynx and in the conjunctival 
 sac. It is frequently present in the normal urethra, both male and 
 female, but rarely in the vagina. It collects on the clothing and makes 
 this a source of infection when carried into wounds. It is often found 
 on cold foods and is a frequent constituent of market milk. The 
 strains showing this wide distribution are generally of low virulence. 
 
 Old filtered bouillon cultures of the staphylococcus have certain 
 well-marked effects. They contain a substance which induces degen- 
 erative and destructive changes in leukocytes and for this reason is 
 known as leukocidin. This substance has not been isolated and its 
 presence is indicated by its effects. It is inactivated at 60 and is sup- 
 posed to be a ferment. When leukocytes are subjected to filtered 
 cultures of the staphylococcus, they soon show degenerative changes 
 and finally lose their nuclei. Leukocytes from different animals vary 
 greatly in susceptibility to this agent. Those from the frog are 
 undisturbed ; from the mice and guinea-pigs, slightly susceptible ; from 
 the dog, more, and from the rabbit, most susceptible. 
 
STAPHYLOCOCCIC INFECTION 163 
 
 The old filtered cultures agglomerate and dissolve red blood cells. 
 Only in dilute or weak solutions is agglutination observable; in strong 
 solutions there is rapid or immediate hemolysis. The hemolytic agent 
 is most in evidence in cultures from six to ten days old. However, 
 this is variable and it may be more abundant in still older cultures. 
 Whether it is the same agent that acts on the white and red corpuscles 
 is not certainly known, but both effects are prevented by heating the 
 filtrate to 60 C. 
 
 Both antileukocidin and antihemolysin are easily prepared by 
 repeated injections of small doses of filtered cultures of the staphylo- 
 coccus in animals. This is further evidence that these bodies are 
 toxins and should be classed among the ferments. 
 
 Filtered cultures when injected into animals have injurious effects 
 on other cells. Hyalin casts are formed in the uriniferous tubules 
 and necrotic areas appear in the kidney cortex. The subcutaneous 
 tissue about the point of injection becomes indurated, the hairs over 
 it fall out and in some instances necrosis results. Some investigators 
 have observed similar changes in the intestinal mucosa and others 
 report degenerative changes in the central nervous system. It will 
 appear from these statements that the staphylococcus, living or dead, is 
 harmful to body cells. Whether the noxious constituents of filtered 
 cultures are to be considered as secretions of the cocci or as frag- 
 ments resulting from autolytic cleavage has not been definitely deter- 
 mined, though the prevalent opinion is in favor of the first alternative. 
 
 It has long been known that amyloid degeneration results in man 
 after long-continued suppurative processes. This change has been 
 induced in animals by repeated small inoculations of living cultures 
 and by injection of dead cultures. 
 
 Bail and his students have used the staphylococcus, as well as 
 other bacteria, in the study of their aggressins. A large amount of 
 an agar culture of a staphylococcus, whose virulence has been greatly 
 increased by passage through animals, is injected into the pleural 
 cavity of a rabbit. The exudate which is formed is drawn off and 
 found to contain cocci, dissolved red corpuscles and degenerated 
 leukocytes. This is freed from bacteria by centrifugation and then 
 it is found that some of the supernatant fluid plus less than a fatal 
 dose of the staphylococcus injected into a half-grown rabbit, kills it 
 
164 STAPHYLOCOCCIC INFECTION 
 
 in a few hours. After death the pleural exudate in this animal is 
 found to be sterile. Therefore, the animal does not die from infection 
 but from intoxication. Bail's explanation is that the exudate is bac- 
 tericidal and in the second animal quickly splits up the cocci with the 
 liberation of enough poison to kill it. This seems not only rational, 
 but the most probable explanation. 
 
 In most of the suppttrative affections of man either the strepto- 
 coccus or the staphylococcus, or both, play some part, either as primary 
 or secondary cause. Other bacteria may be present, but these are the 
 most essential. It is true that there may be an aseptic suppuration 
 and it is also true that other bacteria may incite suppurative processes, 
 but these are rare exceptions. Among the cutaneous and subcutaneous 
 lesions which may be due, either wholly or in part, to the staphylo- 
 coccus, we may mention acne, erysipelas, impetigo, lymphangitis, boils, 
 abscesses, phlegmons and pemphigus. In the alimentary canal this 
 organism may infect any part from the beginning to the end. Rarely 
 it closely simulates diphtheria in the formation of membrane, and the 
 osseous system seems to furnish favorable conditions for its growth. 
 Abscesses in various parts of the body are most frequently due to this 
 organism alone or in company with the streptococcus. Among our 
 domestic animals it causes the same or similar lesions. 
 
 While it is true that the serum of an animal highly immunized to 
 the staphylococcus agglutinates this organism in fairly high dilutions, 
 serodiagnosis of staphylococcic infection has not proved of great value. 
 Fortunately, it is rarely needed. 
 
 The contest between the phagocytes and the pus germs is waged on 
 fairly even terms. Each secretes an agent which is destructive to the 
 other. The cocci prepare and use the leukocidin, and the phagocytes 
 employ a bactericidal ferment. The contestants are wary in approach 
 and frequently retreat. When the cocci are only slightly virulent 
 and form but little or no leukocidin, the phagocytes are bold and 
 rapidly devour their enemies. In this case, we say that the chemotaxis 
 is positive. But when the cocci are highly virulent and pour out large 
 amounts of leukocidin, the phagocytes approach with greater caution 
 or retreat. Then, we say that the chemotaxis is negative. Phagocytes 
 feed voraciously on unarmed cocci, but when the latter are prepared, 
 the former seem less hungry. The leukocidin is best prepared for study 
 
STAPHYLOCOCCIC INFECTION 165 
 
 by filtering old highly virulent cultures of the cocci, while the coccidal 
 agent is obtained by forming pleural exudates and separating the 
 remaining cocci by centrifugation. Evidently the phagocytes may be 
 strengthened in this contest in two ways. First, anything which will 
 improve their effectiveness will improve their chances, and second, 
 anything which will lessen the leukocidin of the cocci or render it inert, 
 will help the phagocytes. Vaccination as introduced by Wright is an 
 attempt to help the phagocytes in this contest. Within a limited field, 
 Wright's method of treating disease by vaccination has proved suc- 
 cessful. The best results have been secured in the treatment of such 
 pustular diseases as acne and furunculosis. In these diseases the cocci 
 are as it were entrenched and the phagocytes are slow to attack. By 
 injecting cocci into the midst of the leukocytes the latter are stimu- 
 lated through devouring easily the prey thus thrown to them. The 
 formation of bactericidal ferments by the phagocytes is improved by 
 exercise and this advantage brings victory to them. In the vaccine 
 treatment of disease there is always danger of overdoing the stimula- 
 tion of the leukocytes. It has worked better with pus bacteria than 
 with others, probably for the reason that the cocci protein is not rich 
 in poison. 
 
CHAPTER XXII 
 
 DIPHTHERIA 
 
 History. Under various names this disease is described in the 
 most ancient medical records. Competent authority states that a 
 disease mentioned in the Babylonian Talmud must have been diph- 
 theria. The Greeks held that it came to them from Egypt, to which 
 country they were wont to ascribe most of their ills. The descriptions 
 of Aretaeus are regarded as accurate records of this disease. Galen 
 spoke of false membranes in the larynx and pharynx and said that the 
 former were sometimes removed by coughing, and the latter by hawk- 
 ing. During the dark ages diphtheria was recognized here and there 
 and undoubtedly added much to the high death-rate of that period. 
 During the sixteenth century it was reported from time to time in 
 malignant epidemic form in Spain, France, Holland and Germany. 
 The unusual mortality in Spain in 1613 gave to this year the name of 
 the disease. In the same country and in the same century, Heredia 
 recognized the asthenic and suffocative types and wrote concerning 
 diphtheria paralysis. Before the middle of the seventeenth century 
 it had found its way into the American colonies and we are told that in 
 the year 1659 Samuel Danforth lost four of his eleven children of "a 
 malady of the bladders in the windpipe." As early as 1761, an Ameri- 
 can physician, Bard, made important contributions to the study of the 
 disease and held that croup is laryngeal diphtheria. However, we owe 
 the beginnings of the modern study of this disease, also its present 
 name, to Bretonneau. He traced an outbreak in a garrison at Tours 
 to common drinking-cups and other table utensils, and demonstrated 
 the infectiousness of the disease. He claimed that croup is laryngeal 
 diphtheria and that the angina of scarlet fever is quite distinct. These 
 views were accepted and emphasized by the great clinician, Trousseau, 
 and were adopted by the profession in France and America, but were 
 ignored in Germany until the development of bacteriology rendered 
 their demonstration possible. 
 
168 DIPHTHERIA 
 
 During the sixties of the past century, many were busy searching 
 for the particulate cause of this disease and several organisms were 
 presented as claimants for this honor, but at that time bacteriologic 
 methods had not been sufficiently developed to enable the most expert 
 to pick out the one responsible for the disease. In 1883 Klebs called 
 attention to a bacillus with well-marked characteristics, frequently 
 found in diphtheritic throats, and a year later Loffler continued this 
 work. 
 
 The Bacillus. The Klebs-Loffler bacillus is a non-motile rod, 
 generally straight, but sometimes slightly bent. Its length is quite 
 variable (from 3 to 5 microns) and its breadth almost one-fourth its 
 length. The most characteristic form of the bacillus is the club shape. 
 All the rods do not have this form, but in every field there are many 
 so characteristically clubbed that the expert has no difficulty in identi- 
 fication at sight. This is true especially of cultures made directly 
 from the throat. Even the presence of other bacteria does not prevent 
 identification. A sterilized cotton swab is drawn over the membrane 
 in the throat and then over the surface of a slant serum tube. After 
 from six to twelve hours in the incubator, a stain is made from the 
 growth on the serum. While the diphtheria bacillus takes most basic 
 stains well, Loffler's alkaline methylene blue is most generally employed. 
 Direct microscopic examination of this stain enables the expert to 
 determine with certainty in the great majority of instances the presence 
 or absence of the specific organism and announce the bacteriologic 
 diagnosis. The bacteriologist does not depend solely on the presence 
 of club-shaped bacilli. The Klebs-LorHer bacillus has a peculiar seg- 
 mented appearance when colored with the stain mentioned above. 
 This is more easily recognized than described, but it becomes so 
 familiar to one engaged in this work that he is seldom mistaken. The 
 morphologic identification is rendered more easy by the fact that as a 
 rule the only other bacteria on the slide are streptococci. If the observer 
 satisfies himself that only streptococci are present, he makes a negative 
 report. In a few instances, there are diphtheria-like organisms which 
 may leave one in doubt. However, when in doubt the only wise thing 
 to do is to make a positive diagnosis, when the case will be properly 
 isolated and treated with antitoxin. 
 
DIPHTHERIA 169 
 
 Subcultures of the diphtheria bacillus show many and varied invo- 
 lution forms. Many attempts have been made to establish a relation- 
 ship between morphology and virulence, but these have led to no 
 practical results. The Loffler serum should be carefully prepared and 
 should consist of three parts of serum (horse, ox or sheep) and one 
 part of neutral bouillon containing 1 per cent, each of peptone and 
 grape sugar. The freshly prepared serum should be shaken for some 
 hours with 3 per cent, chloroform before the bouillon is added. On 
 one day the serum is heated for from five to six hours at from 70 
 to 80 C. (158 to 176 R). On the next day it should be held at 80 C. 
 for one hour and for the same time at 90 (194 F.), and then for half 
 this time at 100 C. (212 F.), and then allowed to harden slowly. On 
 this medium the bacillus will form a good growth in the incubator 
 within six hours. 
 
 The optimum growth temperature is about 37 C., but growth pro- 
 ceeds anywhere between 20 and 41 C. While air is not absolutely essen- 
 tial, growth is most rapid when this is abundantly supplied. In liquid 
 cultures, a scum forms on top, and the subjacent fluid may remain 
 clear. The sides of the tube may be covered with the growth. On 
 ordinary agar the development is slow and scanty. Gelatin colonies 
 are not characteristic and the medium is not liquefied. In the presence 
 of certain carbohydrates there is a slow production of acid, but this 
 does not occur in bouillon when the muscle sugar has been removed. 
 In the absence of carbohydrates from the medium, the alkalinity is 
 increased. 
 
 The resistance of this bacillus to untoward conditions depends on 
 whether it is still protected by its membrane or has been freed from 
 the same. The membrane, even when partially dried, may retain 
 its virulence for many months. On the other hand, silk threads dipped 
 in cultures and exposed to direct sunlight soon become inert. Phenol, 
 5 per cent, and mercury chlorid, 1 : 1,000, destroy the bacillus within 
 five minutes. Absolute alcohol has but little or no effect, but when the 
 strength is reduced to from 60 to 30 per cent, a few minutes suffice to 
 kill the bacilli. According to Meyer, certain tooth pastes destroy diph- 
 theria bacilli in less than one minute. It must not be inferred from 
 this that a diphtheritic mouth could be easily disinfected by such an 
 agent. The bacilli are protected by the pharyngeal folds and the crypts 
 
170 DIPHTHERIA 
 
 of the tonsils. However, since the healthy carrier plays a large part 
 in the distribution of this disease, more attention to oral hygiene might 
 be of service in this as well as other directions. 
 
 Roux and Yersin discovered diphtheria toxin. Cultures several 
 weeks old were filtered through porcelain. The germ-free filtrate in 
 minute doses kills animals. The toxin has not been obtained in a 
 pure state, and we are still in doubt concerning its chemical composi- 
 tion. It resembles in some respects the ferments. It acts slowly 
 and after a period of incubation; it is active in exceedingly small 
 amounts; it is destroyed by heat, and when repeatedly injected into 
 animals in non- fatal, but increasing, doses, the animal becomes immune 
 by elaborating an antibody. In these respects diphtheria toxin 
 resembles the ferments. It differs from many ferments in the fact 
 that a given amount produces only a certain effect and apparently 
 goes no further. Different strains of the bacillus show wide variations 
 in their toxin production, and the highest toxin producers are not 
 always the most virulent bacilli. What is called diphtheria toxin is an 
 old filtered culture, and the strength of this is determined by ascertain- 
 ing the minimum amount necessary to kill a guinea-pig of from 200 to 
 250 gm. weight within four days. This minimum lethal dose may 
 be as small as 0.0005 c.c., though that usually employed in the pro- 
 duction of antitoxin is much less powerful than this. 
 
 The effect of this toxin on animals has opened a new field of 
 research, has given a new understanding of disease processes and has 
 led to one of the most beneficent discoveries, that of diphtheria anti- 
 toxin. When a fatal dose of this toxin is injected into an animal, 
 there is a period of incubation during which the animal shows no 
 marked departure from the normal. This incubation period varies 
 with the size of the dose, but is never less than about eight hours, even 
 when many times the fatal amount has been used. The significance 
 of this incubation has, in the writer's opinion, been misunderstood. It 
 should not be inferred that nothing happens during this time. The 
 disturbance simply does not rise to the plane of gross clinical observa- 
 tion. The toxin begins to act soon after its introduction. Within an 
 hour or two the temperature begins to rise and proceeds slowly until 
 some hours before death when it begins to fall, and at death it is 
 several degrees below normal. The skin about the point of injection 
 
DIPHTHERIA 171 
 
 becomes edematous and later necrotic. The interval between injection 
 and death is the same as after inoculation. With sublethal doses there 
 is often paralysis, beginning in the posterior extremities and extending 
 over the body. The internal organs are hyperemic with hemorrhages 
 in the adrenals, stomach and intestine. Sometimes a gastric ulcer is 
 found. It is important to note that after the first day there is a fall 
 in the blood pressure. The effects of the toxin on temperature and 
 blood pressure suggest the action of the protein poison. It will prob- 
 ably be found that the toxin is a ferment which slowly disrupts some 
 protein, setting free the poison which in small amount increases and 
 in larger, decreases the temperature and lowers blood pressure. The 
 toxin apparently has special avidity for nervous tissue. Whether this 
 action is primarily central or peripheral has not been determined. 
 When the toxin is injected into a susceptible animal it soon disappears 
 from the blood current and manifests its activity on certain organs 
 and tissues. It has not been found in the urine except when massive 
 doses are given. In insusceptible animals, it remains for a long time 
 in the blood stream and is, of course, without action on the tissues. 
 It is not able to digest the animal's proteins and it is for this reason 
 that the animal is refractory. 
 
