key: cord-0034959-8j8n9enn authors: Lu, Puxuan; Zhao, Qingxia title: Highly Pathogenic Avian Influenza date: 2015-04-30 journal: Radiology of Infectious Diseases: Volume 1 DOI: 10.1007/978-94-017-9882-2_18 sha: ec45547f54125b66f7473da05741272de472f83b doc_id: 34959 cord_uid: 8j8n9enn Highly pathogenic avian influenza is an acute respiratory infectious disease caused by some viral strains of avian influenza virus A. Its severity is highly diverse ranging from common cold-like symptoms to septicemia, shock, multiple organ failure, Reye syndrome, pulmonary hemorrhage, and other complications leading to death. According to the laws, human infection of highly pathogenic avian influenza has been legally listed as class B infectious diseases in China. And it has been stipulated that it should be managed according to class A infectious diseases in China. H5N1 is categorized into the genus of Infl uenzavirus A , the family of Orthomyxoviridae , and the order of Mononegavirales , which is a segmented negative singlestranded RNA virus (-ssRNA virus). By electron microscopy, it is demonstrated with a typical sphere shape and a diameter of 80-120 nm. Its nucleocapsid is spirally symmetric with envelope. The isolated strain is initially fi lament-like with a diameter of about 20 nm and a length of 300-3,000 nm. Under an electron microscope, hemagglutinin protrudes into a homotrimer composed of three non-covalent combined protein molecules, while neuraminidase is demonstrated as a mushroom-like homotetramer with a head and a stem. The virus is composed of an envelope, matrix protein, and viral core, consecutively from external to internal of the virus. H7N9 is a subtype of avian infl uenza virus that is categorized into the family of Orthomyxoviridae . Its envelope is covered by two types of surface glycoproteins, hemagglutinin (H) and neuraminidase (N) . H can be further divided into 15 subtypes, while N 9 subtypes. All human infl uenza viruses can cause avian infl uenza, but not all avian infl uenza viruses can result in human infl uenza. Among all avian infl uenza viruses, H5, H7, H9, and H3 can infect humans, and H5 is highly pathogenic. Infl uenza virus can be categorized into 135 subtypes by HxNx, including avian infl uenza virus subtype H7N9. It prevailed in birds with no infection of humans. And its biological properties, pathogenicity, and transmissibility largely remain unknown. H7N9 is a new recombinant virus with its genes from avian infl uenza virus H9N2. Currently, it has been found with mutation of PB2 gene at the site of 701. Laboratory experiments have demonstrated that the mutated virus is highly pathogenic to Canidae. Mutation of 627 amino acid site is also possible. Therefore, avian infl uenza virus H7N9 cannot be transmitted from person to person but only from pets or living poultry to person. HA on the envelope of infl uenza virus is an adhesion protein. In a binding way of Neu5Acα2-6Gal, it can bind to the cell membrane at the human respiratory mucosa. The highly pathogenic avian infl uenza H5N1 virus can break through the barrier of species to acquire the capability of binding to receptor of human host cells. Such a change in binding to receptor is the key for human infection of avian infl uenza virus. Since the avian infl uenza virus H5N1 was fi rstly isolated from chickens in 1995, multiple outbreaks of avian infl uenza has occurred. On May 9, 1997, a strain of avian infl uenza virus was isolated from a young child aged 3 years in Hong Kong, which was etiologically defi ned as avian infl uenza virus. In the same year in Hong Kong, 18 cases were defi ned as human infection of avian infl uenza, with six cases of death. This was the fi rst report about direct human infection of avian infl uenza, arousing worldwide shock and attention. In mid-February 2003, two residents in Hong Kong were infected by avian infl uenza virus H5N1 with one case of death. Since December 2003, outbreaks of avian infl uenza in poultry have been consecutively reported in Korea, Japan, Vietnam, Cambodia, the Philippines, Chinese Taiwan, and some provinces of mainland China. Outbreaks of human infection of highly pathogenic avian infl uenza virus H5N1 have been continually reported in Vietnam, Thailand, Indonesia, China, and other Asian countries since late 2003. By January 1, 2012, a total of 583 cases of human infected highly pathogenic avian infl uenza virus H5N1 have been reported across the world, with 344 cases of death and a mortality