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Les diagrammes suivants illustrent la m6thode. 1 2 3 1 2 3 4 5 6 w //AniffM-^V'T'-^ THE HEMORRHAGIC DIATHESIS IN TYPHOTIT FEVER AND ITS RELATION- SHIP TO PURPURIC CONDITIONS IN GENERAL.i It is a matter of common observation that in certain infectious and presumably infectious diseases like typhus fever, scurvy, Werlhoff's disease, and peliosis rheumatica, hjemorrhagic eruptions develop in the skin and mucous membranes. That which is the primary and cardinal train of symptoms in these diseases may be found exceptionally as a complication in certain others, like variola, scarlet fever, measles, enteric fever, cholera, yellow fever, sepsis, and acute atrophy of the liver. In the course of typhoid fever or enteric fever a number of examples have been recorded during the past two decades where hsemorrhagic complications have supervened. Of course, minor hsemorrhagic manifestations, like epistaxis which so frequently ushers in the attack, or like intestinal haemorrhage which is present iu a considerable proportion of ordinary cases, are common enough, while either of these conditions may, under certain conditions, be part and parcel of a general hsemorrhagic tendency and represent its first symptom. This does not in itself constitute the hsemor- rhagic diathesis. This term should be restricted to those cases where multiple haemorrhages take place and which are evidenced clinically by purpuric eruptions into the skin, oozing of blood from the mucous membranes, epistaxis, haemoptysis, hsematemesis, melaena, or metrorrhagia. All of these symptoms, of course, may not be present simul- taneously, since very varying grades of the condition exist. Most authorities are agreed that such occurrences are very rare, though their possibility has been recognised for many years. I We desire to express our thanks to Dr. \J. F. Hamiltor. of the Royal Victoria Hospital, Montreal, for the opportunity of recording this case of hsemorrhagic typhoid fever. Some hesitation has arisen in oar minds in regard to the proper expression which should be used to designate this interesting form of typhoid fever. The term " hsemorrbagic diathesis " is possibly open to criticism, since to many minds it connotes the idea of some pre-existing conetitutiooal deficiency or dyscrasia of the blocd or some congenital weakness of tbe blood-vessels. With the single exception of certain of Wagner's cases, to be referred to later, such inherited defects can usually be excluded in tbe type of disease under consideration, and yet it is clear tbat there is at work some serious diaturbance of the blood. Further, the term "purpura hsemorrhagica " is not altogether suitable, since it has not been settled between clinicians and patho- logists what conditions are properly to be included under this designation. Litten, for instance, restricts tbe term to WerlhofE's disease, Schonlein's disease, and some others, and would dfny it to the purpuras which occur in variola, typhoid fever, sepsis, and mineral poisoning. We must, how- ever, diseeot strongly from Litten's view, for the trend of recent pathological research, as we shall see, is to prove that tbe prime factor underlying the vast majority of cases is some systemic intoxication, either bacterial, chemical, or animal, and there is no sufficient reason for believing that WerlhoS's disease and the group of so-called "idiopathic purpuras " differ essentially from the others in this respect. That circulating toxins, bacterial or otherwise, do produce marked alterations in the quality and composition of the blood and lead to degenerations of the bloQd-vessels may be regarded as proven. Since, then, we have to admit a serious qualitative vitium in the blood, even though it be acquired, and since we are unable entirely to exclude the presence of some inherited defect, it would seem fairly scientific and at the same time less liable to misapprehension if we use tbe designation " haemorrhagic diathesis" for these cases in pre- ference to any other. We in Montreal have had the unusual experience of meeting with four cases of a more or less haemorrhagic type in a series of about 200 cases of enteric fever from the clinic of Professor James Stewart at the Roya^ ^'^ictoria Hospital. These were recorded by one of us (Ni( jAx ^) in 1896, but at that time little actempt was made to analyse the clinical symptc^.o or to determine pathological conditions. In the present communication we are enabled to report an a Hemorrhagic Typhoid Fever, 1896 (Bibliography). Montreal Medical Journal, June, 5 additional most extreme example of enteric fever with the bsemorrhagic diathesis, which has been very cAref ally worked out and which will, we hope, help to place uhe subject on a more satisfactory basis. The hseoaorrhagic type of enteric fever has for yeaxs been recognised as a clinical entity and was first brought into notice by the earlier French school, notably Trousseau, who referred to it under the name of ^^Jievre putride Mmor- ragique" Liebermeister in Von Ziemssen's Cyclopaedia notes the occurrence of haemorrhages from the nose, gums, stomach, bowels, lungs, kidneys, ecchymoses into the skin, and extravasation of blood into the various organs and serous cavities. He further remarks that haemorrhages into the skin, true petechial vibices, are most likely to occur in patients of a haemorrhagic diathesis, but occasionally appear in others. Murchison^ had occasionally observed haemor- rhages into the muscles. Wilson and Loomis mention haemor- rhages from mucous surfaces and in the skin. Wood and Fitz* state that " haemorrhagic typhoid fever is a very deadly complication of the * disease, especially prone to occur in debilitated subjects suffering from scorbutus, alcoholism, &;c. There is in it a rapid alteration of the blood with profuse haemorrhage from the nose, mouth, intestines, and kidneys— indeed, from all the mucous membranes, the formation of a,bundant ecchymoses, blotches, and suggillations, &:c. In these cases the adynamia is extreme from the beginning, the fever is high, the pulse very rapid and small, heart's action greatly enfeebled, tongue and mouth loaded with a brownish deposit, the breath very foetid and even ammoniacal. Death usually occurs before the tenth day in these cases and has been recorded as early as the third." Osier ' says of haemorrhagic typhoid fever : * ' This is excessively rare Haemorrhages may be marked from the outset, but more commonly they develop dur'ng the course of the diiL ,ase. The condition is nob necessarily fatal." Hare^ in his admirable monograph en " The Medical Complications of Typhoid Fjver " states that "haemorrhagic eruptions may occur in the course of typhoid fever, and, as a rule, they appear in the neighbourhood of the joints, when t'je exudation may be small or quite large." » Continued Fevers, 1873, p. 609. 