 We owe the discovery of diphtheria antitoxin, one of the most 
 beneficent discoveries of all ages, to the labors and genius of von 
 Behring. It is true that others had prepared the way, but this detracts 
 in no way from the debt of gratitude the world owes this distinguished 
 German investigator. To the preliminary work America made two 
 important contributions. Mitchell and Reichert showed that the active 
 principles in the venom of serpents are protein bodies or so closely 
 related to proteins that they have not been separated. Sewall immu- 
 nized pigeons to this venom. Then came the discovery by the French- 
 men, Roux and Yersin, of diphtheria toxin, closely resembling snake 
 venom in its action. Ehrlich immunized animals to the similar 
 vegetable poisons, abrin, ricin and robin, and demonstrated that passive 
 immunity could be established in other animals by the transference to 
 them of the serum of those actively immunized. Von Behring's method 
 of preparing diphtheria antitoxin as now used is as follows: Sound, 
 healthy horses are kept under observation and tested with mallein to 
 insure freedom from glanders. Injections of diphtheria toxin, begin- 
 
172 DIPHTHERIA 
 
 ning with very small doses, are given these animals at intervals of 
 a few days. It is desirable that the first doses should be so small that 
 marked local or general reactions are not induced. Horses differ 
 widely in susceptibility to the toxin. From time to time a small amount 
 of blood is drawn from the horse and its protective power against the 
 toxin is tested on guinea-pigs. The amount of the serum necessary 
 to protect a guinea-pig of 250 gm. weight against 100 minimum lethal 
 doses of the toxin is known as an "immunity unit." When the pro- 
 tective value of the serum has risen to the desired point, from 4 to 8 
 liters of blood are drawn under aseptic precautions into sterilized glass 
 cylinders. These are allowed to stand in a cool, dark place until 
 coagulation is complete, when the serum is treated with some preserva- 
 tive, such as 0.5 per cent, phenol, 0.4 per cent, trikresol or a small 
 amount of camphor, and placed in containers ready to be injected into 
 the sick person. In some countries no preservative is used and the 
 serum is heated to 56 C. In all countries antitoxin is made under 
 governmental supervision and the product is tested in some laboratory. 
 All horses do not produce the same grade of antitoxin, and sera 
 from different animals are mixed and the product tested as to its 
 protective value. Some horses continue to produce a high grade anti- 
 toxin for years and from 4 to 6 liters of serum may be obtained from 
 such animals monthly. It will be understood that in such cases the 
 injections of toxin must be regularly repeated. Immediately after an 
 injection of toxin the antitoxin content of the blood falls, then it rises 
 and generally reaches its highest point in ten or twelve days, remaining 
 at that point for a variable time. The horse has been immunized by 
 the repeated injections of the toxin. The process of immunization 
 consists in developing in the animal's body an antitoxin, the excess of 
 which is in the blood, and in the serum after coagulation. The anti- 
 toxin is capable of neutralizing the toxin both in vitro and in vivo. 
 The diphtheria bacillus is growing in the throat of the child and pour- 
 ing its toxin into the child's blood. The blood serum of the horse 
 is injected into the child and neutralizes the toxin coming from the 
 throat. The horse has been immunized, and when its blood serum is 
 introduced into the child, the child becomes for the time physiologically 
 a part of the horse and partakes of the horse's immunity just to the 
 extent of the amount and potency of the horse's serum injected. It 
 
DIPHTHERIA 173 
 
 should be understood that the blood serum of the horse containing 
 the antitoxin is not bactericidal. It does not kill the bacilli in the 
 throat, but it neutralizes the toxin in the blood and tissues. It must 
 be evident from this that the earlier in the disease the antitoxin is 
 used, the more beneficial it is. When the toxin poured from the throat 
 into the blood meets with no antibody, it acts on the body cells and 
 destroys them, and to the extent to which this has been done before 
 the antitoxin has been administered, it is without value. Kossel has 
 shown that when the antitoxin is injected on the first sign of the 
 disease, the percentage of recoveries is 100. In this every hour counts. 
 Out of 2,428 cases reported by Hilbert, the percentage of deaths 
 varied with the day on which the antitoxin was administred, as follows : 
 First day, 2.2; second day, 7.6; third day, 17.1 ; fourth day, 23.8; fifth 
 day, 33.9; sixth day, 34.1; after the sixth day, 38.2. According to 
 Wernicke the saving of lives during the first year of the use of anti- 
 toxin in Germany amounted to 20,000, and if the agent was properly 
 and promptly used the saving would amount to 45,000 lives annually. 
 The value of this agent, however, is even greater than is indicated by 
 the lowering in the death-rate. For every sick child saved, at least 
 five are saved from being sick. While the curative value of diphtheria 
 antitoxin is great, its preventive value is greater still. The physician 
 called to a family in which one child has diphtheria gives a curative 
 dose to the one and immunizing doses to all others. Even when the 
 sick one has been neglected so long that the curative value of the agent 
 is lost, its preventive value is still potent. Diphtheria antitoxin has 
 lowered not only the mortality rate, but still more the morbidity rate. 
 Unfortunately, the immunity induced by diphtheria antitoxin is only 
 temporary, lasting only from three to four weeks. From this it 
 frequently happens that a child. who has once had an immunizing dose, 
 may a few months or possibly a few years later, need a curative dose. 
 The fear of anaphylactic shock has led many a physician to hesitate 
 about a "reinjection" of horse serum after an interval of ten days or 
 longer, but one may do this with safety. In all cases of "reinjection" 
 after an interval of ten days or longer, a fraction of a cubic centimeter 
 should be injected. If there are or are not untoward symptoms follow- 
 ing this, after an hour or two any amount of the serum may be injected 
 with safety. This procedure should be adopted not only in all cases 
 
174 DIPHTHERIA 
 
 of rein j action, but when the patient has ever shown asthmatic 
 symptoms. With these precautions no physician need fear to use 
 diphtheria antitoxin when it is needed. In order to prevent outbreaks, 
 Heubner, for the past twenty years, has had every child in his hospital 
 injected every fourteen days and no serious result has ever followed. 
 
 When antitoxin is used early in the disease, the extension of the 
 membrane usually stops in a few hours. For this reason, laryngeal 
 diphtheria is now rarely seen except in neglected cases. Not only does 
 the extension of the membrane stop on the administration of the anti- 
 toxin, but as a rule that already formed begins to recede, becomes 
 detached and fades away. It may truly be said that the discovery of 
 antitoxin has largely robbed diphtheria of its terrors, and it might 
 not be amiss to call attention to the fact that without animal experi- 
 mentation this could not have been done. Hundreds of animals have 
 been sacrificed in order that hundreds of thousands of human lives 
 might be saved from one of the most distressing forms of death man 
 has known. 
 
 Notwithstanding the possession of this wonderful and almost mir- 
 aculous preventative and curative agent, the problem of the eradica- 
 tion of diphtheria remains one of the most difficult problems still con- 
 fronting scientific medicine. The bacillus seems well-nigh ubiquitous. 
 Thousands of people in health carry these deadly germs in their throats 
 and mouths. If it has breeding places outside the human body they 
 have not been discovered. The disease is acquired for the most part 
 at least, not from those ill, but from those who are in apparent health. 
 All that we can do at present is to emphasize the desirability of more 
 individuality and less promiscuity in manners of life. The common 
 drinking-cup and other methods of contact with lip to lip directly and 
 indirectly must be discouraged and the importance of oral hygiene 
 must be emphasized, especially among children. 
 
PART II 
 
 IMMUNITY 
 
CHAPTER XXIII 
 
 INTRODUCTION 
 
 Had the animal body no effective means of resistance to bacterial 
 invasion, man could not have developed, and the whole animal world 
 would have perished long since, so abundant in numbers and so wide 
 in distribution are the various forms of bacterial life, both saprophytic 
 and pathogenic. In life our skin is covered with bacteria and our 
 alimentary tract filled with them. Even in the most perfect states of 
 health we are the hosts and they are our guests. Willingly or unwill- 
 ingly, and for the most part unconsciously, we supply homes and food 
 to these parasites. With the approaching death of the host, these 
 myriads begin to penetrate every part of our bodies, and by the time 
 the respiration and pulse cease, both saprophytes and parasites are 
 tearing to pieces our mortal frames. It follows from this that the 
 living animal must possess certain agencies which serve to protect it 
 against bacterial invasion, and it is our purpose to inquire into the 
 nature and action of these agencies. 
 
 Different species of animals differ widely in their susceptibility to 
 a given pathogenic bacterium. As a rule at least, it is true that the 
 more widely separated the species the more marked is the difference 
 in susceptibility to the same infection. We know of no bacterial infec- 
 tion common to the cold and warm-blooded animals. It is true that 
 we acquire typhoid fever by eating oysters taken from infected water, 
 but the oysters do not have typhoid fever any more than the leaves 
 of lettuce, which may be soiled with typhoid excreta, do. Fish, turtles 
 and possibly other cold-blooded animals have tuberculosis, but this 
 is due to quite a different organism from that which causes this dis- 
 ease in man. Some cold-blooded animals may be infected experimen- 
 tally with anthrax and plague, but under natural conditions they are 
 not known to develop these diseases. In some instances at least, the 
 immunity of cold-blooded animals to bacteria pathogenic to the warm- 
 blooded seems to be solely a matter of temperature. When kept at 
 
178 IMMUNITY 
 
 warm-blood temperature, certain cold-blooded animals become sus- 
 ceptible to tetanus and other infections. Likewise, warm-blooded ani- 
 mals are immune to many bacteria because they cannot grow at the 
 temperature of the animal body. This is true of the greater number 
 of the saprophytic bacteria found in drinking-water. A bacterium 
 which cannot grow and multiply at the temperature of the animal body 
 cannot infect the animal. Such an organism may produce a substance 
 outside the body and at its growth temperature, which is poisonous 
 to a warm-blooded animal, but it cannot infect the animal. 
 
 Like differences in susceptibility are observed in birds and mam- 
 mals. So far as we know, under natural conditions, there is no trans- 
 ference of infection between these classes. With larger doses, or 
 under unnatural conditions the infection of mammals may be trans- 
 ferred to birds. Chickens become susceptible to some of these infec- 
 tions, such as anthrax, when the body temperature is kept low. Chick- 
 ens have tuberculosis, but the bacillus of avian tuberculosis grows at 
 45 and even at 50 C. while that of the human does not grow above 
 41 C. (105.8 F.). While barnyard fowls have frequent opportunity 
 to pick up the sputum of tuberculous men, they do not become infected 
 in that way, nor are men infected with avian bacilli, although the 
 opportunities are quite frequent. It must not be inferred that tem- 
 perature is the only factor in these differences in susceptibility. It 
 seems to be one factor. The difference in metabolism is probably 
 quite as great a factor, possibly much greater, but its value is not so 
 easily determined. Here also, the poisons produced by avian infective 
 bacteria may prove harmful to mammals. Man may eat birds dead 
 of chicken cholera and by doing so he does not acquire the disease, 
 but he may be more or less severely poisoned by the bacterial products. 
 
 Between herbivorous and carnivorous animals the differences are 
 not so great. The latter are, as a rule, much less susceptible but suc- 
 cumb to large inoculations. Anthrax, one of the most universal infec- 
 tions, is not known to appear in epidemic form among carnivorous 
 animals under natural conditions. There are traditions that this has 
 happened, but these are not based on reliable information. In his 
 susceptibility to infection man is more closely related to the herbivora 
 than to the carnivora. Beasts of prey may become infected with 
 
IMMUNITY 179 
 
 anthrax or glanders when fed with large quantities of infected material, 
 but this is not comparable with natural infection. Smith reports 
 tuberculosis, due to human bacilli, in a tame bear whose master had the 
 disease. Possibly with closer association such cases would be more 
 frequent. Man seems to possess complete immunity to rinderpest, and 
 apparently none of our domestic animals are susceptible to scarlet 
 fever or measles. The immunity of the lower animals to cholera and 
 typhoid fever may be due to their normal intestinal bacteria. 
 
 When we confine our attention to man, variations in susceptibility 
 among the races is not so great as was once believed. Livingstone 
 found no trace of syphilis among the Africans and believed these people 
 to be immune to this infection, but as early as 1867, Fritsch reported 
 it rare but saw occasional cases which he attributed to contact with the 
 white man. More recently, this disease has become common in the 
 Congo and coast colonies, and in Uganda it is said to have become a 
 veritable plague. Mense states that the bearers of culture have car- 
 ried the gifts of civilization and the scourge of venereal disease to 
 trustful savages. However, venereal diseases are not the only ills 
 which have been disseminated by the white man. Indeed, if the pres- 
 ent opinion concerning the introduction of syphilis into Europe be true, 
 it was one of the jewels borne to Spain by the sailors who accompanied 
 Columbus on his first voyage. Smallpox did much to aid the Spaniard 
 in his conquest of Mexico, and measles and tuberculosis have played 
 important roles in reducing the red man in America. According to 
 Calmette, the white man has done much in spreading tuberculosis to 
 other races and conditions of men. 
 
 Hahn points out that in countries occupied by two races or by 
 peoples of different religions, apparent differences in susceptibility are 
 due to material conditions in life. One race lives more hygienically 
 and more intelligently than the other. This is especially true of those 
 infections which afflict principally the poor and ignorant classes. In 
 India and in the Philippines plague and cholera prevail quite exclu- 
 sively among the natives, while Europeans and Americans live for the 
 most part in safety. In the cholera epidemic in Astrakhan in 1892, 
 the Armenians suffered but little while the Tartars died in great num- 
 bers. Much has been written about the comparative freedom of the 
 Jew in Western Europe and in America from tuberculosis and this 
 
180 IMMUNITY 
 
 has been attributed to racial immunity, but Hahn thinks it due to 
 more hygienic living and calls attention to the high death-rate from 
 this disease among the poor, ignorant Jews of Poland and Galicia. 
 Another illustration is the unequal distribution of leprosy among the 
 Kabyles and Arabs of Algeria. The former live in better houses, select 
 better locations for their homes, are not so crowded and are personally 
 more clean. The truth is that the death-rate from infectious diseases 
 has become the best measure of intelligence. The more intelligent a 
 people, the lower the death-rate. 
 
 It should be understood, however, that the death-rate from the 
 infectious diseases is a measure not of individual, so much as of com- 
 munity, intelligence. In this country the wonderful reduction in the 
 death-rate from infectious diseases in the past fifteen years has been 
 confined largely to the great cities. Smaller cities, villages and rural 
 communities have improved but little. The larger cities are establishing 
 effective health departments. Building regulations prevent the con- 
 struction of unsanitary houses, either public or private. Schoolchil- 
 dren are inspected by competent medical men and first cases are 
 detected and isolated. Proper hospitals for the infectious diseases are 
 provided and scientifically administered. The children of the poorest 
 and most ignorant go to sanitary school buildings and when infected, 
 are scientifically treated. The health officer of the smaller city is a 
 joke and that of villages and rural communities exists, for the most 
 part, only in name. 
 
 It was formerly believed that the African is naturally immune to 
 malaria, but more recent and more thorough studies show that this 
 disease is highly prevalent and fatal among the children of that race 
 and that the apparent resistance observed in the adult is due to acquired 
 immunity. In parts of Greece and Italy malaria has been constantly 
 prevalent for more than two thousand years. During that time it has 
 spared no generation and in many localities scarcely any individual, 
 and yet no marked immunity has been inherited. The young of recent 
 generations retain their susceptibility. How this compares with that 
 of the first generation subjected to the infection we cannot say. How- 
 ever, it is undoubtedly true, that resistance to certain specific infections 
 increases after many generations of continuous exposure. The most 
 intelligent physicians of Cuba believed, before the discovery of the 
 
IMMUNITY 181 
 
 transmission of yellow fever by the mosquito, that the natives are 
 wholly immune to this disease. Now, it is quite evident that all have 
 it lightly in infancy, and the adult is protected by an acquired immunity. 
 When syphilis first appeared in Europe, it manifested a malignancy 
 much greater than that now usually observed in the white man. It 
 is said to be still much less malignant among the Indians of Central 
 America, whose ancestors, far back beyond the Columbian period, 
 probably had the infection. On the other hand, people among whom it 
 has recently been introduced, suffer its full virulence. The increased 
 mortality of smallpox, measles, scarlet fever and tuberculosis, among 
 peoples unaccustomed to these diseases, seems to be well authenticated. 
 We must conclude that increased resistance to specific infection is both 
 inherited and acquired. 
 
 Variation in individuals of the same species to a given infection is 
 a most interesting subject and one which cannot at present be wholly 
 explained. As a rule, the more virulent the infection the less marked 
 the variation. When many guinea-pigs are inoculated with a fairly 
 virulent anthrax culture in the same dosage, all die about the same 
 time. When rabbits are treated in the same way with anthrax, some 
 die within one or two days, others live longer and some do not die. 
 When rabbits are inoculated with the bacilli of chicken cholera, there 
 seems to be no resistance. The reaction at the point of inoculation is 
 slight, a general septicemia results and all the animals die. When 
 guinea-pigs are inoculated with the same organism there is a marked 
 local reaction, as a rule there is no general infection and but few die. 
 When guinea-pigs are inoculated with a virulent culture of the human 
 tuberculosis bacillus all die. With rabbits only a small proportion die. 
 The water-supply of a city becomes infected with cholera or typhoid 
 bacilli. From 5 to 20 per cent, of those who drink the water may 
 develop the disease. Why does not this happen to all? Some answer 
 by saying that the bacilli, being particulate, are not uniformly dis- 
 tributed through the water, consequently all who drink the water do 
 not swallow the infective agent. All soldiers who make a charge in 
 the face of continuous musketry discharges are not killed or wounded. 
 
 There is much of truth in this explanation, but it is not altogether 
 applicable. Many of those who do swallow the bacilli, as can be dem- 
 onstrated by their presence in the stools, do not develop the disease. 
 
182 IMMUNITY 
 
 Then, of those who do develop the disease, some have it lightly, others 
 more severely and some fatally. The relative insusceptibility of nurs- 
 ing infants to diphtheria and certain other infections is well known, 
 and Schick has shown that the blood of many of them contains anti- 
 toxin, possibly acquired through the mother's milk. Certainly, no 
 such marked variations in susceptibility to a chemical poison could be 
 expected. An infection must meet with some resistance to its mul- 
 tiplication and this is not equally effective in all individuals. It seems 
 fair to conclude from this that in all probability the resisting agent is 
 also a living thing or some product or products of living things. 
 
CHAPTER XXIV 
 
 PHAGOCYTOSIS 
 
 Phagocytes. We owe our knowledge of the most important facts 
 in the new science of immunology to the labor and genius of Metch- 
 nikoff, whose elucidation of biologic processes we will follow in some 
 detail. In many forms of life, from the simplest unicellular to the 
 most complex multicellular, there are certain cells, one of whose 
 functions is to engulf and digest other cells. These eating cells are 
 designated by Metchnikoff as "phagocytes." The fungi which devour 
 fallen wood, dead leaves and other decaying vegetable matter consist 
 of sporangia or clusters filled with innumerable round spores or cells. 
 Under proper conditions these zoospores are set free and develop into 
 naked masses of protoplasm known as plasmodia * which vary in size 
 from small bodies to those several feet in length. In the free state, 
 these plasmodia are motile and they may engulf and digest solid 
 matter. They shun dry, and seek moist, places. Certain substances 
 attract and others repel them. This phenomenon is known among 
 botanists as chemotaxis. Most dead vegetable matter attracts them 
 while solutions of salt and sugar repel them. In other words, they are 
 attracted by substances which supply them with proper food, and are 
 repelled by substances which harm them. The former is known as 
 positive, and the latter as negative, chemotaxis. However, in this 
 respect they are capable within limits of accommodating themselves 
 to their surroundings, and negative chemotaxis may become positive. 
 