rate of over 50 %. On April 5, 2013, human infected avian infl uenza virus H7N9 was fi rstly reported in eastern China. Avian infl uenza virus H7N9 has strong pathogenicity with a high mortality rate. By 4 pm on August 10, 2013, a total of 135 defi nitely diagnosed cases, including 1 in Chinese Taiwan, have been reported in China, with 44 cases of death and a mortality rate of 32.6 %. Avian infl uenza virus commonly exists in many domestic poultries, such as turkeys, chickens, guineafowls, geese, ducks, coturnixs, and parrots. The virus might be carried in their secretion and excretion, feathers, organs, and eggs. Avian infl uenza virus H5N1 can infect some wild poultries. Wild water poultries, especially those with asymptomatic infection, play an important role in the natural transmission of the viruses. Wild and water poultries like geese, terns, wild ducks, peafowls, and seagulls, especially migrating water poultries, are more likely to transmit avian infl uenza virus via excretions carrying the viruses. Birds such as swallows, chukars, bar-headed geese, ravens, sparrows, and gray herons can be the source of its infection. Migration of birds plays a signifi cant role in spreading avian infl uenza viruses. The virus can infect humans via inhaling virus-containing droplets and droplet core into the respiratory tract. By such a way of inhaling, the viral particle is inhaled into the human body to cause the disease. Avian infl uenza virus (AIV) also spreads along with air. Direct contact of human to diseased poultry or asymptomatic infected poultry and their secretions or excretions is a route of transmission. In addition, inhaling of viral particles in contaminated environment is another route of transmission. Subsequently, the viral particles adhere to the respiratory tract to cause the disease. Indirect or direct contact is also the route of transmission. Close contacts of human to H5N1-infected poultry or their feces can cause the infection. Direct contact and indirect contact of possibly contaminated utensils can self-inoculate the virus into the upper respiratory tract, mucosa of eye conjunctiva, and skin wound. In addition, avian infl uenza virus can also be transmitted via the alimentary tract, skin wound, the conjunctiva, aerosol, blood, vertical transmission, laboratory and transportation transmission, as well as nosocomial infection. It is speculated that human is infected by avian infl uenza virus mainly via direct contact to the diseased chickens and birds, namely, from poultry to person. It is also speculated that pigs are fi rstly infected by viruses carried by secretion and excretion of diseased poultry. And then human is infected via contacts to secretion, excretion, blood, skin, and fur of the diseased pigs, namely, from poultry to person via pig. The second way of transmission needs further epidemiological studies to verify. Currently, the evidence for human infection of avian infl uenza virus H5N1 supports transmission from poultry to person. And the transmission from environment to person is possible, while the transmission from person to person has not been fully proved. It is generally acknowledged that human is not susceptible to avian infl uenza. Although human infection of avian infl uenza has broken out in many regions, the case of human infection of avian infl uenza has been rarely reported. Based on the data of the outbreaks, any age group can be infected and children aged under 12 years occupy a high percentage, but with mild symptoms. Human infection of avian infl uenza virus has no signifi cant gender difference. Invasion of avian infl uenza virus to the human respiratory epithelium can cause fl u-like symptoms, viremia, and viral pneumonia. In some serious cases, the patients may die from respiratory failure or multiple organ failure. Following pathological autopsy of a death case from avian infl uenza in Hong Kong, China, it was discovered that pathological changes at the lungs are typical viral interstitial infl ammatory changes, necrosis, and fi brous proliferation. The pathological changes of organs are characterized by diffuse phagocytosis of erythrocytes, leukocytes, and platelets by macrophages, which is known as reactive hemophagocytic syndrome. Such a syndrome is the result of cytokinemia caused by the release of multiple cytokines into blood triggered by infection of avian infl uenza virus. After invasion of highly pathogenic avian infl uenza virus into the human body, it