4 Practice of Medicine, 1897. 5 Practice of Medicine, 1899. B Medical Complications, Accidents, and Seque'a^ of Typhoid or Enteric Fever, 1899. 6 It is somewhat singular that the cases of hsemorrhagic enteric fever published during the past four or five years have been regarded chiefly as clinical curiosities and no attempt has been made to study the condition fully or to ascertain its cause. Indeed, in most even the clinical features are very inadequately described, and in a very few where a post-mortem examination has been made the investi- gation has been, to say the least, very superficial. After a careful study of the recorded cases we have been obliged to conclude that they are of little scientific value and do not materially advance our knowledge of the intimate nature of this process. In the case herewith presented we have endeavoured to make a minute examination of the various organs in the hope of arriving at a more adequate conception of the processes involved. The case was as follows. A female, unmarried, aged 21 years, a school-teachei', was admitted to the Royal Victoria Hospital under thn care of Dr. W. F. Hamilton on June 196h, 1900, with headache, anorexia, and pain in the back. Her history was as follows. She was born in Canada. She had had measles eight or nine years previously, but no other illness ; her habits were regular and her food and clothing were satis- factory. Her father was subject to asthma ; her mother was weakly and "bothered with her kidneys"; and two sisters were dead (one from diphtheria). Careful questioning failed to elicit any evidence of haemophilia or rheumatism. The patient first felt ill six days before admission, but kept at work for two days. The illness began with chill, pains in the back, and following this some fever. The condition persisted and gradually got worse until she applied for admission to the hospital. On admission the patient was a well-nourished girl of medium size. Her face was flushed, her eyes were dull, and her lips were dry and sore. The temperature was 100° F., the pulse was 98, and the respira- tions were 22 ; the mucous membranes were pale. The pulse was regular and of good volume; tension was slightly ^^Zws. The apex beat was visible in the fifth intercostal space, two and three-quarter inches from the mid-sternal line. Cardiac dulness was normal. On auscultation the first sound at the apex was rather muffled ; at the base the pulmonary second, sound was extremely accentuated. With regard to the respiratory system expan£ion was good ; a few fine crackling rales could be heard over the base of the right lung posteriorly ; the lungs otherwise were normaL The tongue was dry and caked ; it was moist at the edges. The teeth were covered with sordes ; anorexia was marked ; the bowels were regular. The abdomen was slightly prominent below the level of the umbilicus. There was no rigidity ; general tenderness was present. The percussion note was tympanitic throughout. The spleen was doubtfully palpable. The liver was not palpable and dulness was normal in extent. The skin was hot and dry. Numerous rose-spots were present upon the abdomen. The muscles were small and flabby. The lymphatic glands were not palpable. The intelligence and memory were good ; there was no headache ; the patellar reflexes were increased. Menstruation began at 14 years of age and was normal. On June 7th, 14 days from the onset of the first symptoms, a haemorrhagic area made its appearance near the umbilicus following the application of an ice-bag. There was distinct ecchymosis of the skin of a dark purple colour which did not disappear on pressure. On the 20th the abdomen was still distended but less tender. On the 29th the patch on the abdomen was fading. Daring the night the patient had two intestinal hajmcrrhages and multiple haemorrhages were present o«^er the left half of the trunk posteriorly. On the 30th, during the night, there were profuse epistaxis and haemorrhage from the lips and gums and effusion of blood into the conjunctivse, and daring the day there was haema- turia. A blood count gave 13.000 leucocytes. Widal's reaction was present. On July 1st subconjunctival haemor- rhages of the right eye had partially disappeared, but now there was haemorrhage below the right lower eyelid. The urine still contained blood, but there was no vaginal bl ^d- ing. There were a few subcutaneous haemorrhages upon the trunk. During the night there were epistaxis and haemor- rhages from the back of the throat. On the 2nd ten ounces of saline solution were injected below the mammae. A few subcutaneous haemorrhages appeared upon the lower limbs. The patient was much weaker. A blood count gave 1,640,000 erythrocytes and haemoglobin 35 per cent. On the 3rd the patient did not sleep and became gradually weaker and died at 8.40 A.M. The treatment adopted was as follows. Cold baths, 18 in all, were given until the haemorrhagic tendency develpped. Spirit of turpentine and liquor calcis chloridi were given internally ; applications of suprarenal powder in glycerine were made to bleeding mucous surfaces. This case may be described as one of typhoid fever of moderate severity occurring in a young person in previously good condition. The course was typical except that the disease set in with a chill and the spleen was at no time B definitely discoverable by palpation. The abdomen was not particularly distended aud the bowels were regular, moving generally once daily ; during the last three days of life the bowels were constipated. The highest point which the temperature reached was 1043° on the day ot admission. During the followiog four days the temperature kept about 103" or 102 2°, being reduced about two degrees by the tubs. During the next three days the temperature averaged about 101'2°. On June 29th, when the hasmorrhages from the bowels took place, the temperature in the course of seven hours dropped from 103° to 1002°, but rapidly returned to 102 3°. On the 30&h the incidence of the submucous haemor- rhages led to a mo.e decided fall, the temperature coming^ dojsrn to 982°; the return was almost immediate to 10r3°. Oil July Ist the average was 100°, on the 2Dd 99'2°, and at death on the 3rd the thermometer fell to 95'2°. The cha- racter of the temperature curve at no time suggested the idea of any septic infection, nor was it affected by the develop- ment of the haemorrhagic diathesis in any other way than i* usually seen in enteric fever where there is considerable loss of blood. Necro'p&y. — A post-mortem examination was made two hours after death by Dr. W. W. Ford, Tho body was found to be that of a