 These plasmodia can feed on both soluble and insoluble sub- 
 stances. In the latter instance, they project pseudopodia, surround 
 the solid and digest it. This can be demonstrated by springkling on 
 their food some color such as carmine. These plasmodia absorb and 
 digest not only dead, but also living particles. For instance, they feed 
 upon living algae and the process of digestion within the cell can be 
 studied. Within the cells, green algae can be seen to turn brown, then 
 
 * This has nothing to do with the plasmodia of malaria. 
 
184 PHAGOCYTOSIS 
 
 become granular and then disappear. They also absorb or engulf 
 motile bacteria which may for a while continue to display their 
 motility. Digestion is performed by means of an acid fluid, as can 
 be demonstrated by feeding them on litmus or on substances colored 
 with neutral red. In some instances at least, digestion proceeds not 
 only in feebly acid, but also in neutral and feebly alkaline solution. 
 For this reason the digestive ferment is regarded as a trypsin rather 
 than a pepsin. 
 
 Another phagocyte is the ameba, which by means of its pseudo- 
 podia surrounds and digests not only dead particles, but also micro- 
 scopic plants, animals and bacteria. Intracellular digestion in these 
 unicellular animals has been carefully studied with most interesting 
 results. They take into their bodies both dead and living bacteria, 
 algae and infusoria. It is easy to watch the behavior of living cells 
 after engulfment. Some amebas live exclusively on living cells and 
 some restrict their food to bacteria. Indeed, some are so particular 
 that they prefer one bacterial species, and when supplied with mixed 
 cultures they devour their favorite, leaving others unharmed. Mouton 
 studied a species of amebas which had been fed through many gen- 
 erations wholly on colon bacilli. 
 
 It is especially worthy of note that when colon cultures are fed 
 to those amebas, the bacilli may be agglutinated or bunched outside 
 the amebas and entire clumps are engulfed at once. The similarity 
 between this process and the agglutination of typhoid bacilli with the. 
 serum of one ill with this disease is striking and significant. One is 
 justified in supposing that in each case the phagocytes (in typhoid 
 fever, the body cells) pour out a secretion which prepares the bacilli 
 for absorption. Of course, in the agglutination of typhoid bacilli 
 with serum, the phagocyte is not present, but remains in the body. 
 However, agglutination is not essential and single bacilli may be 
 absorbed and digested. In absorption, the bacteria are taken into a 
 vacuole and the process of intracellular digestion begins. When the 
 bacilli have been previously stained with neutral red, they are seen 
 to become cherry red in the vacuole, showing that the digestive fluid 
 is acid. The ferment is known as the ameba-enzyme. It may be 
 obtained by dissolving or extracting masses of amebas. It acts in 
 feebly acid, neutral, and feebly alkaline solutions. It readily digests 
 
PHAGOCYTOSIS 185 
 
 gelatin and blood fibrin, less markedly, egg albumin. Its optimum 
 temperature is 25 C. (77 F.) or slightly above, but it acts slowly as 
 low as 8 C. At 60 C. it is destroyed. When solutions of this enzyme 
 are treated with bacteria killed with chloroform, the cloudy fluid soon 
 becomes perfectly clear. It must be noted that Mouton did not suc- 
 ceed in digesting living bacteria with the extracted enzyme, but they 
 are digested in living amebas. This suggests that the bacilli are killed 
 by one enzyme and digested by another. The killing enzyme may be 
 poured out into the surrounding fluid from the living cells and when 
 the amebas are killed its formation, quite naturally, stops. The forma- 
 tion of the digestive enzyme also stops when the amebas are killed 
 and the extract contains only the excess already formed. 
 
 Most infusoria depend, in part at least, on intracellular digestion. 
 Most of them accomplish this by acid secretions, while some supply 
 feebly alkaline fluids. While protozoa depend largely on intracellular 
 digestion, this function is not wanting in many multicellular organ- 
 isms. In many invertebrates the digestive cells of the intestinal tract 
 consist wholly of sessile phagocytes. This is largely true of sponges 
 and coelenterates. This is beautifully illustrated in the siphon sponges 
 which are true beasts of prey. They swallow entire Crustacea which 
 are taken into the alimentary canal where they are surrounded by, 
 whole groups of entodermal phagocytes, fusing into great protoplasmic 
 masses, and digested. The actinea seize their victims with their ten- 
 tacles and digest them after absorbing them into their mesodermal 
 cells. Mesnil has succeeded in extracting from these cells an enzyme 
 which digests fibrin and coagulates albumin in feebly acid, neutral and 
 feebly alkaline solutions. The digestion proceeds at from 15 to 20 C., 
 the temperature at which actinea live, but in vitro, it is most effective 
 at from 35 to 45 C. Higher temperature weakens its activity which is 
 wholly arrested at from 55 to 60 C. The actino-enzyme produces pep- 
 tone and amino-acid. In these animals, digestion seems to be wholly 
 intracellular. 
 
 While intracellular digestion is common in the intestinal canal of 
 the lower invertebrates, it is replaced by extracellular intestinal diges- 
 tion in the higher invertebrates and in the vertebrates. The intestinal 
 epithelium loses its ability to project pseudopodia, engulf food and 
 digest it. These cells become glands which pour out enzymes and 
 
186 PHAGOCYTOSIS 
 
 intestinal digestion becomes extracellular. However, certain meso- 
 dermal cells, even in the highest mammals, including man, continue in 
 the possession of ameboid movements and the exercise of intracellular 
 digestion. The burden of digestion for the animal body as a whole 
 rests on certain glands, but as a further protection against invasion by 
 foreign proteins, the white blood cells retain active movements and 
 the ability to engulf and destroy micro-organisms. 
 
 Metchnikoff has shown that the metamorphic change through 
 which many insects and other animals pass is brought about by phago- 
 cytic action. The tail of the tadpole is eaten away by the white blood 
 corpuscles. Some of the tissue changes both normal and abnormal in, 
 man are due to the same agents. The involution of the uterus after 
 childbirth is due to the absorption and intracellular digestion by phago- 
 cytes of the unnecessary tissue. The whitening of the hair with 
 advancing age results from the consumption of the pigment by phago- 
 cytes. The general deterioration of the brain with advancing senility 
 is due to the activity of the neuronophages. In short, the man who 
 lives to die physiologically is slowly but certainly devoured by his own 
 phagocytes. Sometimes, however, they seemingly are not content to 
 let us live out the allotted time, and they fall on and devour some part 
 of our anatomy prematurely. According to Metchnikoff, progressive 
 muscular atrophy is an illustration of this apparently undue greed on 
 the part of our wandering cells. This must not lead us to a hasty and 
 rash condemnation of our eating cells, for if they did not feed on the 
 micro-organisms which are frequently entering our bodies, our lives 
 would be even shorter and more precarious than they are. 
 
 If some of its own blood, or that of another individual of the same 
 species, be injected into the peritoneal cavity of an animal, it is readily 
 absorbed and does no harm. If it be from another species the phago- 
 cytes come from all parts of the body and devour the foreign material. 
 This is true not only of blood but of other foreign cells. Indeed, cells 
 whose normal habitat is limited to one organ or tissue become foreign 
 substances when introduced into another part. Spermatic cells 
 injected into the abdominal cavity of the animal from which they are 
 taken become the prey of the white blood cells. When foreign material 
 is injected into the abdominal cavity, at first the white blood cells, 
 already there, seem to be frightened and run away, but soon they 
 
PHAGOCYTOSIS 187 
 
 return in greatly increased numbers and undertake the destruction of 
 the foreign substance. If this substance be sterile no great harm is 
 likely to result. The surgeon leaves catgut sutures in the tissues, but 
 if they be sterile the phagocytes eat them entirely and no harm comes. 
 
 Among the several kinds of white blood corpuscles, the large mono- 
 nuclear cells are most effective in feeding on animal cells, whether 
 native or foreign to the body, and are designated by MetchnikofT as 
 macrophages. The polynuclear leukocytes play a more important role 
 in bacterial infection and are denominated microphages. The former 
 are able to engulf and completely digest a large number of cells. If 
 lymph glands, the great omentum or the spleen be crushed, ground in 
 a mortar and extracted with salt solution, a fine emulsion is obtained, 
 and this dissolves the red corpuscles of various vertebrates. This 
 hemolytic action is destroyed by a temperature of 56 C. continued for 
 one hour, and at 60 C. in a shorter time. This thermolabile ferment 
 is the cytase of Metchnikoff, the alexin of Buchner, and the comple- 
 ment of Ehrlich. It should be stated that the emulsion of macro- 
 phages contains other and thermostabile hemolytic agents, such as 
 fatty acids and soaps, but with these we are not concerned at present. 
 
 Bordet showed that the ferment obtained from the macrophages 
 is a complex body consisting of two parts. One is thermolabile, the 
 other thermostabile. One combines with red corpuscles even at low 
 temperature, but does not dissolve them until the other enters into the 
 reaction. Bordet calls the thermostabile body the sensitizer. It pre- 
 pares the red corpuscles for the action of the complement. Ehrlich 
 names the thermostabile substance the amboceptor, combining by one 
 hand with the red corpuscle and by the other with the complement. 
 Bordet's conception is that the action of. the sensitizer is a physical one 
 similar to that of a mordant ; Ehrlich's is that of a chemical combina- 
 tion. It is needless to go into a discussion of this difference since all 
 agree that the ferment consists of a thermostabile and a thermolabile 
 part and that joint action is necessary to induce hemolysis or other 
 cytolysis. The alexin or complement does not combine with the red 
 corpuscle or foreign cell directly, and does so only through the sensi- 
 tizer or amboceptor. In his later papers, Metchnikoff retains the term, 
 cytase, for the thermolabile body and adopts the term, fixator, for the 
 thermostabile substance. 
 
188 PHAGOCYTOSIS 
 
 It must be evident from the facts already stated that it is a func- 
 tion of the white blood corpuscles, to fall on invading cells, absorb 
 and digest them. By chemotaxis the phagocytes are called to the point 
 of bacterial invasion. The army of defense is mobilized by the blood 
 and lymph. The individual leukocytes may pass through tissues, 
 including the walls of vessels, and this aids in the movements of con- 
 centration. When the foreign protein, which has found its way into 
 the body, is dead, the only question about it is the ability of the phago- 
 cytes to digest it. If they are not able to do so at once, they may acquire 
 this function. When the foreign protein consists of living organisms, 
 there is a struggle between defenders and invaders. The destruction 
 of the latter does not depend solely on the ability of the former to 
 engulf and digest their opponents. The digestive ferments may be 
 excreted or poured out into the surrounding fluid by the phagocytes, 
 and at their death and dissolution all the ferment contained within 
 their bodies is disseminated throughout the adjacent tissue and exerts 
 its destructive action on the invaders. It seems that in giving their 
 lives for the protection of the body as a whole, the leukocytes may 
 become most effective. The secretions from the phagocytes are con- 
 stantly, in health and in disease, passing into the blood, and, besides, 
 these cells are constantly suffering death and dissolution and in this 
 way blood and serum receive a constant supply of germicidal enzymes. 
 
 Besides the leukocytes, there are certain fixed cells which may be 
 regarded as phagocytes. Such are connective tissue and endothelial 
 cells. However, some of these are modified leukocytes. For instance, 
 the Kupffer cells of the liver are now regarded by Metchnikoff as large 
 mononuclear leukocytes. This leaves the large cells of the lymph 
 glands, the spleen and bone marrow as fixed phagocytes. These are 
 regarded as playing only a subordinate role in immunity when com- 
 pared with the wandering leukocytes. 
 
 Phagocytosis in Natural Immunity. MetchnikofFs attention was 
 called to the subject of phagocytosis by observations on an infection 
 in a small, fresh-water crustacean, the daphnia, which on account of 
 its transparency offers special opportunity for a study of this kind. 
 This organism is infected by the spores of a certain yeast, which gain 
 access to the body cavity, where, when unhindered, they multiply in 
 great numbers and soon destroy their host. However, the invader 
 
PHAGOCYTOSIS 189 
 
 meets with resistance, and when the numbers are not too great, all the 
 spores are taken into leukocytes and digested. When the spores are 
 too numerous, they develop and pour out a secretion which kills and 
 digests the leukocytes, then fatal infection follows. In the trans- 
 parent daphnia all stages of this combat can be followed under the 
 microscope. Metchnikoff applied this knowledge to a study of anthrax 
 infection. He found that when animals naturally immune to this 
 organism, such as dogs and frogs, are inoculated, the bacilli are 
 engulfed in leukocytes which speedily gather at the point of inocula- 
 tion. On the other hand, in highly susceptible animals, such as guinea- 
 pigs and mice, phagocytosis is wholly wanting or but slightly in evi- 
 dence. In moderately susceptible animals, such as rats and rabbits, 
 phagocytosis is more marked and may or may not protect, depending 
 on the virulence and number of the bacilli introduced. Further studies 
 in many laboratories have shown that the greater the susceptibility of 
 an animal to anthrax, the less markedly does phagocytosis occur on 
 inoculation, and the more highly immune the animal the more marked 
 is the phagocytosis. It is generally admitted that natural immunity to 
 anthrax is due to phagocytic effectiveness. 
 
 In the study of certain anaerobic bacteria, as the bacilli of tetanus, 
 symptomatic anthrax and malignant edema, interesting facts concern- 
 ing phagocytosis have been ascertained. Paradoxical as it seems, all 
 animals have a natural immunity to tetanus, but this immunity is sup- 
 pressed when certain non-pathogenic bacteria are introduced into the 
 animal along with the tetanus bacillus. The injection of a large 
 amount of tetanus bacilli or their spores into animals are without 
 effect provided there is no ready-made tetanus toxin injected at the 
 same time. Under this condition, a large number of leukocytes collect 
 at the point of inoculation and soon devour the bacilli and spores. But 
 when the ready-made toxin is present, phagocytosis does not result 
 and a fatal infection follows. The explanation has been found to be 
 due to the fact that the toxin protects the tetanus bacilli by exerting 
 a negative chemotaxic effect on the leukocytes. It holds back or repels 
 the phagocytes until the spores and bacilli develop and produce more 
 toxin. A capillary glass tube filled with tetanus toxin and introduced 
 under the skin of an animal remains for a long time free from leuko- 
 cytes, while a similar tube filled with bacilli and spores, free from 
 
190 PHAGOCYTOSIS 
 
 toxin, attracts the leukocytes. The bacilli and spores exert a positive 
 chemotaxic effect upon leukocytes. In like manner the presence of 
 certain non-pathogenic bacteria occupies the activity of the phago- 
 cytes, giving time for the tetanus bacillus to elaborate its toxin. When 
 this point is reached, the bacilli are protected by their own secretion. 
 Likewise, if a culture containing the spores of symptomatic anthrax 
 be heated high enough (80 to 85 C.) to destroy any toxin that may be 
 present, and be injected into an animal, the phagocytes rush to the 
 point of inoculation and devour the spores. If, however, the spores, 
 free from toxin, be rubbed up thoroughly with fine sterilized sand and 
 particles of this mixture be introduced under the skin, the sand pro- 
 tects the spores long enough for them to develop toxin, infection 
 results, and the animal dies. A similar experiment has been made 
 with the spores of malignant edema. If toxin-free spores be mixed 
 with agar and bits of this be placed under the skin, the phagocytes 
 attack the agar, but while they are at work on this the enclosed spores 
 develop, produce toxin and infect the animal. If the bits of agar after 
 being placed under the skin are crushed between the fingers, the 
 phagocytes reach the spores, devour them and the animal is protected. 
 Certain non-pathogenic bacteria, which are frequently present in the 
 soil, protect the spores of malignant edema. 
 
 In natural immunity to tuberculosis, phagocytes develop into giant 
 cells, destroy the bacilli and lead to calcification. When the spirilla 
 of relapsing fever are injected into the peritoneal cavity of a guinea- 
 pig, they are devoured by phagocytes. In animals naturally immune 
 to certain cocci gonococcus, pneumococcus, streptococcus and staphy- 
 lococcus phagocytosis is in evidence. Natural immunity to pathoy 
 genie organisms other than bacteria, such yeasts, moulds, trypano- 
 somes and protozoa, is apparently largely due to phagocytic activity. 
 
 As has been stated, Metchnikoff holds that the polynuclear leuko- 
 cytes, which he calls microphages, play the important role in the bac- 
 terial diseases. The eosinophils also are capable of taking in and 
 digesting bacteria. This teaching is so fully accepted that a marked 
 increase in polynuclear leukocytes is taken as an indication of bacterial 
 infection. Microphages are transported from one part of the body 
 to another in blood and lymph, and by means of their pseudopodia, 
 they have independent movements. Under the microscope they can be 
 
PHAGOCYTOSIS 191 
 
 seen projecting their pseudopodia, surrounding and engulfing bacteria. 
 The bacterium is taken into a vacuole filled with clear fluid. If the 
 bacterium be motile its movements may continue in the vacuole, but 
 soon active movement ceases. Vibrios crumble into granules and 
 finally disappear. Bacilli become pale and transparent, then are seen 
 only in shadow and finally this is lost. Cocci swell up, become trans- 
 parent and then are lost to sight. However, some bacteria, such as the 
 tubercle and leprosy bacilli, remain in the microphage quite indefi- 
 nitely without recognizable change. The same is true of certain 
 spores. In these cases, there is no digestion, but the body is protected 
 from the multiplication of the organism. Phagocytes take up litmus 
 granules which show no change in color after inclusion, but bacilli 
 stained with neutral red become cherry red in the vacuole, showing 
 that the fluid is feebly acid. While this is the rule, in some phago- 
 cytes, as in the giant cells containing tubercle bacilli, the reaction is 
 plainly alkaline. There can be no question that phagocytes engulf and 
 finally destroy bacteria. A phagocyte, which has recently engulfed a 
 living bacillus, when brought in a hanging drop under the microscope, 
 soon dies itself and the liberated bacterium may begin to multiply, 
 but when the inclusion has continued for a longer time, the liberated 
 bacterium does not grow. There has been some discussion over the 
 question of the identity of the digestive ferments of the mononuclear 
 and the polynuclear phagocytes. A priori we should expect them to 
 be different, and the weight of evidence supports this view. Exudates 
 especially rich in mononuclear leukocytes are active as hemolytic 
 agents but have only feeble germicidal action, while those rich in 
 polynuclear leukocytes have no hemolytic action, but are powerful 
 bactericides. Is this difference in both the complement (alexin or 
 cytase) and the fixator (sensitizer or amboceptor) or in the latter 
 only? This question has given rise to some marked differences of 
 opinion but a positive conclusion is not justified by any undisputed 
 evidence and we will leave it for future investigators to answer. 
 