replicates and multiplies in large quantities within cells to cause structural and functional damages of infected cells and consequent apoptosis. At the same time, a large quantity of specifi c proteins of highly pathogenic avian infl uenza virus acts as a superantigen to activate the immune system and to keep it to be highly active. And large quantities of infl ammatory cytokines are released to damage normal human cells and their structure. Statistical analysis has demonstrated that 60-70 % human infection of avian infl uenza is severe, which may clinically develop into acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Pathological studies have demonstrated that the early changes of pulmonary tissues include pulmonary edema and the formation of hyaline membrane, being consistent with the early manifestations of ALI or ARDS. At the advanced stage, the pathological changes include alveolar injury, erythrocytes and fi brous exudates, hyperplasia of interstitial fi broblasts, and deposition of collagen fi bers. The parenchymal cells at the lung, liver, kidney, gastrointestinal tract, and adrenal glands are subject to retrogressive degeneration and necrosis. Clinical evidence can also be found consistent to these changes, indicating the occurrence of complicating multiple organ dysfunction syndrome (MODS). In some cases, the conditions progress into multiple organ failure (MOF) with an extremely high mortality rate. The possible reasons are as the following: (1) the direct destructive effects of infection of AVI on capillary endothelium; (2) functional increase of vascular permeability mediated by cytokines and infl ammatory mediators such as metabolites of arachidonic acid, prostaglandin, leukotriene, and thromboxane; and (3) structural increase of vascular permeability due to injuries of capillary endothelial cells and basement membrane mediated by infl ammatory cells, endotoxin produced by Gram-negative bacillus, fi brin and its degradation products, complements, polymorphonuclear granulocytes, platelets, free fatty acid, bradykinin, proteolytic enzymes, lysosomal enzymes, inhaling of high concentration oxygen, and formation of microthrombus. The infl ammatory cells pass through infi ltrative lung tissue space and release infl ammatory mediators to exacerbate lung injury. The injuries of capillary endothelial cells lead to increased permeability and increased fl uid overfl ow. Meanwhile, the lymphatic drainage fails to increase correspondingly, leading to fl uid retention. Therefore, interstitial and alveolar edema occurs. In addition, increased permeability of capillary endothelium increases the level of protein in the interstitial fl uid to be close to the level of protein in the plasma. The decreased osmotic pressure of plasma within vascular vessels exacerbates interstitial edema. In addition to alveolar collapse as well as increased interstitial negative pressure, edema is further exacerbated. In the cases with acute lung injury, the infl ammatory cells and mediators can directly cause structural and functional damages to type I and type II alveolar epithelial cells, destructed basement membrane, and leakage of tissue fl uid, protein, and infl ammatory cells into the alveolus. Thus, alveolar edema occurs. Damaged type II alveolar epithelial cells can cause a reduced production of surfactants within the alveolus, impaired sodium icon transportation, as well as weakened or lost function of repairing type I alveolar epithelial cells and synthesizing anti-injury cytokines. All of these changes further exacerbate pulmonary edema and dysfunctional ventilation. Increased Ventilation at the Early Stage Its etiological factors include emotional tension, pain caused by trauma, and hypoxemia. Hypoxemia is the main etiological factor. In the cases with ALI or ARDS, due to lung tissue space edema and alveolar edema, the alveolus is subject to hyperplasia and hypertrophy of alveolar epithelium as well as formation of alveolar hyaline membrane. The gas exchange between the alveolus and capillary is impaired, with disproportion of ventilation and blood fl ow. Consequently, serious hypoxemia occurs. Its etiological factors include as follows: (1) paravascular interstitial edema and the following decreased interstitial negative pressure increase the risk of small airway collapse and consequent atelectasis; (2) pulmonary edema decreases production of surfactant in the alveolus and its activity, which further lead to shrinkage or