well-developed young female presenting the usual signs of death. The skin and mucous surfaces were pale. The breasts were well developed, the genitalia were normal, and the rectum was normal. In the left eye haemor- rhage had taken place into the sclerotic at the internal canthus. There was also slight haemorrhage into the con- junctiva of the right eye in the neighbourhood of the inner canthus. The skin below both lower eyelids was discoloured. The mucous membrane of the lips showed small ecchymoses ; the pharynx was apparently normal. There was subcutaneous discolouration below the right breast at the site of the saline injection. There were a few dark areas of subcutaneous haemorrhage over the left buttock. Petechial spots were scattered rather plentifully on the skin of the trunk in front together with some irregular eccjhymoses ; one most striking feature was a large ecchymosis, roughly oblong in shape, about 12 centimetres across, which was situated near the umbilicus and represented the site where the ice-bag had been applied. A few petechial spots and small ecchymoses were present on the left thigh just above the knee and above the left internal malleolus. The cranium was not touched. The diaphragm reached to the height of the fifth rib 9 in the right side and the fourth on the left. Ttie right lang presented a few old adhesions posteriorly and to the diaphragm. The pleural surface of both lungs showed numerous punctate haemorrhages. The right lung weighed 460 grammes. The bronchi were filled with frothy fluid ; the mucous membrane was normal. The tissue on section was congested and oedematous and numerous indefinite patches of haemorrhage, some of them of the size of small peas, were present throughout the substance. The edges of the lung were emphysematous. The left lung weighed 450 grammes. On section it was found to be con- gested about the posterior surface ; in other respects it was similar to the right. The heart weighed 190 grammes. The right ventricle was filled with red blood -clot ; all the valves were normal. The tricuspid orifice admitted the tips of t-wo fingers. The edges of the mitral valves were a tr.fle thickened ; the mitral orifice admitted three fingers. The left ventricle was filled with blood-clot. The heart muscle was pale and contained a few pin-point haemorrhages. In the abdomen there was a fair amount of subcutaneous fat of a normal deep straw colour except at the umbilicus, where it was discoloured by free extravasation of blood into the tissues. On opening the abdomen the intestines were found to be slighcly distended. The great omentum lay coiled up on the left side below the spleen. The peritoneum was smooth and glistening. The appendix lay on the brim of the pelvis pointing upward and inwaid ; no fluid was found in the peritoneal cavity. The retro- peritoneal tissues over almost the whole of the lower part of the abdominal cavity were occupied by a large recent hasmorrhage which spread over the whole surface of the pelvis, over the top of the bladder to the front, and towards both sides. The spleen weighed 90 grammes ; the surface was smooth and the capsule was rather wrinkled and showed a few minute subcapsular hasmorrhages. On section it was rather friable but was not congested or juicy. Except for the points noted it was practically normal and was far removed from the appearance of the ordinary typhoid spleen. There was nothing special in the stomach. In the duodenum, one inch below the pylorus, there was a minute pale scar as if from a healed peptic ulcer. The peritoneal surface of the small intcslites showed numerous areas of a dark led colour. The serous coat, however, was smooth and showed no signs of exudate. At these points the intestinal walls were thickened and the patches evidently corresponded to haemorrhages into the 10 inflamed patches iu the bowel wall. The mesentery was occupied by a larpe haemorrhage which was dark red in colour. Go cutting into this the blood was found to be coagulated. The lymphatic glanJs of the mesentery were enlarged and succulent. In the ileum the Feyer's patches were only slightly swollen, showing marked hyperplasia of the lymphoid elements. One of these patches showed haemorrhage into its substance. In the lower part a few shallow serpiginous ulcers were present. The peritoneal surface of the rectum and the meso-rectum were occupied by a number of haemorrhages. Numerous haemorrhages were also present in the appendices epiploicae of the sigmoid flexure and the rectum, dark red in colour. The mucous membrane of the large intestine was congested and catarrhal throughout. The solitary follicles were nu-Tierous and somewhat swollen. Many shallow and some deep ulcers were present in the caecum about the ileo- caecal valve and in the first part of the colon. The bases were somewhat indurated. The ulcerations were fairly characteristic of typhoid fever at the end of the third week, except that they appeared to be more indurated than usual This was explained by the fact that many of these were infiltrated with dark-red blood which caused the bases and edges to appear to be thickened, somevvhat mask- ing the typical appearances. The ulcers in the neighbour- hood of the ileo-cffical valve were large and sinuous. About 30 ulcers all told were present in the intestines. The mucous membrane of the rectum was apparently normal ; the rectum was filled with clotted, dark greenish, altered blood. The pancreas weighed 130 grammes. On section it was found to be of pale colour and well lobulated. A few minute haemorrhages were present upon the surface. The lymphatic glands in the neighbourhood were large and succulent. The liver weighed 1225 grammes. Its serous surface was smooth ; on section it was markedly pale with cloudy swell- ing. No faecal necroses were seen. No hjemorrhages were present. The gall-bladder was filled with dark-coloured bile. The wall, where the organ was attached to the liver, was infiltrated with blood. The left kidney weighed 140 grammes. Its capsule peeled oS with ease. Many small pin-point haemorrhages of a dark reddish-brown colour were noticed on the cortex. The surface was congested. On section the organ was very much congested, the glomeruli showing as reddish points. Numerous haemorrhages were seen in the Bowman's capsules and along the course of the interlobular and straight vessels. The cortex measured 18 milli- metres in thickness. The kidney was fairly firm and was of 11 a dark greyish-brown colour. The right kidney weighed 120 grammes ; iu all respects it was similar to the left. The mucoas membrane of the bladder was pale and showed above a few submucoas hsemorrhager. The bladder was filled with clotted blood and there was a very large submucous extrava- sation