 In concluding this part of our subject, it must be admitted that 
 Metschnikoff and those who have labored in the same field have 
 demonstrated that phagocytosis is an important factor in natural 
 immunity. 
 
192 PHAGOCYTOSIS 
 
 Phagocytosis in Acquired Immunity. Metschnikoff has shown 
 that acquired immunity is largely due to stimulated phagocytosis. 
 This is true whether the immunity be due to one attack of the disease 
 or to vaccination. A rabbit which has been immunized to anthrax 
 shows a more marked phagocytosis on inoculation with a virulent cul- 
 ture than does a fresh animal. In the latter there is only a slight 
 serous exudate at the point of inoculation, while in the former there 
 is an abundant accumulation of leukocytes, which ingest and digest the 
 bacilli. A drop of this exudate injected into an animal highly suscep- 
 tible to anthrax, a guinea-pig or mouse, usually results in fatal infec- 
 tion, showing that the included bacilli are not immediately killed. 
 Some hours after inoculation of an immunized animal, microscopic 
 examination of the exudate shows no free bacilli. All are included in 
 the leukocytes and some seem normal while others show granulation 
 and others degenerative changes. Similar observations have been 
 made on other animals immunized to anthrax by vaccines. The phago- 
 cytes are stimulated by the introduction of the attenuated bacilli of the 
 vaccines, and finally become strong enough to contend successfully 
 with those of full virulence. 
 
 Pfeiffer has shown that if guinea-pigs be highly immunized to the 
 cholera vibrio by repeated intraperitoneal injections, the clear peri- 
 toneal fluid dissolves these organisms much as water dissolves sugar 
 or salt. There is no phagocytosis in evidence. In fact, the peritoneal 
 fluid is quite free from leukocytes. This is known as Pfeiffer's phe- 
 nomenon, and it has been held by many that it overthrew Metschni- 
 koff's theory of the importance of phagocytosis in acquired immunity. 
 In fact, this phenomenon has divided immunologists into two camps, 
 the holders of the humoral, and those of the cellular theory. Metsch- 
 nikoff explains Pfeiffer's phenomenon as follows : The repeated injec- 
 tions of the vibrio into the peritoneal cavity have accumulated in that 
 viscus many phagocytes which have been injured and have given up 
 their contents, including their digestive enzyme, to the surrounding 
 fluid. In fact, Metschnikoff has demonstrated masses of these dead 
 leukocytes on the peritoneal walls and the omentum. This destruction 
 and dissolution of the phagocytes he designates phagolysis. The agent 
 in the fluid which dissolves the vibrios is the enzyme from the injured 
 leukocytes. The solvent action proceeds extracellularly, but the sol- 
 
PHAGOCYTOSIS 193 
 
 vent agent is of intracellular origin. Furthermore, he has shown that 
 the phagolysis can be prevented, and when this is done the peritoneal 
 fluid remains rich in leukocytes and phagocytic action is easily dem- 
 onstrated under the microscope. Still further, Levaditi has shown 
 that phagolysis may occur in other parts of the body. If the cholera 
 vibrio be injected into the circulation of a highly immunized guinea- 
 pig, the phagocytes practically disappear from the peripheral blood. 
 On sectioning the lungs they are found in clumps and evidently 
 injured. About them are seen masses of the vibrio undergoing diges- 
 tive changes. Positive chemotaxis still manifests its influence and 
 brings the phagocytes and bacilli together at the place where the 
 former, in undergoing dissolution, pour out a secretion which is fatal 
 to the latter. 
 
 If cholera vibrios be injected into the anterior chamber of the eye 
 of a highly immunized guinea-pig, a place where there has been no 
 phagolysis, the phagocytes concentrate here and phagocytosis may be 
 demonstrated. 
 
 Further elucidation of this subject seems unnecessary. It is evi- 
 dent that in acquired immunity there is increased activity and effec- 
 tiveness on the part of the phagocytes in the destruction of the invad- 
 ing organism, which may be destroyed by intracellular or extracellular 
 digestion. In either case the destructive agent is supplied by the 
 phagocytes. Metschnikoff holds that in the body intracellular digestion 
 is the rule and that extracellular destruction plays only a subordinate 
 role. 
 
 Phagocytosis in Injuries and Disease. In this section we continue 
 to follow the teachings of Metschnikoff. In inflammation there is an 
 accumulation of phagocytes at the point of injury. When the injury 
 is aseptic, the functions of the phagocytes are to remove the injured 
 body cells and to repair the tissue. In septic wounds the additional 
 duty of destroying the foreign cells falls on the phagocytes. In the 
 lower animals which possess neither nerves nor blood vessels, the 
 motile connective-tissue cells devour the invading organisms. In the 
 higher animals the process is more complicated. Through nerve stim- 
 ulation, the blood vessels of the injured part are dilated, phagocytes 
 from distant parts of the body are brought to the locality and pass 
 
194 PHAGOCYTOSIS 
 
 through the walls of the vessels. Inflammatory transudates which 
 contain but few leukocytes are the exceptions. They occur only when 
 the injury is so slight that great activity is not needed or at the other 
 extreme when it is so great or the infection is so virulent that repair 
 and resistance are impossible. The mononuclear cells, the macro- 
 phages, may become fixed connective tissue and form scar-tissue. The 
 polynuclear cells, the microphages, do not serve this purpose. 
 
 There are inflammations which are due to soluble irritants with- 
 out cellular elements. In these instances the phagocytes assemble and 
 feed on the fluid. Strictly speaking, there are probably but few 
 wounds absolutely free from bacteria, but when these are few in 
 number and non-virulent, they are soon destroyed by the phagocytes 
 and healing by first intention results. 
 
 Fehleisen has studied phagocytosis in erysipelas. In the initial 
 stage the streptococci are, for the most part, free ; in the second, many 
 are included in phagocytes; in gangrenous areas there are but few 
 leukocytes and these show degenerative changes ; in healed areas there 
 are but few free cocci, many in leukocytes, also many macrophages. 
 Beyond the inflammatory area the cocci are free; on the edge many 
 cocci are included in phagocytes ; in the third zone the cocci are want- 
 ing and there is marked small-cell infiltration. In pneumonia the 
 favorable progress of the disease is indicated by an increase in the 
 sputum of phagocytes containing pneumococci. Immediately after a 
 slight leakage from a diseased appendix all the bacteria are free, with 
 time more and more are found in leukocytes, and in case of recovery, 
 all are disposed of in this way. 
 
 Phagocytosis is in evidence in certain systemic infections, for 
 instance, relapsing fever. This has been studied in apes. The first 
 febrile stage lasts a few days and generally ends in permanent recov- 
 ery. Several apes were killed at different hours in the febrile stage. 
 Before the fever, the spirilla may be abundant in the blood, but with 
 the rise in temperature they can no longer be detected in the peripheral 
 circulation. At the crisis, the polynuclear cells of the spleen are filled 
 with the spirilla, some of which seem quite normal while others show 
 degenerative changes. A fresh ape inoculated with these cells develops 
 the disease, showing that at least some of the included spirilla are still 
 alive and virulent. An examination of the spleen after recovery shows 
 
PHAGOCYTOSIS 195 
 
 all the spirilla markedly changed and inoculation with this material 
 does not induce the disease. It is true that the serum of one in the 
 febrile stage of relapsing fever is markedly bactericidal to the spiril- 
 lum, but this is due to the destruction of the leukocytes and the pass- 
 ing of the enzyme into solution. There seems no doubt that recovery 
 from relapsing fever is due to phagocytic activity. 
 
 Uhlenhuth found that phagocytosis is responsible for the sponta- 
 neous healing of experimental syphilis in rabbits. Like success is not 
 in evidence in this disease in man, although here also phagocytosis 
 seems to deserve credit for the healing of specific lesions so far as 
 they spontaneously occur. 
 
 The fact that the plasmodia of malaria are engulfed by the phago- 
 cytes of the blood, spleen and liver is well known. Many of them are 
 undoubtedly destroyed in this process, but unfortunately many escape 
 to multiply and continue to induce their deleterious effects. 
 
 Rindfleisch holds that phagocytes are more or less effective in the 
 removal of gouty deposits. 
 
CHAPTER XXV 
 
 SPECIFIC PRECIPITINS 
 
 History. In 1897 Kraus discovered that the blood serum of ani- 
 mals immunized to a given bacterium gives a precipitate when mixed 
 with a germ-free nitrate of a culture of that organism. Further study 
 showed that this reaction is specific. Cholera serum precipitates only 
 cholera filtrates ; typhoid serum only typhoid filtrates, etc. Two years 
 later Tchistowitsch and Bordet ascertained that this is a general pro- 
 tein reaction. A rabbit which has had several injections of horse 
 serum yields a serum which precipitates horse serum and no other. 
 One treated with cow's milk furnishes a serum which precipitates 
 cow's milk and no other. One treated with the white of the hen's egg 
 precipitates egg albumin and no other protein. This test is now used 
 practically in the identification of blood stains, in the detection of 
 mixed meats and in the study of the blood relationship of animals. 
 
 If a blood stain be dissolved in salt solution and then mixed with 
 the blood serum of a rabbit which has been repeatedly treated with 
 human blood, a precipitate will form if the stain is human blood. If 
 a Hamburger steak be extracted with water, the clear filtrate will be 
 precipitated with the blood of an animal which has been treated with 
 horse's blood provided the steak contains horse meat. The meat of 
 any other animal in the steak can be detected in the same way. If 
 the steak contains beef and horse meat, its extract will precipitate the 
 serum of an animal treated with extract of horse meat also the serum 
 of one which has been treated with an extract of beef. The serum 
 of a rabbit treated with human blood will give a marked precipitate 
 even in a high dilution of human and a slighter one in undiluted chim- 
 panzee's blood serum. This supplies a method of detecting and iden- 
 tifying different proteins in quantities too small to be detected in any 
 other way. 
 
 The Precipitinogen. The substance which is injected into the ani- 
 mal is known as the precipitinogen (producer of the precipitin). Pre- 
 cipitinogens are bacterial, vegetable, and animal. A culture of the 
 
198 PRECIPITINS 
 
 typhoid bacillus, preferably one several weeks old, is filtered through 
 porcelain, in order to free it from the bacterial cells, then every third 
 or fourth day some of the filtrate is injected into a rabbit. Some days 
 after the last injection, serum obtained from this rabbit precipitates 
 the typhoid filtrate and that of no other bacterium. Other precipi- 
 tinogens are used in like manner with like result. The thing in the 
 bacterial culture or other fluid, which produces this effect, has never 
 been isolated. We only know that all precipitinogens are albuminous 
 substances, or derivatives of these, and that no fat, carbohydrate or 
 crystalloid has such action. Some precipitinogens contain only simple 
 proteins and these in small amounts, as is shown by the application 
 of tests for proteins. 
 
 The Precipitins. The substance in the immune serum is known as 
 a precipitin. In the sera of certain animals, which have had no 
 treatment, there are natural precipitins. The serum of the untreated 
 ox, undiluted, precipitates many bacterial filtrates. Normal goat's 
 serum gives precipitates with the sera of rabbits and dogs. These 
 normal precipitins do not interfere with our tests because (1) they 
 are not specific and (2) they do not give the precipitates in high 
 dilutions. Not every animal produces precipitins. The best laboratory 
 animal for the production of precipitins is the rabbit. It is best in 
 case of blood tests not to select an animal closely related with that 
 from which the precipitinogen comes. The blood of one animal will 
 not develop a precipitin in another of the same species. The precipi- 
 tinogen may be administered intra-abdominally, subcutaneously or 
 intravenously. Administration by the mouth produces a precipitin 
 only when for some reason the precipitinogen is absorbed undigested. 
 This may result from overfeeding and easily happens in the young. 
 Puppies, kittens, and rabbits, up to ten days old, frequently absorb 
 unchanged proteins from the alimentary canal and this leads to the 
 production of precipitins. It has been found in a few instances that 
 the serum of infants precipitates cow's milk. This indicates that the 
 casein of the food has been absorbed undigested. It is possible that this 
 is a factor in the causation of cholera infantum. Especially is milk 
 partly changed by peptonizing bacteria likely to be absorbed without 
 digestion. 
 
PRECIPITINS 199 
 
 The tissue in which the precipitin is formed is evidently not the 
 same in all cases. It depends on the nature of the precipitinogen and 
 the avenue of its introduction. When a foreign protein is introduced 
 parenterally, it has a predilection for certain tissues and this is dif- 
 ferent for different proteins. We only know at present that precipitins 
 are formed in organs rich in leukocytes. The mononuclear cell is 
 believed to be active in this function. It is probable that the endo- 
 thelial cells of the blood vessels also have this function. 
 
 The precipitin can be thrown down in serum by one-third satura- 
 tion with ammonium sulphate and seems to be contained in the 
 euglobulin fraction. Attempts to obtain a protein-free precipitin have 
 failed; indeed, I think it highly probable that the precipitin is a pro- 
 tein. When heated to 70 degrees the serum no longer reacts with the 
 precipitinogen. 
 
 The Precipitate. This results from a reaction between the pre- 
 cipitinogen and the precipitin. In case of bacterial nitrates, the precipi- 
 tate does not form directly on adding the precipitin to the precipi- 
 tinogen and it is customary to allow the mixture to stand at incubator 
 temperature for from two to twenty-four hours. The rapidity and 
 abundance of the formation of the precipitate depend on the richness 
 of the fluids in their respective active constituents. With animal pre- 
 cipitinogens the precipitate may appear immediately on the mixture of 
 the fluids. Precipitation takes place in neutral, feebly alkaline and 
 feebly acid solutions. When the acidity is due to organic acid or acid 
 salt, the action is promoted. In the complete absence of inorganic 
 salts the reaction fails. The precipitate consists essentially of pro- 
 tein. It contains no carbohydrate group, is insoluble in mineral acid 
 and alkali, and is highly resistant to the digestive ferments. There 
 seems no doubt that the bulk of the precipitate is derived from the 
 precipitin. Pick employed a precipitinogen which did not give the 
 biuret reaction and with this obtained a voluminous albuminous pre- 
 cipitate. Welch and Chapman obtained with a precipitinogen which 
 contained only 1 mg. of protein, a precipitate which contained 25.1 
 mg. of protein. Evidently, in these cases, the bulk of the precipitate 
 must come from the serum. However, this is not always true since 
 the bulk of the precipitate produced with lactosera consists of 
 casein. It is probable that in many instances substances other than the 
 
200 PRECIPITINS 
 
 precipitinogen and the precipitin are carried down mechanically. When 
 a new dose of precipitinogen is injected into an animal whose blood 
 already contains the corresponding precipitin, the amount of the latter 
 is for a time markedly decreased. This leads to the inference that the 
 union between precipitinogen and precipitin takes place in the body, 
 but there is no evidence that a precipitate is formed in vivo. 
 
 That both factors enter into the formation of the precipitate quan- 
 titatively is known, but it is not known whether or not the whole of 
 each factor exists in the product, nor is it known whether the reaction 
 is a physical or a chemical one. Evidently the presence of electro- 
 lytes is essential to the reaction. Quantitatively the reaction is spe- 
 cific. The serum of animals immunized to one strain of the colon 
 bacillus precipitates the filtrate from this strain in higher dilution than 
 it does the filtrate from other strains, and there may be strains of the 
 colon bacillus whose filtrates it will not precipitate at all. It is quite 
 certain that the precipitation of filtrates agrees with the agglutination 
 of the living bacilli. It is difficult not to believe that the specificity 
 of both these reactions, precipitation and agglutination, is due to the 
 chemical structure of the protein molecule and that both are due to 
 definite cleavage of this molecule in the process of parenteral digestion. 
 
CHAPTER XXVI 
 
 AGGLUTINATION 
 
 History. In 1889 Charin and Roger in studying the action of the 
 serum of sick and immunized animals on homologous bacteria, 
 observed that the Bacillus pyocyaneus behaved peculiarly when placed 
 in the serum of an animal immunized to this organism. In the serum 
 of a normal rabbit, this bacillus grows as it does in beef-tea, form- 
 ing an opaque culture, while in the serum of an animal immunized to 
 it, it forms floccules which soon subside leaving a clear supernatant 
 fluid. Two years later, Metschnikoff noticed that the vibrio which 
 bears his name behaves in a similar manner. He recorded this obser- 
 vation as follows: 
 
 In the blood and serum of non-vaccinated guinea-pigs, the vibrio develops 
 as it does in ordinary liquid media, the individual organisms retaining their 
 motility and remaining distinct, one from the other. On the other hand, in 
 the blood and serum of vaccinated animals the vibrios become immobile, and 
 form smaller or larger floccules which float in the liquid. 
 
 In 1893 Issaeff, and later he and Ivanoff observed the same phe- 
 nomenon and described it as follows : 
 
 In the blood serum of healthy, non-immunized guinea-pigs the vibrio develops 
 rapidly, and after from four to five hours at 37 there is a uniform cloudiness 
 throughout the fluid, while the surface is covered with a scum; but in immune 
 serum, the microbes sink to the bottom of the tube, while the supernatant fluid 
 remains clear. This condition continues for from eight to nine days, and it 
 is not until the tenth day that the culture becomes cloudy and a scum appears 
 on the surface. 
 