collapse of the alveolus; and (3) pulmonary vascular congestion and increased pulmonary blood volume. Pulmonary compliance refers to change of lung capacity caused by change of unit pressure. In the cases with acute pulmonary injury due to infection of avian infl uenza, their functional residual capacity decreases, with pulmonary interstitial congestion and edema as well as decreased surfactants. Therefore, the pulmonary compliance is subject to decrease. Therefore, oxygen demand in breathing signifi cantly increases, with shallow and rapid breathing and reduced tidal volume. The effective alveolar ventilation decreases to aggravate hypoxia. At the advanced stage, pulmonary interstitial fi brosis occurs to further decrease pulmonary compliance. Hemodynamic Change at Lung Due to hypoxia, the blood fl ow is rapid, with shortened time for blood passing through the alveolus. Meanwhile, hyperplasia of the alveolar capillary membrane prolongs the time needed for gas exchange. Therefore, venous blood passing through the alveolus fails to be suffi ciently oxygenated, resulting in return of a certain quantity of mixed venous blood into the left heart. Blood shunt refers to the percentage of venous blood in the arterial blood, which is normally below 3 %. However, in the cases with acute lung injury or ARDS, disproportional ventilation and blood fl ow causes insuffi cient gas exchange in the alveolus. And the venous blood circulating in the capillaries fails to be suffi ciently oxygenated. Therefore, obviously increased venous blood is mixed in the arterial blood to fl ow back to the left heart. In some cases, the blood shunt may increase even to 30 %. In the early stage after onset, mixed alkalosis may occur in severe patients due to hyperventilation. In the advanced stage, a large quantity of anaerobic metabolites gains their access into blood fl ow due to severe hypoxia to cause severe metabolic acidosis. In the terminal stage, respiratory failure leads to respiratory acidosis. Therefore, acid-base imbalance in the cases of acute lung injury or ARDS evolves from transient metabolic or mixed alkalosis at the early stage to mixed acidosis at the advanced stage. Human infection of avian infl uenza commonly causes systemic infl ammatory response syndrome (SIRS), which further progresses into MODS. In severe cases, multiple organ failure occurs at the terminal stage. Primary pathological changes of human infection of highly pathogenic avian infl uenza include severe pulmonary lesions, toxic changes of immune organs and other organs, and secondary infection. The causes of death include: (1) progressive respiratory failure caused by diffuse alveolar injury; (2) multiple organ functional impairment of the liver, kidney, and heart; and (3) compromised immunity and secondary infection. By naked eye observation, the lung is subject to swelling, increased weight, obvious consolidation that is more serious at the lower lung lobe, and dark reddish in color. Mild adhesion can be found between the lung and parietal pleura. On the section of lung, blood stasis and edema are obvious, with exudates of light reddish foamy bloody fl uid. The trachea and bronchus are subject to mucosal congestion. In their canals, there are light reddish foamy secretions. In the thoracic cavity, a small quantity of light yellowish fl uid can be observed. At the early stage, diffuse alveolar injury can be observed at both lungs, characterized by acute diffuse exudation. The alveolar cavity is fi lled with exudates of light reddish fl uid and infl ammatory cells in different quantities, mostly lymphocytes, monocytes, plasma cells, and phagocytes, but rarely neutrophils. In the alveolus, there are also shedding, degenerative, and necrotic alveolar epithelial cells. In some alveoli, hemorrhage, cellulose, and hyaline membrane can be observed. In addition, hyperplasia of type II alveolar epithelium can also be observed. Under an electron microscope, there are injury of alveolar epithelial cells, protein-like fragments in the alveolar cavity, as well as necrotic and apoptotic epithelial cells, lymphocytes, and histiocytes. The alveolar wall is severely damaged, and lysed erythrocytes can be observed in the alveolar cavity. Nuclear margination is observable in some residual alveolar epithelial cells. There are also expansion of rough endoplasmic reticulum, swelling of mitochondria, and vacuole. The lymphocytes are subject to decrease in quantity and scattering distribution. The