of blood in the lower two-thirds of the organ posteriorly, from which the oozing apparently had taken place. The uterus was small ; the external os contained blood-stained mucus. The vagina contained no blood. The ovaries were small ; the left contained a few clear cysts of small size ; there were no haemorrhages. The Fallopian tubes were normal. Microscopical examination. — Stained with Ehrlich's haematoxylin the fibres of the heart muscle were somewhat thin and wavy. The staining of the nuclei was faint and the transverse striation was indistinct. The longitudiual fibrillation was well marked. Beyond some cloudiness thero was no special change. In sections stained by the carbol- thionin and Gram-Weigert methods no bacteria were se6jn. Hsematoxylin preparations of the lung showed small irregular haemorrhagic patches here and there throughout the tissue These were somewhat poorly defined at the margins, ^j.ssing oS. gradually into the more healthy condition. The alveolar walls throughout were on the whole rather thin and those within the infarcted areas were much compressed. Th walls everywhere stained fairly well. The interstitial tiss^ 'howed slight anthracosis. Small areas of collapse were noted in many portions. There was distinct catarrh of the lining endothelium of the alveolar processes, many of the alveoli being filled with, in addition to a few red cells, large mononuclear cells containing granules of pigment and debris. The debris in part con- sisted of broken-down erythrocytes. No emboli were seen. Portions of the tissue were stained with osmic acid (Fleming's solution) and Sudan III. for fat. The osmic preparations were the less satisfactory since it was hard to distinguish fatty particles from pigment grannies. The Sudan preparations, however, showed very well in places modfc:?.te fatty degeneration of the endothelium covering the alveolar walls. Sudan III. possesses the property of staining fat-dioplets n golden yellow or carmine colour, according to the size of the droplet. In some places the alveolar walls were distinctly picked out by the stain, showing as a 12 pinkish network. With a high power this was seen to be due to minute particles of fatty matter dot^^ed throaghout the endothelial plates. Certain of the desquamated mononuclear cells within the alveoli were loaded with fatty matter. Many others, and some :ilso of the lining cells of the walls, contained pigment of a brownish colour, which was not fat but was apparently derived from the broken-down red cells. By the ;'>ram-Weigert stain no bacteria wore noted. By carbol-thionin certain of the bronchi were seen to be plugged with exudate, the lining columnar epithelium being de- squamated and in part degenerated. The exudate consisted in large part of oval or spindle-shaped mononuclear cells together with crowds of bacteria consisting of coccus forms and medium-sized bacilli having rounded ends. These bacilli varied much in length, some being very short, some were slightly curved, and others were bulbous at the ends. Most showed bipolar staining. Similar bacilli were present in great numbers in the collapsed areas. One small bronchiole was found to contain blood, an infarct having presumably burst into it. Spleen : the staining agent used was hsematoxylin. It was not congested and was without any special abnormality except some hyperplasia of the so-called epitheloid plates. The tissue was not cedematous and there was no peri- splenitis. By the Gram-Weigert and carbol-thionin methods no bacteria were seen. Liver : the staining agent used was hsematoxylin. The tissue stained fairly well and the nuclei were distinct. The cells were swollen and cloudy. No particular fatty change was observed and there were no haemorrhages. Everywhere could be seen in the intercellular spaces within the lobules little scattered groups of two or three poly nuclear cells. In the portal sheaths, by the carbol-thionin method, a small amount of acute interstitial infiltration could be made out chiefly along the course of the portal vein. These aggregations were not at all striking, however. In one or two sections also a few small lymph- omatous masses could be observed consisting of small round mononuclear cells, with a few larger mononuclear hyaline cells resembling macrophages. No true focal necroses were noted. No bacteria were observed. By the Gram-Weigert method no bacteria were noted. Pancreas: haematoxylin was the staining agent used. Except that the tissue stained rather faintly there was nothing specially worthy of note. Kidney : haematoxylin was the staining agent used. Numerous areas of haemorrhage were present both ia the cortical 13 portions and in the medulla. This hsemonhage was marked in the interstitial substance in various places but was very strikingly shown in those parts where the blood had forced its way into the kidney-tubules, many of which were greatly distended with blood. In the cortical portion the haemorrhages appeared to be most marked in the neighbourhood of the interlobular vessels running vertically . forwards to the cortex. In one section a Bowman's capsule contained much blood and the glomerulus was distinctly compressed. The tubules, maioly the tubuli contort!, which contained the blood, were over-distended and the lining secretory cells were greatly flattened. In the medullary portion the straight and collecting tubules contained blood. Everywhere the extravasa<;ion was oi recent appearance. Small, more wedge-shaped, masses were common just beneath the capsule. The glomerular tufts were not con- gested but the lining endothelial cells of the Bowman's capsules were swollen and occasionally desquamated. In a tew capsules small masses of albumin could be made out. In the remaining parts 'ae lining cells of the secreting tubules were snroUen and granular-looking and the staining was defective. In the medulla and in one specimen surrounding a glomerulus and capsule near the cortex there was fairly extensive round celled infiltration consisting of inflammatory leucocytes. The surro'inding congestion was not great, however. The endothelium of the affected capsule was notably catarrhal. One of these infll- trated areas was large enough to suggest an abscess'. A few small areas of round-celled infiltration were seen in some sections consisting of mononuclear elements and no doubt to be regarded as the so-called " lymphomata " of Wagner. The osmic acid and SuJan III. preparations showed practically the same features. There was a moderate degree of fatty degeneration affecting in some instances the basement membranes of the Bowman's capsules and very generally the secreting cells of the con- torted tubules and the descending loops. Those tubules which contained blood showed this in a