 These observations attracted no attention and in all probability their 
 significance was not appreciated by the observers themselves. In 
 1896, Gruber and Durham ascertained that this reaction is specific. 
 Each bacterium is clumped by the serum of animals which have been 
 inoculated with it and not by other sera. They suggested that the 
 phenomenon be designated as "agglutination" and that it would prove 
 
202 AGGLUTINATION 
 
 serviceable in the identification of bacteria. A given bacterium is the 
 typhoid bacillus if it is agglutinated by the properly diluted serum of 
 an animal immunized to this organism. If an unknown culture is not 
 agglutinated by the serum of an animal immunized to the cholera 
 bacillus, the culture does not contain this organism. I have carefully 
 read the original paper of Gruber and Durham and fail to find therein 
 any reason for concluding that these investigators at that time had 
 any idea that the phenomenon which they were investigating was soon 
 to become one of the most certain and easily applicable methods for 
 the diagnosis of typhoid fever. It is true that they speak of the 
 serum test as a diagnostic measure, but from the context it is plainly 
 evident that by the term diagnosis they mean the specific and positive 
 identification of a suspected bacterium. A few months after the pub- 
 lication of this paper of Gruber and Durham, Widal demonstrated the 
 value of this reaction in the diagnosis of typhoid fever. 
 
 Factors. It is evident that in such a reaction as that observed in 
 agglutination there must be two factors. One of these, designated the 
 agglutinin, is found in the serum, and the other, known as the agglutin- 
 able substance, exists in the bacterial culture. The product of the 
 reaction is known as the agglutinate. The serum of certain normal 
 animals has a slight agglutinating action on certain bacteria, notably 
 typhoid and colon bacilli. The normal serum of the horse, dog, 
 donkey, and rabbit, in an undiluted state, agglutinates typhoid cul- 
 tures. Some effect may be observed when the serum is diluted 1 : 30. 
 The serum of a man, who has never had typhoid fever, may agglutin- 
 ate typhoid cultures when the dilution is not higher than 1 :30. The 
 period in the progress of typhoid fever when marked agglutination 
 manifests itself varies widely. Usually it is not before the seventh 
 day, but it may occur as early as the second day, and it may be delayed 
 until the second week and in rare cases even later. Likewise the dis- 
 appearance of the reaction after recovery is variable. It may fail 
 within ten days after the loss of the fever, and it has been known to 
 continue for years. In intensity the reaction is variable and bears no 
 indication of the severity or seriousness of the disease. There are 
 many ways in which the phenomenon may be observed and measured. 
 One recommended by Widal and Sicard and much employed is the 
 following : 
 
AGGLUTINATION 203 
 
 A number of small diameter tubes each containing 1, 2, 3, 4, or 5 c.c. of 
 bouillon, are kept on hand. When a test is to be made, one adds a drop of 
 the serum to each of these tubes and then inoculates each with a typhoid cul- 
 ture. The tubes are then kept at incubator temperature for from four to six 
 hours. At the expiration of this time it may be seen at a glance in which tubes 
 agglutination has taken place, since these will be unclouded and the floccules 
 will be seen on the bottom. The first tube has a dilution of 1 : 20 ; the second, 
 1 : 40, etc. 
 
 Johnston was the first to show that a drop of blood allowed to 
 dry on non-absorbent paper, may be transported any distance and 
 kept indefinitely and still be capable after solution in water of giving 
 the agglutination test. However, accuracy in dilution is not reached. 
 The reaction may be observed in a hanging drop under the microscope 
 when only one drop of blood is available. 
 
 Agglutinins exist not only in the blood, but in other fluids of the 
 body. The agglutinating power of the urine in the same individual 
 is variable not only from day to day, but from hour to hour, and is 
 always feeble compared with that of the serum. Serum obtained by 
 blisters has a relatively high agglutinating value. That of the bile is 
 marked. Pus from typhoid abscesses markedly agglutinates. Agglu- 
 tinins may pass from the mother to the fetus and to the nursing child. 
 Typhoid serum may be treated with formaldehyd in 40 per cent, solu- 
 tion and kept quite indefinitely without loss of its agglutinating 
 property. However, the use of antiseptics is not necessary to preserve 
 agglutinating sera. A highly active serum will retain its agglutin- 
 ative action after it has become putrid from bacterial contamination. 
 Dilute mineral acids decrease the agglutinating property of typhoid 
 sera, but when the contact has not been prolonged, full activity may 
 be restored by neutralization. Alkalies act similarly. App arently the 
 agglutinins are not altered by either pepsin or trypsin. In experimental 
 animals, sera can be obtained which will agglutinate typhoid bacilli 
 in dilutions as high as 1 : 1,000,000 and colon bacilli, 1 : 2,000,000. 
 
 Quantitatively the agglutinins are specific, but in order to be so 
 considered they must be active in high dilutions. A positive diagnosis 
 of typhoid fever should not be made unless the serum acts decidedly 
 in a dilution not less than 1 : 50, and even in this dilution there is a 
 rare chance of mistake. A paratyphoid serum may agglutinate typhoid 
 
204 AGGLUTINATION 
 
 bacilli in a dilution of 1: 1,000; or a typhoid serum may act in like 
 dilution on a paratyphoid bacillus. In making a clinical diagnosis such 
 a mistake would be of little or no importance, but in the identification 
 of a bacterium it would be important. According to Paltauf the fol- 
 lowing dilutions are necessary for the positive identification of the 
 named bacteria: plague bacillus, 1: 1,000; typhoid and cholera bacilli, 
 1 : 10,000. The active substance in the serum, the agglutinin, is 
 undoubtedly a globulin. It is inactivated at temperatures which range 
 from 75 to 90 C. in different sera. 
 
 The active constituent of the culture, the agglutinable substance, 
 is not, in my opinion, an essential constituent of the bacterial cells, 
 but consists of one or more proteins closely associated with the bac- 
 terial cells. It may be a protein already split off from the bacterial 
 pabulum in the culture medium preparatory to absorption, or it may 
 be an excretory product. The reasons for this belief may be briefly 
 stated as follows: 
 
 1. Agglutination does not destroy the viability or virulence of 
 bacteria; therefore, the reaction does not disrupt the living bacterial 
 cell. 
 
 2. Thoroughly washed typhoid bacilli are not agglutinable. 
 
 3. When typhoid bacilli are thoroughly shaken in salt solution so 
 as to remove the flagellae and the bacilli are deposited in a centrifuge, 
 the emulsion of flagellae is agglutinable. 
 
 4. Cholera bacilli, as shown by Neufeld, when shaken with 1 per 
 cent, alkali, which does not dissolve the cells but washes away the 
 adherent matter, the cleansed cells are not inagglutinable, but when 
 injected into animals they produce no agglutinin. 
 
 Agglutination and precipitation are like phenomena. When a 
 bacterial culture is filtered, some of the proteins adherent to the bac- 
 terial cells pass into solution and constitute the precipitinogen, some 
 of the same class of near-cell proteins remain in close connection with 
 the cells and constitute the agglutinable substance or the agglutinogen. 
 Inorganic salts are essential to agglutination. The reaction is that of 
 a colloid and the specificity is due to the chemical structure of the 
 proteins entering into the reaction. The agglutinable substance is 
 
AGGLUTINATION 205 
 
 shaped and its chemical structure determined by the ferments of 
 specific bacteria, consequently it is specific. 
 
 As Widal concluded years ago, agglutination is not a reaction of 
 immunity, but a reaction of infection. Both agglutination and pre- 
 cipitation are evidences of parenteral digestion. 
 
CHAPTER XXVII 
 
 OPSONINS 
 
 Metschnikoff ascribes both natural and acquired immunity to the 
 activity of the phagocytes. In the former the leukocytes fall on the 
 invading bacteria and devour them. In acquired immunity the phago- 
 cytes are stimulated by the attenuated cultures, or vaccines, and learn 
 how to cope with the invaders. The phagocytes constitute the mobile 
 army of defense. Without previous training they are able to destroy 
 certain bacteria; this constitutes natural immunity. By first bringing 
 them in combat with attenuated cultures, which they satisfactorily dis- 
 pose of, they are so trained that they become able successfully to 
 combat virulent forms ; this explains acquired immunity. Both depend 
 on the efficiency and aggressiveness of the phagocytes. In the main, 
 MetschnikofFs facts have been corroborated, even by those who have 
 desired to controvert them. Phagocytosis is more marked in an 
 immunized animal than in a fresh one of the same species. Is this 
 due to increased efficiency on the part of the phagocytes or to impair- 
 ment of the bacteria ? This is the question now before us. 
 
 The fundamental facts essential to the solution of this problem 
 were discovered by Denys and Leclef in 1895. They showed that 
 phagocytes can be obtained and mixed with bacteria in vitro and that 
 phagocytosis may be observed under conditions controlled by the 
 investigator. They established the following: 1. Phagocytosis pro- 
 ceeds in vitro the same as in vivo. 2. When the phagocytes are col- 
 lected from an animal immunized and from one not immunized and 
 these are washed free from all serum and mixed with the immunizing 
 bacteria suspended in either salt solution or normal serum there is no 
 phagocytic action in either tube. The phagocytes from the immunized 
 animal and those from the non-immunized animal are alike impotent. 
 3. When the two kinds of phagocytes are mixed with the bacteria and 
 suspended in the serum of an immunized animal, phagocytic action 
 begins promptly and is equally marked in the two tubes. 
 
208 OPSONINS 
 
 These facts show that the agent which develops and stimulates 
 phagocytosis is in solution in the blood of the immunized animal, is 
 not present in the blood of the non-immunized animal, and is apart 
 from the leukocytes. 
 
 The work of Denys and Leclef seems to have been ignored for 
 some years, and quite ignorant of it, Leishman in 1902 showed that 
 phagocytic action can be demonstrated in a drop of human blood 
 freshly taken. He determined the degree of phagocytic action by 
 counting the included bacteria in a number of phagocytes and showed 
 that these were greater in the blood of one vaccinated with staphylo- 
 cocci than in normal man. In this way, Leishman opened the way for 
 "vaccine therapy," which has since been widely employed. Wright and 
 Douglas developed this treatment and proposed that the substances in 
 the blood which favor phagocytic activity should be designated 
 "opsonins" (from the Greek, t<t><rwvfa f meaning, "I prepare the food"). 
 They showed that the opsonins in normal blood vary in narrow limits 
 and that they are greatly increased by the subcutaneous injection of 
 dead bacterial cultures, known as vaccines. It is only fair to state 
 that many years earlier Wright had used heated typhoid bacteria in vac- 
 cination against this disease. It is not my purpose to discuss here 
 either the methods of employment or the value of bacterial "vaccines." 
 
 The normal blood of man and other animals contains opsonins or 
 substances which favor phagocytic action with numerous bacteria, and 
 these are increased by proper vaccination. When the normal blood 
 contains no opsonin for a given bacterium, one can be developed by 
 vaccination, that is, by repeated parenteral administration of that 
 bacterium either in numbers too small to endanger life or attenuated 
 or killed by heat. In some instances the bacterium while in the body 
 forms a capsule. This is strikingly true of anthrax and plague bacilli. 
 The apparent purpose of this is self-protection. Not all bacteria which 
 are taken into phagocytes are killed. However, even in these cases 
 phagocytosis is protective to the body. When bacteria undergo com- 
 plete disruption outside a phagocyte, its poisonous content is set free 
 and exerts its deleterious effects. The inclusion of dead bacteria is 
 protective for the same reason. When there is no phagocytosis and 
 the bacteria are rapidly split up by a bactericidal serum, the greater 
 
OPSONINS 209 
 
 is the danger to life. It follows from this that a large opsonin blood 
 content is more protective than a powerful bactericidal blood. 
 
 Certain bacteria are readily devoured by phagocytes in normal 
 salt solution or in inactivated normal serum. In other words, with 
 these bacteria opsonins are not essential to phagocytosis. Naturally 
 these are avirulent organisms. It must not be inferred, however, that 
 all avirulent bacteria are phagocitized without the aid of opsonins. The 
 phagocytic-favoring substances are of two kinds. The first, known as 
 tropins, are evidently of relatively simple structure, are not inactivated 
 by heat, and consequently are present in heated serum. The true 
 opsonins are more complicated, consisting of a thermolabile part, known 
 as alexin or complement, and a thermostabile part, known as fixator 
 or amboceptor. Since both parts are essential to complete action, 
 serum is inactivated by heat. Neither tropins or opsonins induce recog- 
 nizable alterations in the bacteria which they prepare for phagocyto- 
 sis. In the study of phagocytosis in vitro, MetschnikofFs finding that 
 bacteria are devoured by the polynuclear leukocytes has been confirmed. 
 The large mononuclear cells are not wholly indifferent in the disposal 
 of bacteria but in this they play a very subordinate role. On the 
 other hand, the macrophages are the chief consumers of animal cells, 
 such as red corpuscles, spermatozoa, etc. 
 
 It was shown early in these studies that dead, highly virulent bac- 
 teria are not readily taken up by leukocytes except in the presence of 
 immune serum. This indicates that dead, as well as living bacteria, 
 especially if of virulent strains, are prepared by the opsonins as food 
 for the leukocytes. From this we infer that in whatever reaction there 
 may be between the opsonins and the bacterial cells, the later show 
 no vital activity. 
 
 It was shown by Neufeld and Handel that when rabbits have been 
 treated with injections of milk or egg white, their serum causes leu- 
 kocytes to engulf milk globules and albumin emulsified with oil. The 
 engulfment is not due to the oil but to the casein or albuminous 
 envelopes. 
 
 It is well to show that the opsonins do not act by stimulating the 
 leukocytes. When leukocytes are kept in contact with immune serum 
 for twenty minutes at 37 C, then removed and washed wholly free 
 from the serum and then brought into contact with the bacteria there 
 
210 OPSONINS 
 
 is no phagocytosis. On the other hand, when the bacteria are kept 
 in contact with the immune serum, then washed and brought in 
 contact with the leukocytes, active phagocytosis begins. This shows 
 that the serum of an animal immunized to a streptococcus, for instance, 
 does not stimulate the leukocytes but in some way makes the strepto- 
 cocci more inviting as a food. 
 
 Parenthetically it should be stated that there are substances which 
 stimulate phagocytes, such as nuclein, peptone, quinin, potassium 
 iodid, etc., but these have nothing to do with opsonins. Anesthetics 
 inhibit phagocytic action and the same is true of narcotics. 
 
 The study of phagocytosis in vitro has shown that the immune 
 serum and the leukocytes need not come from the same animal, not 
 even from the same species. Hektoen has shown that immune sera 
 from horses, dogs, rabbits, guinea-pigs, etc., prepare streptococci so 
 that they are readily devoured by leukocytes from man. This list of 
 animals has been extended by Hektoen's students so that it includes 
 certain cold-blooded ones. Streptococci sensitized with immune sera 
 from warm-blooded animals are readily devoured by phagocytes from 
 cold-blooded ones. This makes it all the more certain that the reaction 
 is between the serum and the bacteria. When the latter are prepared 
 by the former, a phagocyte from any kind of an animal will eat them. 
 
 The opsonins do not kill the bacteria; indeed, they do not stop 
 their growth nor lessen their virulence. When bacteria have been in 
 contact with homologous immune sera long enough to be sensitized 
 and are then placed in ordinary culture media, they multiply, and 
 their progeny are not found to be sensitized. We infer that the union 
 between cell substance and opsonin has no destructive or radical effect 
 on the former. In fact, Hektoen has shown that anthrax bacilli, strep- 
 tococci and pneumococci grow abundantly in homologous immune 
 sera. 
 
 Phagocytosis proceeds in the same way in vitro and vivo. The 
 serum from a rabbit immunized to streptococcus, will sensitize the 
 streptococcus in a test-tube or in the abdominal cavity of a guinea- 
 pig, and a healthy phagocyte from any source will eat the prepared 
 food in either place. Indeed many bacteria are more readily disposed 
 of by the phagocytes in test-tubes than in the body, because in the 
 latter they develop in the second and subsequent generations, protec- 
 
OPSONINS 211 
 
 tive capsules. Some show other alterations which evidently have the 
 same purpose. We distinguish between "animal" and "culture" bac- 
 teria inasmuch as the former are more resistant especially to the 
 destructive secretions of the body cells. 
 
 Observation shows that most of the bacteria taken into the leuko- 
 cytes are completely digested. The bacterial cells become pale, then 
 granular, and finally disappear altogether. Occasionally a phagocyte 
 takes in more bacteria than it can digest and injures itself, in some 
 cases, fatally. The digestive phenomena are identical in the test-tube 
 and in the body. The tubercle bacillus, although readily engulfed by 
 phagocytes, is not digested. These bacilli probably owe their protec- 
 tion to the abundant deposits of wax and fat which they contain. The 
 intracellular ferment of the phagocytes is studied by collecting a large 
 number of leukocytes and dissolving them in very dilute acid or alkali 
 or breaking them down by alternating freezing and thawing. . This 
 ferment is not destroyed by a temperature of 65 C. It is able to 
 digest many bacteria, such as streptococci and pneumococci, which are 
 not affected by extracellular ferments. Levaditi found that the intra- 
 cellular ferment of the polynuclear cells acts on bacteria but is with- 
 out effect on red corpuscles, trypanosomes and spirochetes, while that 
 of the large mononuclear cells acts on the latter group and has but 
 little or no action on bacteria. Opie found the ferment from the poly- 
 nuclear cells, which he calls leukoprotease, acts in neutral or feebly 
 alkaline solution, while that from the large mononuclear cells, which 
 he calls lymphoprotease, acts only in acid solution. When leukopro- 
 tease is set free in the body by the disruption of the polynuclear leuko- 
 cytes, its action is inhibited by soluble substances in the plasma. When 
 lymphoprotease is set free in the blood, its action is inhibited by the 
 alkalinity of the fluid. It appears from this that, physiologically, both 
 of these ferments are active only within the cells which elaborate them. 
 It is by virtue of these intracellular ferments that the phagocytes kill 
 and digest the bacterial and other cells which they engulf. 
 
 Whether the action of opsonins on bacteria is wholly physical, 
 wholly chemical, or both, we do not know. Neufeld states that this 
 action is not chemotaxic, because unsensitized bacteria, in suspension 
 with phagocytes, collect about the latter quite as plainly as sensitized 
 bacteria do; but with the former there is no phagocytosis. It seems 
 
212 OPSONINS 
 
 justifiable with our present knowledge to conclude that the opsonins rob 
 the bacteria of some defensive weapon and thus make them easy prey 
 for the phagocytes. To go farther than this at present would result in 
 unprofitable speculation. 
 