lymph sinus is dilated, possibly with focal necrosis. The histiocytes are subject to proliferation, with phagocytosis of erythrocytes and lymphocytes. The spleen is subject to slight swelling and smooth and dark reddish surface. Under a microscope, the fi ndings include blood stasis, edema, expanded red pulp, and atrophic white pulp. Around the white pulp, atypical lymphocytes can be found. In addition, infi ltration of small quantities of infl ammatory cells can be observed in the splenic sinus, with histiocytosis and phagocytosis of blood cells. In the bone marrow, reactive histiocytosis and phagocytosis of blood cells can be observed. Human infection of avian infl uenza might have a longer incubation period than other human infl uenza, which generally lasts for 1-3 days, commonly 1-7 days but 21 days in some cases. The interval between the familial onset is generally 2-5 days, with a maximum of 8-21 days. The duration of incubation period is related to the virus pathogenicity, the quantity of invading viruses, route of infection, and the immunity of infected person. Human infection of avian infl uenza commonly occurs in winters and springs. It has an acute onset and rapid progress. Within 1 week after onset, the conditions may rapidly progress and deteriorate into acute lung injury, acute respiratory distress syndrome, pulmonary hemorrhage, pleural effusion, pancytopenia, multiple organ failure, shock, Reye syndrome, and secondary bacterial infection and septicemia. Death may occur due to these complications. Severe cases are commonly found in adults with a past history of good health, with higher fever persisting for a long period of time. Nearly all patients with pneumonia receive artifi cial ventilation, and it is often complicated by ARSD and MODS, with a high mortality rate. Almost all patients with avian infl uenza experience fever, mostly with a body temperature of mostly above 38 °C and rarely 41 °C. The fever types are diverse, but continued fever, remittent fever, and irregular fever are the most common. The patients with mild avian infl uenza experience fever for 1-7 days, mostly 3-4 days. With the conditions improved, the body temperature gradually returns to normal. However, the body temperature of patients with severe avian infl uenza might rise to above 39 °C within 2-3 days, sometimes even 41 °C. The high fever is persistent. Some patients might experience persistent high fever but gradually drop of the body temperature to normal, with improved toxic symptoms. The patients with avian infl uenza experience serious systemic toxic symptoms in the early stage after onset, such as headache, fatigue, general muscular soreness, and general upset. According to the clinical data of 59 cases of avian infl uenza in Hong Kong of China, Thailand, Vietnam, especially Ho Chi Minh City, and Cambodia, 28.1 % (9/32) of the cases develop headache and 28.9 % of these cases develop general muscle soreness, costalgia, and general upset. But according to clinical data in China, 45 % of the cases develop headache, 40 % muscular pain, 80 % fatigue, and 60 % aversion to cold. Symptoms of the respiratory system include respiratory catarrh symptoms, cough and expectoration, dyspnea, cyanosis, acute respiratory distress syndrome, pulmonary hemorrhage, pleuritis, and pleural effusion. The respiratory catarrh symptoms include rhinorrhea and nasal obstruction and pharyngalgia in some cases. Most patients with avian infl uenza develop cough and expectoration at day 3 after onset. Cough is paroxysmal and violent, with a small quantity of white or yellowish white mucous sputum. Sometimes, the sputum is bloody. Dyspnea commonly occurs at day 6 after onset, mostly mixed dyspnea characterized by diffi culty exhaling and inhaling as well as accelerated respiratory rate. The patients with avian infl uenza may develop cyanosis at the lips and skin mucosa. The extensive lung lesions cause decreased proportion of ventilation to blood fl ow, with consequent occurrence of hypoxemia. As a result, increased hemoglobin reduction in capillaries during the systemic circulation causes the occurrence of cyanosis. Acute respiratory distress syndrome (ARDS) is characterized by progressive dyspnea, with a respiratory rate of above 20 times per minute. The rate is progressively accelerated, which may reach up to 60 times per minute. The patients experience cyanosis, irritation, restlessness, and consciousness disturbance. Refractory hypoxemia may