very extreme degree. The capillaries of the tufts were, as a rule, free, though certain of them showed slight fatty change. The sections stained by carbol-thionin showed that in the small inflam- matory areas there were to be seen short, fine bacilli with rounded ends and with well-marked bipolar staining. By the Gram-Weigert method no bacteria were observed. The small intestine showed by the hsematoxylin method marked 14 of the mucosa, with some mucoid and cellular upon the surface. The lining epithelium was n . The mucosa showed a On the snbmucosa the and proliferated, the numerous. The acute through the muscular numbers being found muscle. The serosa catarrh exudate swollen and the cells were active, moderate round-celled infiltration, lymphoid follicles were swollen epithelioid plates being specially inflammatory infiltration extended wall, round cells in considerable between the various layers of was free. Small hsemorrhagss were present in the submucosa and muscularis. The carbol-thionin method showed a few short bacilli with rounded ends and of moderate size im- bedded in the mucus on the surface. None were seen in the deeper layers. By the Gram-Weigert method no bacteria were seen. The blood-vessels were examined very carefully in the lung, liver, and kidney with the view of ascertaining if any clots were present. The most that could be said was that in these different organs the blood in both arteries and veins showed a tendency to break down, the red cells being apparently converted into a line granular material of pale brownish colour in which a few leucocytes were imbedded. Besides these there were certain large clear mononucleated cells which appeared to be swollen and desquamated endo- thelial cells. These endothelial cells of the small vessels and capillaries were everywhere more prominent than usual, a condition which has been described by F. B. Mallory'as a constant feature in typhoid fever, but found also in diph- theria and some other infectious fevers. Nowhere were definite fibrinous clots of emboli observed. The condition of alteration of the blood is one that we would lay no particular stress upon, for it is one which we have often seen in other cases, particularly in specimens which have been kept for some time in methylated spirit. Nowhere were bacterial emboli, acute arteritis, or phlebitis discovered. The arterioles and the larger vessels showed no histological peculiarities. V '\ Bacteriological examination. — Unfortunately, through an oversight, cultures were not taken from the spleen or mesen- teric glands. Agar cultures were made from the heart- blood, peritoneal cavity, and the kidneys. Small round pearly- white growths were developed in the peritoneal fluid. These were elevated and discrete ; they proved to be cocci " A Histolo^jical Study of Typhoid Fever : Medicine, 1898, p. 6111. Journal of Experimental 15 staining by Gram's method. They grew readily on all media, liquefied gelatin, coagulated milk, and produced acid. They were regarded as the staphylococcus pyogenes albus. From the heart-blood two varieties were isolated : the first was a hick, elevated, soft, moist growth of a whitish colour and the second was a thinner, more pearly growth, in the shape of more star-like colonies. These were isolated. The first variety were '^ncci, positive to Gram's method, giving all the cultural peculiar! iiievs u2 t^e staphylococcus pyogenes albus, and were identical with tlioiiie. !o.:nd in the peritoneal fluid. The pure growth of the second vaiitiuj showed a variety of forms, short fine bacilli with bipolar st&L^^ng, pairs of oval short bacteria, cocci or single short ovoids. Some bacilli <^i present were thicker than the others and somewhat swollen \\y*' at the ends, apparently involution forms ; when ot full size < r^ the bacilli had rounded ends and were about four times as ^ long as broad. No spores were seen. All were non-motile. These turned litmus milk red and coagulated it, although it took some time to do this. The coagulum was at first in the form of small flakes. It did not liquefy gelatin and did not produce gas in glucose broth. Inoculated into rabbits it proved ^>o be non-pathogenic. Three forms were isolated from the kidney. The first conformed in morphology and cultural peculiarities to the staphylococcus albus. The second presented a variety of forms, short ovoids or cocci, baoillary forms about three times as long as broad with bipolar staining. They were non- motile and without spores • they did not liquefy gelatin and did not produce gas. Litmus milk was unchanged. They were non-pathogenic for rabbits. The third variety was a rather small delicate bacillus producing a greenish fluorescence. The chloroform test did not show any true pigment production. The bacillus was motile ; it liquefied ^^ gelatin ; it did not produce gas or acid and did not ' I coagulate milk. Its reaction to the Gram method was un- certain. A rabbit inoculated through the auricular vein died six weeks later from purulent peritonitis. The original germ was not recovered, however, and the lesions found did not suggest the presence of the bacillus pyocyaneus. The rabbit probably died from some intercurrent infection, the bacillus coli being found in the various organs. The bacillus was finally regarded as the bacillus flaorescens liquefaciens. The anatomical diagnosis was typhoid fever ; typhoidal ulceration of the small, but principally of the large, intes- 16 tine ; general hsemorrhagic diathesis ; mixed infection ; maltiple hsemorrbages from the mouth and nose, the bowels and into the skin, lungs, heart, spleen, kidney, intestines, bladder, gall-bladder, and connective tissues ; small spleen ; cloudy organs ; acute diffuse nephritis ; fatty degeneration of the capillaries of the lungs and kidneys ; healed old duodenal ulcer ; and right old pleural adhesions. A careful scrutiny of this case shows that it was enteric fever, atypical in the particulars that the intestinal lesions were moat marked in the large bowel, that the f pleen was small, that there was a general hEemorrhagic diathesis, and that there was a mixed infection with the staphylococcus albus. We do not think that the fact that the bacillus typhi was not found in the cultures invalidates the conclusion that the case was one of enteric fever, for the intestinal ulcers were characteristic for the age of the condition and the Widal reaction was positive, both facts together being practically conclusive. Owing to an oversight cultures were not taken from the spleen and mesenteric glands, and even if the bacillus typhi had originally been present in the kidney in such a situation it would be apt to be attenuated and would be the more easily overture svn by other forms of germ life. Further, it is notorio sly difficult to obtain the bacillus typhi from the blood, su ^ I Philadelphia. ) 147 37 Bosanqueti* ... Charing Cross. 