CHAPTER XXVIII 
 
 GERMICIDAL SERA 
 
 Normal Sera. As early as 1872 Lewis and Cunningham demon- 
 strated the fact that bacteria injected into the circulation rapidly dis- 
 appear. In the blood of twelve animals which had been given such injec- 
 tions, bacteria could be found after six hours in only seven. In a 
 second series of thirty, bacteria were found after twenty-four hours 
 in the blood of only fourteen, and in a third experiment with seven- 
 teen animals, bacteria were found in only two when the examination 
 was made within from two to seven days. 
 
 In 1874, Traube and Gscheidlen found that arterial blood taken, 
 under aseptic precautions, from the jugular vein of rabbits into which 
 a small amount of a putrifying fluid had been injected forty-eight 
 hours previously, failed to undergo decomposition for months. They 
 attributed the germicidal properties of blood to the ozonized oxygen. 
 Grohmann found that anthrax bacilli decrease in virulence on being 
 kept in plasma. 
 
 In 1887, Fodor found that anthrax bacilli rapidly decrease in 
 numbers when injected into the circulation. He then took blood from 
 the heart with a sterile pipette, inoculated it with anthrax, kept it at 
 incubator temperature and plated it out at intervals. He found that 
 the number decreased for some hours and then multiplied abundantly. 
 
 In 1888 Nuttall found that defibrinated blood from various species 
 of animals, sheep, rabbits, mice and pigeons, destroys both pathogenic 
 and non-pathogenic bacteria. He also confirmed the finding of Fodor 
 that after a time the blood loses its germicidal action and becomes a 
 suitable culture-medium in which the bacteria multiply abundantly. In 
 his studies, Nissen reached the following conclusions: 1. The addition 
 of small quantities of salt solution or bouillon to the blood does not 
 destroy its germicidal properties. 2. Cholera and typhoid bacilli are 
 easily destroyed by fresh blood. 3. In a given volume of blood there is 
 a maximum number of bacilli, which can be destroyed. 4. Blood, the 
 coagulability of which has been destroyed by the injection of peptone, 
 
214 GERMICIDAL SERA 
 
 is still germicidal. 5. Blood in which coagulation is prevented by 
 the addition of 25 per cent, of magnesium sulphate, has its germicidal 
 properties decreased. 6. Filtered blood plasma from the horse is 
 germicidal. 
 
 At one time, Behring attributed the action of the blood of the 
 white rat on anthrax bacilli to its alkalinity. He made titrations which 
 showed that the blood serum of the rat is more alkaline than that of 
 certain susceptible animals, as the cow, rabbit and guinea-pig. How- 
 ever, there are other and more important points in which these animals 
 differ from the rat than in slightly less blood alkalinity. Had he shown 
 that the blood of the adult rat, which is highly resistant to anthrax, is 
 more alkaline than that of the young rat, which is more susceptible, 
 his argument would have been more reasonable; but even then it 
 would not be convincing evidence. 
 
 In 1890, Buchner made valuable contributions to our knowledge 
 of the germicidal properties of blood and stated his conclusions as fol- 
 lows : 1. The germicidal action of blood serum is not due to phagocytes, 
 because it is not influenced by the alternate freezing and thawing of 
 the blood, by which the leukocytes are destroyed. 2. The germicidal 
 properties of the cell-free serum must be due to its soluble constituents. 
 3. Neither neutralization of the serum, nor the addition of pepsin, nor 
 the removal of carbon dioxid gas, nor treatment with oxygen, has any 
 effect on the germicidal properties of the blood. 4. Dialysis of the 
 serum against water destroys its activity, while dialysis against 0.75 
 per cent, salt solution does not. In the diffusate there is no germicidal 
 substance. The loss by dialysis with water must be due to the with- 
 drawal of the inorganic salts of the serum. 5. The same is shown to be 
 the case when the serum is diluted with water and when it is diluted 
 with salt solution ; in the former instance the germicidal action is 
 destroyed while in the latter it is not. 6. The inorganic salts have in 
 and of themselves no germicidal action. They are active only in so 
 far as they affect the normal properties of the albuminates of the 
 serum. The germicidal properties of the serum reside in its albumin 
 constituents. 7. The difference in the effects of active serum and 
 that which has been heated to 55 C. is due to the altered condition of 
 the albuminate. The difference may possibly be a chemical one (due 
 to changes within the molecule) or it may be due to alterations in 
 
GERMICIDAL SERA 215 
 
 mycelial structure. The albuminous bodies act on the bacteria only 
 when the former are in an active state. 
 
 Vaughan pointed out an inconsistency between Buchner's experi- 
 mental results and his conclusions. Experimentally he ascertained that 
 peptic digestion of blood serum does not destroy its germicidal proper- 
 ties and yet he concludes that the active principle is serum albumin. 
 Since serum albumin is converted into peptone by peptic digestion and 
 since peptone forms an excellent medium for bacterial growth, Buch- 
 ner's conclusion that serum albumin is the germicidal constituent of 
 blood serum cannot be true. This criticism has held. 
 
 In 1893 Vaughan and McClintock, after reviewing the literature 
 up to that time, reported their work on the germicidal constituents of 
 blood serum as follows: 1. Serum albumin is not the germicidal con- 
 stituent. 2. The germicidal substance must belong to the proteins. 
 Otherwise, it would be difficult to explain the fact that a temperature 
 of 85 C. renders blood serum inactive. 3. The only protein likely to 
 be present in blood and which is not destroyed by peptic digestion is 
 nuclein. 
 
 Having reached these conclusions, the following questions naturally 
 presented: 1. Is there a nuclein in blood serum? 2. Has this nuclein, 
 if there be any, germicidal properties? Their work answered both 
 these questions in the affirmative. The existence of nuclein in blood 
 serum was confirmed by Lilienfeld and by Kossel, and its germicidal 
 action by the latter. Furthermore, it was demonstrated that injec- 
 tions of nucleinic acid, prepared from yeast and spleen cells, increased 
 both the number of leukocytes in the blood and the germicidal action 
 of the serum. However, Buchner very properly declined to accept 
 nucleinic acid as the chief germicidal constituent of serum, since the 
 latter is inactivated at from 56 to 58 C., while aqueous solutions of 
 nucleinic acid are not altered by much higher temperatures. 
 
 It should be stated, parenthetically, that the relation of nucleinic 
 acid to the intracellular ferment of the polynuclear leukocytes has 
 never been satisfactorily worked out. The researches of Schattenfroth 
 and others have shown marked differences between the extracellular 
 and intracellular constituents of the blood. The latter has no hemo- 
 lytic action on the red corpuscles of other species while the former 
 may have. The intracellular germicide is not affected by the salt 
 
216 GERMICIDAL SERA 
 
 content of the medium, while the extracellular substance is inactivated 
 by the removal of salt from the serum by dialysis. Daubler came to 
 the conclusion that the germicidal constituent of the serum and that of 
 the leukocytes are not identical, the latter remaining active after being 
 heated to 60 C. He also found that the germicidal substances 
 obtained from the leukocytes of different species differ in measurable 
 degree when tested on the same bacteria. Many other investigators 
 produced evidence of the fact that the intracellular and extracellular 
 germicidal constituents are not identical. 
 
 Petterson designates the intracellular bactericidal constituents of 
 leukocytes and other cells as "endolysis" and his pupil, Kling, sum- 
 marizes our knowledge on this subject as follows: 1. The germicidal 
 substances (endolysins) of the polynuclear leukocytes may be obtained 
 by the following methods (a) By digesting the cells for half an hour 
 at 50 C. in bouillon; (b) by extracting the cells with weak acid or 
 alkali; (c) by alternate freezing and thawing of the cells. They 
 cannot be obtained by digesting with bouillon at 37 C., nor with salt 
 solution, nor with 5 per cent, inactivated serum. 2. As tested on 
 Bacillus subtilis, the endolysin bears a temperature of 65 C. without 
 recognizable effect on its germicidal action, and it is not until the 
 temperature is increased to 75 C. that any such effect is noticed. The 
 endolysins can in daylight at room temperature, and in the dark at 37 
 C.,- be evaporated to dryness, and in this state they may be heated for 
 half an hour at 100 C. without being destroyed. The serum germi- 
 cides may be obtained in the dry state in the same manner, but when 
 heated to this temperature they are inactivated. The endolysis, as 
 tested on the subtilis, does not pass through a Pukall filter, while the 
 serum germicide does. The endolysins, as tested on the subtilis, the 
 anthrax and the typhoid bacillus are destroyed by the Roentgen ray, 
 while the serum germicide is not. The endolysins can be extracted 
 with ether, while the serum lysins are destroyed by ether. 3. The 
 activity of an inactivated extract of the leukocytes of the rabbit, as 
 tested on the subtilis, may be restored by the addition of a small 
 quantity of the serum extract in a fresh state. Likewise, an inacti- 
 vated normal serum of the rabbit or the inactive serum of the guinea- 
 pig may be complemented by the addition of a small amount of the 
 leukocytic extract from the rabbit or guinea-pig, respectively. Fur- 
 
GERMICIDAL SERA 217 
 
 thermore, an inactivated leukocytic extract from a guinea-pig can 
 be activated by the addition of a small amount of the normal serum 
 of a rabbit. 4. Extracts from the polynuclear leukocytes of rabbits, 
 guinea-pigs, and cats destroy in vitro the timothy, grass and butter 
 bacilli. The extracts from rabbits' leukocytes have a bactericidal action 
 on the bacillus tuberculosis of man. Extracts of rabbit, guinea-pig 
 and cat macrophages (mononuclear cells) do not destroy these acid- 
 fast bacilli in vitro. The same is true of the extracts from the thymus 
 glands of rabbits. Living polynuclear leukocytes injected into guinea- 
 pigs decrease the virulence of the bacillus tuberculosis of man. The 
 leukocytes of the guinea-pig do not have this effect. This must 
 suffice to show that the intracellular and extracellular germicidal con- 
 stituents of the blood are not the same and we will now return to a 
 consideration of the germicidal action of blood serum. 
 
 Buchner named the germicidal constituents of serum, "alexins" 
 (defenders). These are inactivated at from 56 to 58 C. At first he 
 believed alexins to be protein bodies, but later he regarded them as 
 proteolytic ferments or enzymes. He did not succeed in isolating the 
 alexins, but he believed that they are secretions of the polynuclear 
 leukocytes and he proposed that these should be designated "alexo- 
 cytes," which, however, has not been adopted. Metschnikoff holds 
 that the alexins from the polynuclear cells (microphages) are bac- 
 tericidal, while those from the large mononuclear cells (macrophages) 
 destroy red corpuscles and other animal cells. He designates all 
 alexins as cytases and divides these according to the cells supposed 
 to secrete them into microcytases and macrocytases. However, it 
 has not been demonstrated that the production of alexins is limited 
 to the leukocytes, both mononuclear and polynuclear. Furthermore, 
 Metschnikoff did believe that alexins are intracellular ferments and 
 that their presence in blood serum is due to the dissolution of the 
 leukocytes and that there are no free alexins in blood plasma, except 
 possibly a trace due to the physiologic dissolution of the leukocytes. 
 As has been seen, this view is no longer tenable. 
 
 It was shown by the work of Metschnikoff and Bordet that a 
 germicidal serum which has been inactivated by heating to from 56 
 to 58 C. may be reactivated on the addition of fresh serum. Further 
 work has shown that the bacteriolytic substances, present in both nor- 
 
218 GERMICIDAL SERA 
 
 mal and immune sera consists of two parts, one of which is ther- 
 molabile and the other is thermostabile. This is probably true of most, 
 if not all, enzymes. The thermolabile part is now known as alexin 
 or complement; the thermostabile part is known as fixator, sensi- 
 tizer or amboceptor. The former is present in all sera and the 
 weight of evidence is that it is non-specific. The amboceptor is the 
 specific part. According to Ehrlich's theory the amboceptor, which 
 he has, at different times, designated as intermediary and immune body, 
 but which is now generally known as amboceptor, combines on the one 
 hand with the bacterial or other cell and on the other with the com- 
 plement. The union between the amboceptor and cell may take place 
 at low temperature (even at C, 32 F.), but the complement enters 
 into the reaction only at temperatures not far above or below that of 
 the animal body. The complement is destroyed by a temperature of 
 from 56 to 58 C., but the amboceptor is not injured at this temperature. 
 When a serum is heated to this temperature it is inactivated; its bac- 
 teriolytic or cytolytic action is interrupted because the complement is 
 destroyed, but the ambocepter is not impaired and the serum is reacti- 
 vated by the addition of fresh complement which exists in both normal 
 and immune, unheated serum. This applies to all cytolytic sera, 
 whether they manifest their activity on bacteria, red blood cells, sper- 
 matic cells or other kind of cell. According to Ehrlich's teachings the 
 union of amboceptor with cell on one hand and with the complement 
 by the other is chemical, while Bordet believes the amboceptor, which 
 he calls a sensitizer, acts as a mordant in coloring and the complement 
 may be regarded as a dye. In other words, Bordet's explanation 
 supposes the action of physical rather than chemical forces. 
 
 To conclude this part of our subject, we may say that normal blood, 
 and the serum obtained from it, contains non-specific bactericidal fer- 
 ments or enzymes. These vary in amount, kind and efficiency in 
 different species. In a general way, the blood is a germicidal fluid and 
 it owes this function to the presence of proteolytic enzymes. In normal 
 blood these enzymes are not specific and they display marked, destruc- 
 tive action on certain bacteria, and are wholly without effect on 
 others. Living cholera cultures, in doses that might infect by way 
 of the intestines, can be injected into man subcutaneously or intra- 
 venously without ill effect. Cattle bear large injections of the organ- 
 
GERMICIDAL SERA 219 
 
 isms of symptomatic anthrax provided all goes into the blood current 
 directly and the subcutaneous tissue is not infected. 
 
 Immune Sera. The words, immune sera, are likely to be mis- 
 leading in this connection. Immunity due to bactericidal constitu- 
 ents of the blood, whether it be natural or acquired, is always rela- 
 tive. Even the immunity secured by one attack of the disease may be 
 overcome, in most instances at least, by the administration of an over- 
 whelming dose of the virus in virulent form. The man who has 
 once had smallpox may have it again when brought into intimate 
 and long-continued contact with the virus. The immunity induced 
 by one attack of yellow fever is probably the most complete and per- 
 sistent form known among the diseases to which man is susceptible. 
 The only way in which a man who has had this disease may be exposed 
 again is through the bite of an infected mosquito, and the virus intro- 
 duced in this way is always limited and fairly constant in amount. 
 We do not know what would happen to a yellow fever immune should 
 100 or 1,000 infected mosquitos bite him in the same hour. Experi- 
 mentally the injection of a large number of bacteria into the peritoneal 
 cavity of highly immune animals kills quickly, and the more marked 
 the immunity, provided it be due to germicidal substances in the blood 
 and lymph, the more promptly and more certainly does it kill. The 
 explanation of this fact is that the fluids of the body promptly split 
 up the bacterial cells, setting the protein poison free in large amount. 
 Nothing exactly similar to this occurs in nature, but the experiment 
 is of great value in demonstrating the phenomena of bacteriolysis. 
 A highly germicidal blood is of great value in preventing infection, 
 because the first few organisms that find their way into the body are 
 promptly killed before they can multiply and while the amount of 
 poison set free is too small to produce any marked effect. On the 
 other hand, it would be highly disastrous for the blood to become sud- 
 denly and highly germicidal when the body is filled with bacteria. This 
 would mean sure and speedy death. Phagocytes not only serve the 
 body in feeding on bacteria, but they protect the body from the poison 
 which results from the extracellular cleavage of the bacteria. 
 
 The essential difference between the germicidal constituent of nor- 
 mal serum and that of immune serum is that the latter is specific 
 
220 GERMICIDAL SERA 
 
 while the former is not. Whether the general enzyme is so changed 
 as to have specific action or a wholly new enzyme has been developed, 
 no one can say with certainty. Pfeiffer found that when a mixed 
 culture of the vibrio of cholera and another vibrio was injected into 
 the peritoneal cavity of a guinea-pig immunized to cholera, all the 
 cholera vibrios were dissolved and all the others were left whole. 
 When the same mixed culture was injected into the abdomen of a 
 guinea-pig immunized with the Nordhafen vibrio, all these were dis- 
 solved and the cholera vibrios left unharmed. The great majority 
 of bacteria are harmless because they are speedily destroyed by the 
 digestive secretions of the animal body. The germicidal constituent 
 of man's blood is easily made specific by vaccination with cholera 
 or typhoid bacilli. So far no specific bacteriolytic substance has been 
 developed in the blood of any animal with anthrax bacilli or strepto- 
 cocci. It is true that Pasteur developed highly efficient vaccines against 
 anthrax, but these increase phagocytic activity, probably through the 
 formation of opsonins, and do not develop immune sera. It will 
 be understood that we are not now concerned with toxin immunity. 
 We are confining ourselves to the study of specific bacteriolysins. 
 
 It has been positively shown that the proteolytic enzyme which 
 destroys the bacteria is not an albuminous substance. Pfeiffer and 
 Proskauer precipitated a highly active cholera serum with alcohol 
 and allowed it to stand for three months with frequent change of 
 the alcohol. From the hard mass which formed, they extracted with 
 distilled water a highly active body which responded to none of the 
 protein reactions. Some serum preserved by the addition of 0.5 per 
 cent, phenol stood for ten years in Pfeiffer's laboratory and was found 
 to be active at the end of that time. The enzyme is not always so 
 susceptible to heat as was first supposed and some samples at least 
 require a temperature of 70 C. for one hour for complete inactivation. 
 