occur. Due to excessive ventilation induced by obvious hypoxemia, PaCO 2 is subject to decrease, contributing to respiratory alkalosis. The patients with severe avian infl uenza can develop pulmonary hemorrhage due to diffuse alveolar injury and diffuse intravascular blood coagulation. The clinical manifestations include cough-up typical bloody sputum. In severe cases of human infection by avian infl uenza, the patients develop pleuritis and pleural effusion at the middle or advanced stage, mostly 6-12 days after the onset. Most patients have rough breathing sound, with accompanying bronchial breathing sound. The breathing sound at the affected lung is weak, with rare moist or wheezing rales but no pleural friction. Some patients can develop digestive symptoms at the early stage, including poor appetite, nausea, vomiting, abdominal pain, abdominal distention, diarrhea, and watery stool. Some patients experience subjective palpitation, often accompanied by precordial upset and chest distress. In severe cases, the patients experience rapid heart rate and decreased blood pressure, which rapidly develop into shock. In rare cases, the patients might be hospitalized due to hypotension and shock. Some patients may experience neurological symptoms, such as headache, irritation, vomiting, convulsion, and lethargy. In rare severe cases, the patients experience initial symptom of serious diarrhea, with following occurrence of convulsion and coma. Death may occur in such patients. Multiple organ failure includes respiratory failure, heart failure, renal insuffi ciency or failure, liver dysfunction, and disseminated intravascular coagulation. The typical course of human infection with avian infl uenza can be divided into three stages: the early stage, the progressive stage, and the convalescent stage. The early stage refers to the initial 1-4 days after the onset. It is characterized by an acute onset with fever as the fi rst symptom and a body temperature of above 38 °C. Other symptoms might also occur, including respiratory symptoms like cough with sputum as well as headache, fatigue, general muscle soreness, costalgia, and general upset. The progressive stage usually begins at day 5 after the onset and lasts for about 16 days, which may be longer in rare cases. Compared to the patients with SARS, the progressive stage of human infection with avian infl uenza is longer. After the progressive stage, the conditions gradually develop into the convalescent stage, which is usually 22 days after the onset. The patients experience gradual alleviation and absence of toxic symptoms. The body temperature returns to normal and the lung lesions are gradually absorbed and improved. More than 50 % of the patients can be discharged after their convalescent stage lasting for about 2 weeks. Based on the severity of clinical symptoms, human infection of avian infl uenza can be divided into mild, common, severe, atypical, and asymptomatic. The patients experience mild respiratory symptoms like mild dry cough, no obvious cough, no tachypnea, and no dyspnea. The liver function shows no obvious abnormality. Radiological examination demonstrates no sign of pneumonia. And the prognosis is good. The patients experience typical symptoms of human infection with avian infl uenza, including fever with a body temperature above 38 °C, headache, general pain, fatigue, dry throat, and poor appetite. The patients may also experience respiratory symptoms including cough with bloody sputum, even shortness of breath and cyanosis. By auscultation, low breathing sound at both lungs can be heard with moist or wheezing rales. X-ray demonstrates shadows at the lungs. The peripheral leukocyte count is normal or slightly decreased and there is no hypoxemia by blood gas analysis. The patients experience no serious complications such as ARDS or multiple organ failure. Clinically, severe type is common. The conditions develop rapidly with dramatic deterioration and a high mortality rate. The conditions of severe type may rapidly progress into acute lung injury or ARDS, leading to respiratory failure. Multiple system dysfunction or failure commonly occurs to complicate the conditions. Secondary infection of multiple systems at multiple locations by multiple pathogens may also occur. Most patients of this type die from progressive respiratory failure or multiple organ failure. The patients with one of the following conditions can be defi ned as the severe type: 1. Dyspnea with breathing rate during rest being at least 30/ min, accompanied by one of the following conditions: First, X-ray demonstrates multilobar lesions or anterior-posterior X-ray demonstrates a total area of lesions accounting for over one-third of both lungs. Second, the total area of lesions increases by above 50 % within 48 h and by anterior-posterior X-ray accounts for over one-fourth of both lungs. 