215 2 — J. M. Anders" ( Med. Chir. ) < Hospital, J- i Philadelphia. ) 266 2 — Osier" i Johns Hopkins ) ] Hospital, > ( Baltimore. ) 685 1 — — Authors i Royal Victoria ) ^ Hospital, > ( Montreal. ) j 543 3 2 i — Totals — 12,000 18 p 1 ? Of course, fairly numerous cases are met with in the literature in addition to the above, but they could not be included in the table since they did not form part of any extended series of observations. Examples, for instance. * Archives des Sciences Biologiques, St. Petersburg, ii., No. 1, 1893. 9 Deutsches Arehiv, Band liv., S. 161, 1895. 10 Ziemssen, Handbueh, 1876. Band ii., S. 198 ; ref. in Curschmann. Der Unterleibstypbus, 1898, Wien, S. 297. 11 Ibid. (ref.). 18 Typhoid Fever Report, Philadelphia Medical Journal, Feb. 25th, 1899. 13 Notes on 215 Cases of Typhoid Fever, Brit. Med. Jour., July 8th, 1899 1* Philadelphia Medical Journal, Feb. 25th, 1899, p. 416. 1" Johns Hopkins Hospital Reports, Studies in Typhoid Fever, vol. vlii., 1900. 10 have been recorded by Trousseau,''' Barlow/^ Gerhardt,'- Wagner,'^ Hawkins,-^ Hughes and Levy,^^ Adami,*^ Nicholls,=^3 Gilman Thompson, 2' and Hamburger.^' It is possible that some of the cases are not examples of the condition under discussion, as many either occurred before the day of the Widal test or were not controlled by post-mortem examination. The following remarks are based upon a careful study of the recorded cases, any doubtful ones being neglected. Etiology of the, hcemorrhagic tendency. — Comparatively little is known as yet as to the causative factors in the rendition. The few authors who have dealt with the sub- ject confine themselves to general statements, nor do the various opinions expressed altogether coincide. A study of the cases recorded, however, goes to show that some of the etiological factors, so-called, have really little weight. A pre-existing scorbutic, hsemophilic, or rheumatic taint does not' seem to have been noted. Alcoholism, on which Fereol and Roger 26 and Ourschmann ^^ laid stress, cannot be of much importance. It was not present in any of Wagner's or our cases, though present in Gilman Thompson's and two of Curschmann's cases. Others, like Gerhardt 2** and Griesinger,^'' regard defective nutrition due to scurvy, overcrowding, and scanty food as powerful contributory causes. The state of the previous nutrition, however, which on a priori grounds would seem to be an important consideration, does not appear to be a factor in all cases. Most of the cases recorded were in a previously healthy condition and some were of unusually good physique. i« Clinlque Medicale, tome i., 1865. >7 The Lancet. April 26th, 1884, p. 745. i» Zeltschrift fiir Klinische Merticln, Band x., S. 201. li* Deutsches Archiv fiir Klinische Medicin, Band xxxvii. ; ibid., Bandxxxii.,8. 298. 20 Transactions of the Clinical Society, vol. xxvl., 1892, pp. 50, 51. 21 Archivfts de Medecine et de Pharmacie Militaires, August, 1892. 22 Montreal Medical Journal, 1894, p. 691. 2» Loc. cit. 2* Unusual Complications of Enteric Fever, Medical and Surgery Reports of the Presbyterian Hospital, New York, 1898. 25 Johns Hopkins Reports: Studios in Typhoid Fever, vol. viii., 1900. 28 Ref. in Brouardel et Thoinot, La Fidvre Typhoide, 1895. 2T Der Unterlei jstyphus, Nothnagel's Specielle Pathologie und Therapie, Band iii.. No. 1, 1898. 28 Loc. cit. 2!» Virchow's Handbuch der Infektionskrankheiteii, Band ii., S. 217. 20 One of Wagner's cases was scrofulous in childhood and one of the Royal Victoria Hospital patients was puny as a child. A case under the care of Gerhardt had gone through an attack of measles three weeks before and the patient in Adami's case had had pneumonia and cupyema. How far these factors were concerr ed in the subsequent development of the haemorrhagic tendency is very problematical. In this connexion the views of Gerhardt are of some interest. He thinks that the haemorrhagic tendency has been more frequently observed since the introduction of the cold-bath treatment, and thinks further that a too rigid restriction of the patient to an animal diet is an important cause as tending to induce a scorbutic condition. Leudet^*^ in an epidemic which occurred at Rouen in 1869-70 lays stress upon a certain "epidemic influence," whatever th?t may mean. Wagner has recorded a curious instance where a family idiosyncrasy seemed to play a part. Of five children in one family suffering at the same time from typhoid fever three developed a more or less pronounced haemorrhagic tendency. That this was not due to poverty and malnutrition was shown by the fact that one of the sisters so aSected was not living at home and was well nourished. Wagner, Gerhardt, and Curschmann agree that the con- dition is commonest in childhood and early adult life. Of the cases recorded one patient was eight years and another was 16 years old. The vast majority were considerably under 25 31 ears of age ; the oldest was 32 years of age. The age average was 214 years. With regard to sex there seems to be an equal liability of males and females to the complication. The type of the original typhoidal disease seems to be of some importance. The vast majority of cases are found in those suffering from typhoid fever of a f-evere form. The patients are much prostrated, the temperature is high, the heart's action is weak and rapid, and there may be coma or lelirium. The mouth is usually very foul and the excretions may have an ammoniacal odour. In certain rare cases, as Curschmann points out, the haemorrhagic diathesis may be one form of the " foudroyante " typhoid fever. One of our Montreal cases was, on the contrary, comparatively mild. The character of the onset of the original typhoidal attack does not give any clue to the development of the baemorihagic complication. More than half the cages 30 Clinique Medicale de I'Hotel Dieu de Rouen, 1874. 21 occurred in the ordinary gastro-intestinal type of the disease. In certain cases severe pains in the legs, rhachialgia, and cutaneous parassthesiae have been noted. Pathology. With the exception of the changes due to the special com- plication the necropsies show that the anatomical lesions diflEer very little from the ordinary typhoid. The anaemia is usually marked, as would be expected. Of 11 necropsies of which we have notes the typhoid ulcers were in tw^ cases mainly confined to the large intestine, the ileum ..