 When a highly immune serum is injected into an animal it increases 
 its resistance to its homologous bacterium. Animals are actively 
 immunized by repeated treatments with the bacteria, either in attenu- 
 ated form or in small doses of the virulent form. Animals thus actively 
 immunized furnish an immune serum with which other animals may 
 be passively immunized. It is generally believed that living bacteria 
 give a better active immunization than dead cultures. Many years 
 
GERMICIDAL SERA 221 
 
 ago Feran used living cholera bacilli subcutaneously as a vaccine against 
 this disease. Wright introduced typhoid vaccination with heated cul- 
 tures and this has proved highly successful and is now widely used, 
 not only among soldiers but among civilians. Strong recommends 
 highly attenuated typhoid cultures. Besredka combines active and 
 passive immunity in vaccination against typhoid. The growth from 
 a forty-eight hour agar-culture is mixed with a small amount of 
 salt solution. To this is added a homologous immune serum and the 
 mixture allowed to stand for twelve hours. This results in agglutina- 
 tion. The bacteria are washed in salt solution, heated to 56 C. for one 
 hour and then injected. Vaccines thus prepared cause no inflamma- 
 tion. The bacteria are sensitized or combined with the amboceptor 
 in the immune serum and probably are more easily split up when 
 introduced into the body. Dead and avirulent plague bacilli have 
 been employed as a vaccine against this disease. The serum of men 
 and animals actively immunized shows a higher bacteriolytic titer than 
 normal serum, but we are not sure that the increased resistance is 
 due solely to this. It must be evident that this method of securing 
 increased resistance to a given infection is in principle the same as 
 that secured by a light attack of the disease. The body cells learn how 
 to combat the infection. They learn how to elaborate a specific enzyme 
 which will destroy the specific bacteria if they should subsequently find 
 their way into the body. For instance, the blood of a man contains no 
 specific enzyme capable of destroying the cholera bacillus. A small 
 amount of this organism is injected under his skin, and the cells of his 
 body under this new irritant learn how to elaborate a specific enzyme 
 which destroys the cholera bacillus. Later, if he drinks water contain- 
 ing this organism, it must be plain that he has a distinct advantage over 
 the unvaccinated man in resisting the infection. The world is indebted 
 to the Spanish physician, Feran, who first had the intelligence and 
 courage to employ this method in combating cholera. He was wiser 
 than his time and from his work has come vaccination against typhoid 
 and plague in man. 
 
 PfeifTer and Mark have endeavored to ascertain in what part of 
 the body this specific immunizing enzyme is formed. For this purpose 
 they inoculated rabbits and killing one from time to time tested 
 extracts from the various organs. They found that the bacteriolytic 
 
222 GERMICIDAL SERA 
 
 enzyme appears in the spleen first, and within twenty-four hours after 
 the inoculation. The bacteriolytic titer of the spleen extract increased 
 before that of the circulating blood. However, it must not be inferred 
 that the spleen is the only organ in which the specific enzyme is 
 formed. It is possible that many of the cells of the body are capable 
 of performing this function and that an organ specially active in 
 resisting one infection may play a subordinate role in another. Heck 
 made a comparative study of the persistence of the typhoid bacilli in 
 various organs of normal and immunized animals after intravenous 
 injections. In the normal animals, they were not found in the circu- 
 lating blood after six hours; were present in the kidneys and lungs 
 up to the third day; in the liver after the fifth day; in the spleen 
 after the twentieth day and in the bone marrow up to the sixtieth 
 day. In immunized animals, they disappeared first from the spleen 
 and bone marrow, and all organs were sterile on the third day. 
 
 The constitution of the specific bacteriolysins is similar to that of 
 the non-specific in normal blood. They consist of alexin or complement 
 and fixator or amboceptor. Their specificity lies in the amboceptor 
 and it is this which combines with, or acts on, the bacterial cells. 
 PfeifTer describes the action of a highly immune serum on its homol- 
 ogous bacterium as follows : "The micro-organisms first lose their 
 motion, then swell and finally contract into balls, in which some motion 
 may be still seen, showing that living bacilli are being dissolved. For 
 a time the granules seem like micrococci and can be stained. They 
 gradually grow smaller and smaller and finally dissolve in the fluid 
 just as sugar or salt dissolves in water." 
 
CHAPTER XXIX 
 
 THE GENERAL PRINCIPLES AND MECHANISM 
 OF INFECTION AND IMMUNITY 
 
 Each and every living thing must feed, assimilate and eliminate. 
 Living matter cannot continue in active life without performing these 
 functions. There are certain resting forms in which these functions 
 are, for the time, held in abeyance. Such are, eggs, spores, seeds and 
 reproductive cells. These organisms possess only potential life; they 
 are not in active life. A grain of corn or wheat, or any vegetable 
 seed, contains a germ cell, a store of food and an enzyme. When 
 placed in the ground, under suitable conditions of temperature and 
 moisture, the enzyme begins to split up the stored food, the germ 
 cells begin to utilize the split products and potential life awakens into 
 active life. The revivified germ cell is now able to feed on the con- 
 stituents of the soil, the stalk grows and the grain or seed is repro- 
 duced. The spores of anthrax are only potentially alive and active 
 life begins anew only in the presence of proper nutriment. The 
 granules into which certain other bacteria are changed in the absence 
 of food are further examples of resting forms. Ova, whether those 
 of lower or higher animals, after stimulation by the spermatic cells, 
 and under proper conditions, begin to develop into active life. In all 
 cases life in one form or another is potentially, at least, continuous. 
 
 No thing in active life remains in a condition of equilibrium. It 
 absorbs, assimilates and eliminates. Metabolism is a life function 
 and there can be no active life without it. Indeed, it is metabolism, 
 active and latent, that distinguishes between living and dead matter. 
 When matter becomes endowed with this function, it is no longer 
 dead, but is alive. Nothing in active life can be conceived of as exist- 
 ing alone. It must have food or die. 
 
 The morphologic unit of life is the cell, although the physiologic 
 unit is the molecule or the group of molecules essential to the celL 
 All living things are essentially proteins. The cell may contain carbo- 
 
224 MECHANISM OF INFECTION AND IMMUNITY 
 
 hydrates, fats and extractives, but the functions of life reside in its 
 protein molecules. Each kind of life must consist of its own specific 
 proteins and there are as many kinds of proteins as there are kinds 
 of cells. It follows that proteins are specific. Those of the colon 
 bacillus are not identical with those of the typhoid and differ more 
 widely still from those of the tubercle bacillus. Relationship between 
 varieties and species depends on similarity in the chemical constitution 
 of the molecules. The essential proteins of wheat and barley are not 
 identical, but are more closely related in chemical structure than are 
 those of barley and those of pumpkin seed. 
 
 All cells, so long as they are in active life, must feed. Otherwise, 
 they cannot grow and multiply. This is equally true of cells which 
 have an individual existence and constitute unicellular forms of life, 
 and of those which have a communal life and exist in the organs of 
 multicellular beings, such as man. A living cell can feed only on 
 that with which it comes in contact. Some of the cells of man's body, 
 such as the leukocytes, can go in quest of food, while others are fixed 
 and must depend on what is brought to them. 
 
 Each cell feeds by means of its enzymes which split up the pabulum 
 into blocks which can be fitted into its molecular structures. Each kind 
 of cell must have its own specific ferment or ferments and there are 
 as many kinds of ferments or enzymes as there are kinds of cells. 
 There are enzymes which split up carbohydrates, known as* diastases, 
 and those which split up fats, known as lipases, but in our studies 
 of infection and immunity, we are especially concerned with those 
 that split up proteins, known as proteases or proteolytic enzymes or 
 ferments. These enzymes are specific in two senses; first they are 
 products of specific cells and second, they can act only on proteins of 
 certain chemical structure. It must be evident that a cell can feed only 
 on that material which is digestible by its enzymes. This is true of 
 single cells and of multiple cells. Horn contains proteins and other 
 nitrogenous substances, but man cannot live on it because the enzymes 
 of his alimentary canal cannot digest it. Only that which its enzymes 
 can properly prepare for assimiliation is food for the organism, 
 whether it be unicellular or multicellular. With this understanding 
 of the conditions under which cells grow and multiply, we are ready 
 
MECHANISM OF INFECTION AND IMMUNITY 225 
 
 to study some of the phenomena of infection. In doing this we will 
 confine ourselves to bacteria. 
 
 Bacteria. There are some widely prevalent views concerning bac- 
 teria which in my opinion are quite erroneous. It is generally stated 
 that bacteria are low forms of plant life. This belief is founded on 
 an early observation that they are not readily soluble in dilute acids 
 or alkalies. Is this enough to justify their classification as plants? Hair, 
 skin and horn are not readily soluble in dilute acid or alkali and still 
 they can hardly be called plants. Plant cells, generally, at least, con- 
 tain cellulose; bacteria do not. Plants, under normal conditions, take 
 in carbonic acid and give off oxygen ; bacteria absorb oxygen and give 
 off carbonic acid. Many think that bacteria contain no nuclei, because 
 there is no differentiation in staining, but it should be remembered 
 that their staining properties show that they are practically wholly 
 composed of nuclein. Some think that they are of simple chemical 
 structure, because morphologically they are simple. I and my students 
 have shown that, chemically, bacteria are quite as complicated and as 
 highly developed as are the cells of man's body. Functionally, they 
 are highly developed. It is important to hold this in mind in studying 
 the contests between bacterial and body cells, which so often end 
 in the discomfiture of the latter. 
 
 Bacteria live and multiply through the activity of their enzymes. 
 Their extracellular enzymes split the pabulum within their reach into 
 proper blocks and their intracellular enzymes fit these blocks into the 
 bacterial molecule. It must be plain that a bacterium, whose enzymes 
 cannot act on body proteins, cannot infect that animal. Such a 
 bacterium may grow outside the animal body, feed on dead material 
 and elaborate a poison which may harm the animal. Such a bacterium 
 is the Bacillus botulinus. The peptonizing bacteria of milk so change 
 the milk proteins that they are absorbed through the intestinal walls 
 of infants and are further digested in the blood and tissues with the 
 formation of poisons which cause the symptoms and lesions of cholera 
 infantum and the other diarrheal diseases of infancy. During intra- 
 uterine life, all the processes of digestion are parenteral, that is, they 
 do not occur in the intestine but in the blood and tissues. In infancy, 
 the walls of the intestine are easily permeable and parenteral digestion 
 
226 MECHANISM OF INFECTION AND IMMUNITY 
 
 continues, especially when the food proteins are altered by bacterial 
 growth. In rare cases of summer diarrhea, casein, but little altered, 
 has been detected in the blood by biologic tests. Bacteria which cause 
 disease by the elaboration of toxins or poisons in foods before they 
 are taken into the body are known as toxicogenic organisms. This term 
 was proposed by me many years ago. 
 
 Body Cells. These live, like the bacterial cells, by means of their 
 enzymes which also are extracellular and intracellular. The former 
 cleave the pabulum properly and the latter fit the blocks into the mole- 
 cules. The feeding cells are not confined to the leukocytes. All the 
 living cells of the body, so long as they are alive, feed. They eat, 
 assimilate and eliminate. In the higher animals, including man, the 
 gross digestion for the whole is done in the alimentary canal. This is 
 known as enteral digestion. The special preparation of food for the 
 cells of the different organs, however, is done by their own specific 
 enzymes and this process is known as parenteral digestion. Moreover, 
 occasionally, proteins in small amounts pass from the alimentary canal 
 into the lymph and blood without complete digestion. Fine bits of 
 organic matter are inhaled and find their way into the system without 
 being subjected to any form of enteral digestion. Finally, and of 
 the greatest importance in the present study, living proteins, known 
 as bacteria, find their way into the tissues. These not only have 
 escaped enteral digestion, but they are capable of growth and multi- 
 plication, and if their development in the body be prevented it must 
 be through parenteral digestion. Whether they are engulfed by phago- 
 cytes or destroyed by the fluids, it is in either case parenteral digestion. 
 It must be evident that parenteral digestion is the big and deciding 
 factor in most cases of infection. If it fails or if it is slow in pro- 
 cedure, the invading bacteria may multiply. If it proceeds promptly 
 and efficiently the invaders, which under natural conditions are few 
 in number, are destroyed before they can multiply and the body is 
 protected. Now, we have the great problem of infection and immunity 
 fairly before us. It is a contest between bacterial and body cells and, 
 as we have seen, they are armed with similar weapons. The bacterial 
 cells have their enzymes, poisons and toxins. The body cells have 
 their enzymes, bactericidal and bacteriolytic agents, opsonins, and 
 phagocytes. The phagocytes constitute the mobile army of defense 
 
MECHANISM OF INFECTION AND IMMUNITY 227 
 
 and the fixed cells elaborate destructive weapons. Which of these 
 bears the brunt of the defense depends on the armament of the invader. 
 Whether a given bacterium is pathogenic to a given animal or 
 not, depends essentially on two things. First, can it feed on the pro- 
 teins of that animal's body ? If it cannot, it can do no harm. Secondly, 
 can the cells of the body destroy the invading cells before they can 
 multiply ? 
 
 The Phenomena of Infection. It should be clearly understood 
 that only a living thing can infect. It must not only be alive, but it 
 must be able to multiply in the animal body. It is true that the injec- 
 tion of diphtheria or tetanus toxin into an animal may cause all the 
 symptoms and lesions of disease, but this is an artificial procedure, and, 
 besides, the toxin is the product of bacterial growth. An infectious 
 disease arises when foreign cells find their way into the body and 
 multiply to the detriment of the body cells. Simply carrying virulent 
 bacteria on the surface or in the cavities of the body does not constitute 
 infection. It is not rare to find tubercle bacilli on the hands of those 
 who care for others ill of this disease. According to Fliigge, 70 per 
 cent, of those in houses where there is a case of epidemic meningitis 
 carry the organisms. In a schoolroom in which a child has developed 
 diphtheria, 30 per cent, of all the children may have the diphtheria 
 bacillus in their throats and are not infected. In order to develop 
 infection, the bacterium must feed on the body. Carriers of infection 
 are of importance to the epidemiologist, but they are not necessarily 
 infected. The bacterium must not only feed on the animal tissue, but 
 it must multiply. The essential difference between saprophytic and 
 pathogenic bacteria is that the latter can multiply in the animal body, 
 while the former cannot. Saprophytic bacteria contain in their cellular 
 substance just as much protein poison as the pathogenic organisms 
 do and it is easy to kill an animal by injecting a relatively large amount 
 of them into the abdominal cavity, but this is not infection. A bacterium 
 is not pathogenic to a given animal unless it can convert that animal's 
 proteins into its own proteins. 
 
 Saprophytic bacteria are speedily digested by the enzymes in the 
 blood and tissues of the body, and if they be injected in large amount 
 the protein poison set free may be sufficient to quickly kill the animal. 
 
228 MECHANISM OF INFECTION AND IMMUNITY 
 
 So great is the bacteriolytic action of the blood that even some patho- 
 genic bacteria do not infect when injected directly and wholly into 
 the blood. This is true of the bacillus of symptomatic anthrax. A 
 dose which infects when administered subcutaneously, fails when given 
 intravenously. The cholera bacillus is harmless when introduced sub- 
 cutaneously in doses which would infect by the intestine. In the first 
 instance, it is speedily killed by the bactericidal constituents of the 
 tissues ; in the second it grows and multiplies in the intestine in which 
 it does not come in contact with the germicidal agents. 
 
 There are many conditions which influence the capability of bac- 
 terial growth in the animal body. A given bacterium may be patho- 
 genic to one species of animal and without effect on another. Some 
 are active in mixed cultures, one bacterium being of assistance to 
 another. Some grow in certain tissues of the body and not in others. 
 The number of bacteria introduced into the animal is an important 
 factor. One anthrax bacillus may kill a mouse and one tubercle 
 bacillus may have a like effect on a guinea-pig, but these are exceptions, 
 and whether or not an infection results depends, in most instances, in 
 part, on the number and virulence of the organisms introduced. 
 
 While the blood has a marked bactericidal action on some bacteria, 
 it forms an excellent culture-medium for others. Virulent streptococci, 
 plague and tubercle bacilli grow abundantly in the blood and kill the 
 more promptly the sooner they find their way into the circulation. Quite 
 naturally, many bacteria grow most vigorously in injured and necrotic 
 tissue on account of the lessened resistance. The readiness with which 
 streptococci take possession of tissues already weakened by cancer, 
 tuberculosis or syphilis is an illustration. 
 
 Incubation. The period of incubation of an infectious disease is 
 the time interval between the introduction of the infecting agent 
 and the first appearance of the symptoms of the disease. This varies 
 greatly in different diseases and for the same diseases in different 
 animals. With the same disease in the same species there are also 
 variations, but not so marked. For instance, one swallows typhoid 
 bacilli, he does not develop fever the same day or the next, but as a 
 rule between the sixth and tenth day. In some individuals the period 
 of incubation for this disease may be longer. During this period 
 
MECHANISM OF INFECTION AND IMMUNITY 229 
 
 there is no recognizable disturbance in the health of the individual, 
 either subjectively or objectively. He considers himself well and 
 attends to his usual duties, and yet this is an important and critical 
 time in the development of the infection. The bacilli are growing and 
 multiplying enormously in the man's body. They are converting body 
 proteins into bacterial proteins, native into foreign proteins, and this 
 goes on without the host being conscious of it. The ferments of the 
 bacterial cells are fitting the body proteins into the cellular molecules 
 of the bacteria. During the period of incubation, the bacterial cells 
 supply the enzymes, the body proteins constitute the substrate, the 
 process is synthetic and constructive, no poison is set free and conse- 
 quently no symptoms are manifest. It follows that the multiplication 
 of the typhoid bacillus in man's body is not the direct cause of the 
 symptoms of the disease. There is no evidence that the growth and 
 multiplication of the bacilli proceed at the expense of, or directly 
 cause injury to, body cells. The bacilli feed on the simple, soluble 
 proteins of the body. A tubercle bacillus passes through the intestinal 
 wall and leaves no lesion. A plague bacillus may penetrate the skin 
 of an animal and make no visible alteration. The rate at which the 
 virus multiplies during the period of incubation is an important factor 
 in determining the final outcome. The more virulent the virus, the 
 more rapidly does it multiply, and this means a larger amount of 
 body protein converted into bacterial protein. The phenomena of the 
 period of incubation may be studied in a guinea-pig into the abdominal 
 cavity of which a fatal dose of a virulent culture of the colon bacillus 
 has been injected. In this experiment the incubation period is from 
 eight to twelve hours, during which time the infected animal is in its 
 behavior undistinguishable from its untreated fellows. However, if 
 a drop of the abdominal fluid be taken out from hour to hour it will 
 be seen that the bacilli are multiplying rapidly. 
 
 The Disease. In some cases the period of incubation passes 
 abruptly, in others more gradually, into that of the active disease. 
 Symptoms, both subjective and objective, develop and indicate a more 
 or less marked departure from health. In some diseases there is a 
 chill, which may vary greatly in severity, and this is followed by 
 fever. Evidently something has happened which disturbs physiologic 
 
230 MECHANISM OF INFECTION AND IMMUNITY 
 
 processes. The body cells have begun the contest against the invaders. 
 Since the invasion began they have been preparing for the war and 
 now the battle has begun. The bacilli have gained entrance and multi- 
 plied at the expense of the soluble proteins of the body because the 
 animal cells were not at first prepared to combat them. Now they have 
 developed bactericidal and bacteriolytic ferments and opsonins, possibly 
 antitoxins, and with these the further development of the bacteria is 
 to be contested. When the infecting organism is a toxin producer, like 
 the diphtheria or tetanus bacillus, it is not the cellular substance of 
 the bacteria which directly and immediately endangers the body cells, 
 so much as its soluble product, the toxin. In this case, the contest is 
 decided by the ability of the body cells to elaborate and make available 
 enough antitoxin to neutralize the bacterial toxin. In this case, the 
 therapeutic administration of antitoxin has secured to curative medi- 
 cine its greatest triumph, and success or failure depends on the early 
 administration of this magical cure in sufficient amount. The cells 
 of the horse have been trained to produce this body and now it is 
 poured into the blood current of the child to save its cells from destruc- 
 tion. The diphtheria bacilli contain a cellular poison, quite different 
 from the toxin, but since the bacilli, except in small numbers, are not 
 in the child's blood and tissue, but in its throat, the cellular poison 
 may be neglected, for as a rule the few in the body do not contain 
 enough poison to endanger the life of the child. Cure, then, depends 
 on the neutralization of the toxin before it has done irreparable harm. 
 When the infecting bacterium is one best combated by phagocytes, 
 the body cells supply opsonins which, in some way yet unknown, ren- 
 der the invaders less resistant to the leukocytes. In these cases, the 
 result depends on the effectiveness with which both the fixed and 
 mobile cells of the body perform their functions. One of the important 
 factors is the number as well as the virulence of the invading bacteria 
 at the time when the contest begins. The greater the number, the more 
 must the phagocytes devour, and feeding is a limited function. The 
 more virulent they are, the less effective will be the opsonins. Rosenow 
 has shown that the opsonins are not effective against the more virulent 
 strains of streptococci and that infection with these generally proves 
 fatal. It is worthy of note that bacteria devoured by phagocytes do 
 not endanger the life of their host to the extent and in the same way 
 
MECHANISM OF INFECTION AND IMMUNITY 231 
 
 as do those which suffer extracellular digestion. In the latter instance, 
 the cellular poison of the bacteria is set free and in its death it becomes 
 most dangerous to its host. 
 
 By far the larger number of bacteria which infect man do not 
 elaborate soluble toxins and for these we can have no antitoxin. Of 
 the other pathogenic bacteria there are many which, in first infections 
 at least, are not to any large extent devoured by phagocytes. The 
 members of this large class, which cannot be met with antitoxins or 
 disposed of by stimulated phagocytosis, must be dealt with by bacteri- 
 cidal and bacteriolytic enzymes. The potent poison which they con- 
 tain is set free and exerts its deleterious effect, which is determined 
 by the rapidity with which the bacterial cells are disrupted. It must 
 be evident that the development of powerful bacteriolytic enzymes at 
 a time when the body is filled with bacteria would be most disastrous. 
 The faster the invaders are destroyed, the more danger is there to 
 the host. This is well illustrated in typhoid fever, in which the bacillus 
 produces no soluble toxin and consequently there can be no antitoxin 
 developed and in which there is no increase in the phagocytes. The 
 greatest misfortune that happens in the progress of typhoid fever is 
 the rapid development of a powerful bacteriolytic enzyme and the 
 speedy destruction of the invading bacteria in large numbers. This is 
 true of plague and typhus, as well as of typhoid fever. It does not 
 apply to diseases due to soluble toxins, such as diphtheria and tetanus, 
 and probably not to those combated exclusively by phagocytes, if there 
 be such. 
 
 The assertion has been made that the infectious diseases have bene- 
 fited the race by the destruction of the unfit. This idea I have com- 
 bated most vigorously since our study of typhoid fever in the army 
 in 1898. My colleagues and I found that out of 9,481 soldiers who 
 had previously been on the sick report and could not be regarded as 
 possessing standard health, 648, or 6.8 per cent., contracted typhoid 
 fever; whereas, out of 46,383 men who had no preceding illness, 7,197, 
 or 15.3 per cent., developed typhoid fever. More than 90 per cent, of 
 the men who developed typhoid had no preceding intestinal disorder. 
 
 Under ordinary conditions the strong, busy man, especially the 
 one whose activities demand wide excursions from his home, is more 
 likely to become infected than the one whose sphere of action is more 
 
232 MECHANISM OF INFECTION AND IMMUNITY 
 
 limited on account of infirmity. The reason for this is too obvious to 
 need statement, and it follows that more men than women and more 
 adults than children have typhoid fever. Moreover, the case mortality 
 is greater among the strong, because death in this class of infectious 
 diseases is often due to the rapidity with which the invading organism 
 is broken up by the secretions of the body cells and the protein poison 
 made effective. From this I have concluded that contagion, like war, 
 destroys the very flower of the race. This view is sustained by the 
 historians of the pestilences of former times. 
 
 Thucydides, in his description of the plague at Athens, says: 
 "Moreover, no constitution, whether in respect of strength or weakness, 
 was found able to cope with it ; nay, it swept away all alike, even those 
 attended to with the most careful management." Procopius, in his 
 account of the Justinian epidemic, states that youth was the most 
 perilous season, and females were less susceptible than males. Cogan, 
 in describing an outbreak of typhus at Oxford in 1577, writes: "The 
 same kind of ague raged in a manner over all England and took away 
 very many of the strongest sort, and in their lustiest age, and for the 
 most part, men, and not women and children, culling them out here 
 and there, even as you would choose the best sheep of a flock." In 
 his account of the plague of 1665 in London, Boghurst makes the 
 following statement: 
 
 Of all the common hackney prostitutes of Luteners-lane, dog-yard, cross- 
 lane, Baldwins-gardens, Hatton-gardens and other places, the common criers 
 of oranges, oysters, fruits, etc., all the impudent drunken, drubbing bayles and 
 fellows and many others of the rouge route, there is but few missing verify- 
 ing the testimony of Diemerbroech that the plague left the rotten bodies and 
 took the sound. 
 
 Like testimony comes from an account of the plague at Moscow: 
 "Drunkards and persons of feeble temperament were less subject to 
 attack." Davidson observed that typhus fever was more frequent 
 among the robust than the weak. He states that out of 429 cases, the 
 spare and unhealthy taken together made only about 17 per cent. He 
 adds that the death-rate among the poor was one in twenty-three, while 
 among the well to do, it was one in four. The greater mortality of 
 typhus among the higher classes has been noted by Barber and Cheyne 
 and by Braken. Hurty, nearly a century ago, wrote : "A fever which 
 
MECHANISM OF INFECTION AND IMMUNITY 233 
 
 consigns thousands to the grave, consigns tens of thousands to a 
 worse fate to hopeless poverty, for fever spares the children and 
 cuts off the parents, leaving the wretched offspring to fill the future 
 ranks of prostitution, mendicancy and crime." Creighton says : 
 
 The best illustrations of the greater severity and fatality of typhus among 
 the well to do come from Ireland in times of famine, and will be found in 
 another chapter. But it may be said here, so that this point in the natural 
 history of typhus may not be suspected of exaggeration, that the enormously 
 greater fatality of typhus (of course, in a smaller number of cases) among 
 the richer classes of the Irish families, who had exposed themselves in the 
 work of administration, of justice, or of charity, rests on the unimpeachable 
 authority of such men as Graves, and on the concurrent evidence of many. 
 
 In the active stage of disease due to bacterial invasion of the body, 
 the body cells supply the ferment, the bacterial cells constitute the 
 substrate; the process is essentially destructive and analytic; complex 
 cellular proteins are split into simple soluble bodies ; the protein poison 
 is set free, exerts its deleterious effects on the body cells and disturbs 
 the health ; the evidence of infection rises to the plane of clinical obser- 
 vation; the symptoms of the disease become manifest and the contest 
 between bacterial and animal cells continues until one or the other 
 holds possession. 
 
 It should not be understood that there is always a sharp line of 
 demarcation between the period of incubation and the appearance of 
 active disease. The bacterial growth may be extending into new parts 
 of the body coincidently with its destruction in other regions. 
 
 Fever. All bacteria are capable of inducing fever, and this is a 
 most constant accompaniment of infection. Fever is not directly due 
 to the growth of bacteria in the body. It is not in evidence during 
 the period of incubation when bacterial growth is most abundant. The 
 early progress of tuberculosis is without fever, because at this time 
 the number of bacilli in the body is few and most of these are living. 
 It is not until the body becomes sensitized against the invading organ- 
 ism and begins to digest and destroy it that fever makes its appear- 
 ance. The face may be covered with acne pustules, each of which con- 
 tains streptococci, and still there is no elevation of temperature, 
 because the cocci are not reached and digested by the bacteriolytic 
 enzymes of the blood and lymph. The fever of infection results from 
 the parenteral digestion of the bacterial proteins. 
 
234 MECHANISM OF INFECTION AND IMMUNITY 
 
 Many years ago Gamaleia showed that fever follows the parenteral 
 introduction of dead as well as living bacteria, either pathogenic or 
 non-pathogenic. He concluded that fever is not a phenomenon of 
 bacterial growth in the body. Furthermore, he found that the less 
 virulent the organism, the higher and more persistent is the fever. A 
 rabbit inoculated with the anthrax bacillus suffers a fever for only a 
 few hours, when the temperature falls and death results, while one 
 inoculated with a highly attenuated anthrax culture (the second vac- 
 cine) shows fever for three days and then recovers. With a highly 
 virulent culture, there may be but little or no elevation of temperature 
 and death comes within from five to seven hours after inoculation. 
 The febrile process is not a result of the activity of the bacteria, but, 
 on the contrary, is due to a reaction of the body against their presence 
 and marks their destruction. 
 
 More recently it was shown by experiments in my laboratory that 
 fever can be induced in animals by the subcutaneous injection of pro- 
 teins of diverse origin and structure, and that by modifying the size 
 and frequency of the dose, the type of fever can be determined at will. 
 By injecting egg-white into rabbits and by regulating the size and 
 interval between doses, one may induce an intermittent, remittent, 
 continued or acute fever. In the last mentioned, the temperature can 
 be carried to 107 F. with a fatal termination. Not only fever but 
 its accompaniments also may be developed. In the continued fever 
 thus induced, there is the morning fall and the evening rise so con- 
 stantly seen in typhoid. There is loss of appetite with lassitude, 
 gradual emaciation, decreased urinary output and increased nitrogen 
 elimination. Protein fever, which includes all infective and practically 
 all clinical fevers, results from parenteral digestion. In this process 
 the animals' cells supply the ferment and the foreign protein constitutes 
 the substrate. The foreign protein may enter the body living or dead, 
 with or without form. It may be detached and dead tissue from 
 the animal's body, as after burns. It may be absorbed from some 
 mucous surface, as in hay fever. It may be artificially introduced, 
 as in serum disease. It is usually a living protein, as in the infectious 
 diseases. 
 
 There are other causes of fever, but that of the infectious diseases 
 results from the parenteral digestion of the infecting agent by specific 
 
MECHANISM OF INFECTION AND IMMUNITY 235 
 
 secretions elaborated by the body cells. It is a phenomenon of the 
 disposal of foreign and harmful material and it must be recognized 
 as beneficent. However, there is a point above which it becomes a 
 danger per se. In parenteral digestion, the following sources of heat 
 production must be evident: 1. The unaccustomed stimulation and 
 consequent increased activity of the cells which supply the enzyme 
 must be the source of no inconsiderable increase in heat production. 
 
 2. The cleavage of the foreign protein increases the heat liberation. 
 
 3. The reaction between the digestive products and the tissues leads 
 to increased heat production. I regard the first and third as the 
 important sources of the overproduction of heat in the infectious 
 diseases. 
 
 There are many conditions affecting the course of a fever and 
 some of these may be mentioned. Some viruses sensitize more quickly 
 and thoroughly than others. It is possible that the living bacterial 
 cells, so long as they are living, do not sensitize. Some of the bacterial 
 protein must pass into solution before cell penetration, which seems 
 essential to thorough sensitization, can occur. A living colon bacillus 
 of not more than twenty-four hours' growth, when injected intra- 
 abdominally in a guinea-pig, requires about ten hours to sensitize. 
 With dead bacilli the time is reduced to half, while with old autolyzed 
 cultures, in which the sensitizing group is already in solution, the time 
 is further shortened. Some pathogenic bacteria, like the tubercle 
 bacillus, have been so long parasitic that they have learned to protect 
 themselves by deposits of fats and waxes. Others form capsules which 
 serve a like purpose. In this way they are probably protected to some 
 extent against the destructive enzymes elaborated by the body cells. 
 In all the infectious diseases, the destruction of the invading organism 
 is modified and delayed by the altered relation between ferments and 
 substrate and the accumulation of fermentative products. The blood 
 is a highly active digestive fluid with a finely adjusted balance between 
 ferment and anti ferment, which will soon be better understood and 
 the solution of this problem will add another triumph to scientific 
 medicine. When the ferment in the blood is suddenly activated, 
 immediate death results, as is seen in anaphylactic shock. When 
 properly regulated, this delicate mechanism protects against harmful 
 bodies, both those introduced from without and those generated within. 
 
INDEX 
 
 Agglutination 201 
 
 factors 202 
 
 history 201 
 
 Agglutinin 202 
 
 Alexins 217 
 
 Amboceptor 218 
 
 Anthrax 77 
 
 avenues of infection 85 
 
 bacillus 80 
 
 history 77 
 
 symptomatic 127 
 
 symptomatic, bacillus 127 
 
 symptomatic, history 127 
 
 Bacteria 27, 225 
 
 antagonism between 28 
 
 capsules of 16 
 
 flagella of 30 
 
 metabolism 32 
 
 morphology of 27 
 
 multiplication 28 
 
 oxygen need of 30 
 
 pathogenicity 33 
 
 spore formation 27 
 
 structure 31 
 
 symbiosis of 29 
 
 Body cells 226 
 
 Botulism 137 
 
 bacillus 138 
 
 history 137 
 
 Cells, body 226 
 
 Cholera, Asiatic 57 
 
 bacillus 58 
 
 history 57 
 
 sources of infection 62 
 
 Death-rates from infectious diseases 14 
 
 Disease, theories concerning 19 
 
 Diphtheria 167 
 
 antitoxin 170 
 
 bacillus 168 
 
 history 167 
 
 Dysentery 87 
 
 Flexner bacillus 89 
 
 history 87 
 
 Shiga bacillus 88 
 
 sources of infection 91 
 
 Edema, malignant 131 
 
 bacillus 131 
 
 history 131 
 
 Endolysis 216 
 
 Eye as portal of entrance for bacteria 35 
 
 Fever of infection 233 
 
 Gas phlegmon 132 
 
 Germ theory 23 
 
 Germicidal sera 213 
 
 Glanders 133 
 
 avenues of infection 134 
 
 bacillus 134 
 
 history 133 
 
 Immune sera 219 
 
 Immunity 177 
 
 acquired, phagocytosis in 192 
 
 and infection, mechanism of 223 
 
 natural, phagocytosis in 188 
 
 Incubation period of infection 228 
 
 Infection and immunity, mechanism of . . . 223 
 
 avenues of 35 
 
 fever of 233 
 
 phenomena of 227 
 
 Infectious diseases, death-rates from 14 
 
 disease, incubation period 228 
 
 Intestines as portal of entrance for bac- 
 teria 37 
 
 Koch, work of 25 
 
 Leprosy 51 
 
 avenues of infection 54 
 
 bacillus 53 
 
 history of 51 
 
 present distribution 52 
 
 Lungs as portal of entrance for bacteria. . 36 
 
 Malta fever 139 
 
 history 139 
 
 organism 139 
 
 Miasm, theory of 22 
 
 Mouth as portal of entrance for bacteria. . 35 
 
 Normal sera 213 
 
 Nose as portal of entrance for bacteria. . . 35 
 
 Opsonins 207 
 
 Pasteur, work of 24 
 
 Phagocytosis 183 
 
 in acquired immunity 192 
 
 in injuries and disease 193 
 
 in natural immunity 188 
 
 Plague Ill 
 
 bacillus 117 
 
 history Ill 
 
 mode of infection 121 
 
 Pneumonia 143 
 
 bacillus 144 
 
 history 143 
 
 Precipitate 199 
 
 Precipitinogen 197 
 
 Precipitins , 198 
 
 specific 197 
 
 specific, history 197 
 
238 
 
 INDEX 
 
 Pseudotuberculosis 49 
 
 Sausage Poisoning: see Botulism 137 
 
 Sera, germicidal 213 
 
 immune 219 
 
 normal 213 
 
 Skin as portal of entrance for bacteria... 35 
 
 Staphylococcic infection 161 
 
 infection, organism 161 
 
 Stomach as portal of entrance for bacteria. 37 
 
 Streptococcic infection 153 
 
 infection, history 153 
 
 infection, organism 154 
 
 Tetanus 149 
 
 bacillus 149 
 
 history 149 
 
 Tuberculosis 39 
 
 avenues of infection 47 
 
 avian type of 44 
 
 bacillus 40 
 
 bovine bacillus 42 
 
 history 39 
 
 piscidian variety of 45 
 
 pseudotuberculosis 49 
 
 sources pf infection 48 
 
 Typhoid fever 65 
 
 history 65 
 
 sources of infection 70 
 
 Typhus fever 93 
 
 history 93 
 
 organism 103 
 
 transmission . . 106 
 
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