^owing only very moderate involvement of the Peyer's patches. In Trousseau's case, where death occurred on the eleventh day, the Peyer's patches were softened but not ulcerated. In one of Wagner's, where death occurred on the thirty- ninth day, the ulcers showed signs of healing. In our own case the only feature of note about the ulcers was the extensive hasmorrhages into their bases and margins, giving them a much more red and swollen appearance than usual. The spleen is, as a rule, found enlarged. The haemorrbagic patches in the skin may be infected and break down, forming gangrenous ulcers. Coming to the haemorrbagic manifestations there ic con- siderable diversity in their character and distribution. Ha3morrhage into a muscle, perhaps one of the slightest forms of the complication, is not very uncommon even in ordinary typhoid fever, but may be part of the general haemorrbagic tendency. It is supposed to be due to a vitreous degenera- tion (von Zenker) of the muscle. The haemorrhages may be minute, petechial, ecchymotic, or may form tremendous extravasations into all the loose tissues. Petechiae may be present on the skin and all the mucous and serous surfaces. Parenchymatous haemorrhages occur in the various organs. In fact, no organ or tissue of the body is necessarily exempt. Nor are the external manifestations of the condition a true index to the extent of the internal lesions, for, as Ham- burger ^^ points out, the most extensive involvement of the internal parts may be present wheu but little suspected. The recorded necropsies show that the skin, subcutaneous tissues, and the various mucous membranes are by far the most frequently involved ; next to them the lungs, spleen, and urinary organs. Infarcts have been found in the lungs, spleen, and kidneys, and thrombi in the renal and femoral 31 Loc, cit. 22 veins, the chambers of the heart, the pulmonary artery, and the cerebral arteries. Curschmanu says that embolism of arteries is very rare, but when found is usually in the kidneys and spleen. In certain cases the clotting of the blood has been undoubtedly ante-mortem. With regard to the ultimate cause of the bsemorrhagic tendency but little is known ; no cases have up to the present been studied with sufficient detail finally to settle the question, but, as already binted, various theories have been propounded. Curschmann says: "We are uncertain what is the exact nature and mode of origin of htemorrhagic typhoid, whether it is to be looked for in a certain peculiarity or activity of the typhoid germ or in some complication or state of the body." The older writers supposed that there was some special change in the blood, a dusolutio sanguinis ; but while this view has been ridiculed in certain quarters very little better has been proposed for it. Trousseau noted that the blood in "putrid haamorrhagic fever," as in yellow fever, was of a dark colour and was deficient in coagulating power. This theory is interesting in connexion with Osier's case where the coagulation time of the blood was 10 minutes, sinking to four minutes during convalescence. No doubt this change in the blood is due to the character of the bacterial toxins present, for we know that in diseases like croupous pneu- m tnia and acute rheumatism the coagulating power of the blood is increased. This seems to depend in part upon the number of the leucocjtes present in the blood, for they are very abundant in pneumonia and rheumatism. Leucopenia, on the contrary, is the rule in ordinary uncomplicated typnold fever. We would expect a priori that in typhoid fever daring the acme the coagulating power of the blood would be diminished. The thrombosis of the crural vein which not infrequently is met with in typhoid fever is never seen during the height of the disease but invariably in the stage of profound asthenia and anaemia, when arterial relaxa- tion and weak driving power of the heart are the rule. An interesting confirmation of this view is seen in a recent case of haamorrhagic typhoid fever recorded by T. V. Openchowdki ^^ where the bleeding from the mucous mem- branes was very obstinate, not yielding to the usual remedies. Suddenly the blood began to clot and the hasmor- rhage ceased. The next day signs of croupous pneumonia became manifest. On the contrary, in a case examined by 32 Klininche Therapeutische Wochenschrift, Jan. 2ad, 1898. w 23 Curschmano, no special external or histological peculiarity of the blood was observed. Further, neither haemoglobinuria nor ha3moglobiDsemia have been noted in these cases. Any vitiated state of the blood must necessarily react upon the vessels and, arguing from what has been found in symptomatic purpura of other types, would aflford a probable clue to the mystery. Uskow ^'^ demonstrated swelling of the lining epithelia of the vessels in the gums and periosteum in cases of scurvy, and von Kogerer 3' has observed thrombosis of the vessels in hhe neighbourhood of the subcutaneous haemorrhages in both scurvy and morbus maculosus Werlhofii. Letzerich ^^ in a case of purpura isolated a bacillus which when injected into rabbits produced widening of the capillaries with hsemorrhagic injection of the gums. Bacilli were present in the capillaries. The haemorrhages were said to be due to hyaline plugs which were present at the bifurca- tion of the vessels. It should be remarked, however, that the presence of thrombi in the various vessels must be in- terpreted with caution. It is very possible that these thrombi are due to the weak circulation aiid the relaxed and degenerated condition of the vessels which are presen*-. at the time of impending death. They are to be regarded as associated conditions rather than the true cause of the haemorrhagic tendency. In one case of purpura occurring in the course of acute endocarditis which we examined recently the subcutaneous tissues were found to contain large numbers of a rather slender bacillus in pure culture and both arteries and veins showed considerable acute inflammation of their walls with some surrounding leucocytic inflammation. In sepsis and variola haemorrhagica bacterial emboli have been found in the capillaries and give rise occasionally to ring-like haemorrhages, particularly about the hair follicles. According to Litten ^^ these are not present in bsemor- rhagic typhoid fever and this observation is confirmed by von Recklinghausen" and Meyer and by our own studies. It is probable that a variety of factors enter into the cau?a- 85 Centralblatt fiir (lie Medicinischen Wissenschaften, S. 498, 1878. 3< Zur Enstehung der Hauthiimorrhagien, Zeitschrift fiir Klinische Medicin. Band x., S. 234, 1886. ^^ Ueber Purpura Htemorrhagica, Leipsic, 1889 (V.i el). 38 Die Hiimorrhagischen Diathesen. Nothnagel's Specielle Pathologie und Therapie, Band viii., Thiel iii., 1898. 3^ Handbuch der allgemeioen Pathologie der Kreislauf und der Brniihrung, S. 87, 1883. 24 tioD, a deficiency in the fibrinogen of the blood, together with relaxation and fatty degeneration of the vessel-walls. No doubti a feeble circulation may be an important element as in our first Montreal case, where the heart was much dilated and its action very rapid, together with cyanosis and coldness of the extremities. These conditions would certainly promote clotting of the blood and since old decolourised thrombi have been found post mortem the possibility of such an occurrence during life cannot be denied. Numerous attempts have been made to connect purpura haemorrhagica with bacterial activity, Klebs, Ceci, Jones, Tizzoni, Petrone, Babes and Letzerich, Hanot and Luzet, Widal and Therose found streptococci ; Lebreton and Litten found staphylococci in their cases. Hamilton and ^ates^"* in a well-marked case isolated the staphylococcus aureus, the bacillus aerogenes capsulatus, and an unknown bacillus. Kenneth Cameron^'' has also noted a hsemorrhagic tendency in general infection in children with the bacillus pyo- cyaneus. It seems to us that this at*^c;mpt to connect the haemorrhage with the action of those micro- crganisms found post mortem is open to fallacy. Patients who are bleeding into the skin and mucous mem- branes are in the best of all conditions for bacterial invasion, and, in fact, we see this in ihose cases which develop abscesses or gangrene in various parts, as they often do. These cases no doubt die, not merely from the exhaustion of anjemia, but from septicaemia. When germs are found in the various organs post mortem under such conditions it is impossible to deny that they may be a result rather than the cause of the haemorrhagic condition. Still, we know that in some cases bacterial emboli have been found in the vessels strongly suggesting a causal relationship, and to a cer- tain extent the condition can be reproduce! in experi- mental animals. Further, the absence of haemophilia or other blood dyscrasia points strongly to the action of a bacterial cause. While, then, the bacterial origin of the haomorrhagic condition is extremely probable the final proof is still wanting. •*'* Montreal Medical Journal, August, 1897. 39 Ibid., March, 1896. 25 0NS1:T and CHA.BACTEU OF SYMPTOMS. Analysis of the cases recorded shows that the haetuorrhagic tendency may occur at any time during the course of the primary attack. Daring the first week the condition is rare. In two cases recorded by Roger the haemorrhage began on the third and fourth days and in one by Ferreol on the fifth. Such are undoubtedly cases of primary typhoidal purpura and strictly comparable to purpura variolosa and scarlatinosa. Griesinger remarks : "In all forms of typhoid, exactly as in small-pox, cases occur where very early, in the ^rst week or later, abundant petechia} and suggillations into the skin, sometimes into the muscles, fet in ; intractable nose-bleeding, ecchymoses, and bloody extravasations into the serous sacs, infarct of the lungs, bloody urine, intestinal haemorrhages, meningeal and brain apoplexy, haemorrhage into the connective tissue of the iliac fossa and formation of tumours." Cases are slightly more frequent in the second week and most common in the third week. The condition, may occur during a relapse, as in Osier's case, or later in a protracted course, as in one of ours where it developed on the fortieth day. The fact that most cases occur during the third week when the sloughs are separating from the ulcers is an argument in favour of the view that some at least of the cases are due to secondary infection. The recorded cases fall naturally into three groups : (1) primary typhoidal purpura ; (2) purpura due to secondary bacterial invasion ; and (3) cachectic purpura, occurring later in the disease or during convalescence. It is quefationable, however, whether the third class is to be properly separated from the infective category. The onset of the symptoms varies considerably. Some- times, though rarely, epistaxis, melaena, or ha?tnaturia is the first symptom ; generally, however, the first signs are in the buccal mucous membrane or in the skin. The baimorrhages are generally multiple in distribution, petechiae, bleeding from the mucosaes, haematuria, and epistaxis frequently going together. Haemoptysis is met with and is due to oozing from the bronchi or to infarction. The skin legions consist of petechiae or ecchymoses, the latter being sometimes of large size. If rose spots are present the eruption may take place into or between them. The petechiae do not disappear on pressure. Sometimes haemorrhagic pustules are present. Small bluish, elevao. ,» subcutaneous nodules are occasionally met with. In some 20 cases a sort of diSase subcuticular purplish mottling has been observed. The skin haemorrhages have been known to occur into a bed-sore or on the application of cold . Gangrene may supervene and oedenia. No special symptoniss seem to usher in the hsemorrhagic condition. Neither chills, sweating, nor a septic temperature seem to have been noted , Marked distension of the abdomen is not uncommon anr Marrhoea is fairly frequent at the onset. The effect on tue temperature is usually very slight, though in severe cases a gradual fall to subnormal has been noted, as in other cases of hasmorrhage. Profound aneemia usually develops, The haemorrhage is not sudden, but rather a gentle oozing from all the surfaces of the body, and is apt to be precipitated by any slight injury. Prognosis. The condition is generally very grave. About two-thirds of the cases recorded ended fatally. The previous history of the patient has some weight. As a rule the earlier the con- dition sets in and the more extensive it is the more serious is the prognosis. Treatment. Treatment is purely symptomatic. Gerhardt, in accordance with his views as to the etiology, discontinues the cold-bath treatment and substitutes a daily warm batl j a temperature of from 33° to 34° C. He includes potato, spinach, and vegetable juices in the diet. To control the hasmorrhage many plans have been tried. On the assumption that the cause is a secondary infection small doses of calomel or other mercurial have been given. One of our Montreal cases recovered under this treatment, as did one which was left alone. Turp«}ntine and ergot were used by Gilman Thompson in his case which recovered. Attempts have been made to increase the coagulability of the blood by means of calcium chloride as suggested by Wright. "^ In severe cases 15 grains should be given twice daily. This treatment has to be carefully controlled by repeated blood examinations, as if it is too vigorously pressed it may have the contrary effect to that intended. The same writer also advocates inhalation of carbonic *" Brit. Med. Jour., Dec. 19th, 1891 ; vol. ii., 1893, p. 223 ; and vol. i., p. 237, and vol. ii., 1894, p. 57.