2. Obvious hypoxemia occurs with an oxygenation index below 300 mmHg (1 mmHg = 0.133 kPa). 3. Shock or multiple organ dysfunction syndrome develops. 4. Invasion of the virus to the central nervous system causes viral encephalitis. 5. Reye syndrome occurs in children. 6. Serious secondary bacterial infection occurs, especially septicemia or septic shock. Atypical type refers to rare patients with mild symptoms, no fever or only mild upset, and no sign of pneumonia. The patients experience no obvious respiratory symptoms, with favorable prognosis. Epidemiological studies have demonstrated that rare patients develop no onset of the disease despite of a history of close contact to patient with avian infl uenza or diseased poultry and positive H5N1 antibody. Clinically, the patients show no obvious symptoms and signs. It has been reported by WHO on January 11, 2006, that two children in Turkey were detected with positive avian infl uenza virus antibody but show no corresponding symptoms. During the outbreak of avian infl uenza in 1997 in Hong Kong of China, a nurse with close contacts to patients with avian infl uenza showed positive H5N1 virus antibody. H7N9 is a subtype of avian infl uenza virus. The patients with its infection commonly show fl u-like symptoms, such as fever and cough with a small quantity of sputum, and accompanying headache, muscle soreness, and general upset. In severe cases, the conditions progress rapidly, characterized by severe pneumonia, a body temperature persistently above 39 °C, dyspnea, and bloody sputum. The disease can rapidly progress into acute respiratory distress syndrome, mediastinal emphysema, sepsis, shock, consciousness disturbance, and acute renal injury. Pathogenic Avian Infl uenza-Related Complication In China, the patients with avian infl uenza often develop ARDS 8-11 days after the onset. The typical symptoms include progressive dyspnea and even respiratory distress. With the progress of conditions, the patients develop cyanosis, irritation, restlessness, extensive interstitial infi ltration in both lungs, and accompanying dilation of umbilical vein, pleural reaction, or a small quantity of effusion. The condition may further develop into multiple organ failure. At the early stage of human infection with avian infl uenza, the pulmonary interstitium may be involved. But in most patients, the interstitial lesions can be gradually absorbed. In extremely rare severe patients, after pulmonary infl ammation lesions are absorbed at the convalescent stage, pulmonary interstitial fi brosis or hyperplasia still remains. The severity of pulmonary fi brosis is related to the severity of pulmonary lesions, age, obviously compromised immunity, and existence of basic disease. In most cases, pulmonary fi brosis can be healed 6 months after discharge from hospital. In rare severe cases, pulmonary fi brosis may persist a longer period of time. The patients with avian infl uenza show different degrees of infl ammatory exudates at lung tissue. Respiratory bronchiolitis obliterans causes breakage of alveolar elastic fi ber, which further develops into pneumothorax or bronchopleural fi stula. In the cases complicated by secondary lung infection, purulent changes are found to aggravate lung injury. In some patients with prior basic lung disease, such as chronic obstructive lung disease and congenial lung diseases, pneumothorax is more likely to occur. The patients of severe type need treatment of noninvasive or invasive ventilation, which is more likely to induce pneumothorax. The occurrence of mediastinal emphysema and subcutaneous emphysema in patients with avian infl uenza commonly follows the use of respirator. During the progress of human infection with avian infl uenza, the conditions are more likely to be complicated by infections, especially bacterial pneumonia. Secondary bacterial pneumonia is the main cause of death in patients with avian infl uenza. The most common pathogenic bacteria include Streptococcus pneumoniae , Staphylococcus aureus , or Haemophilus infl uenzae . Infection of mixed bacteria may occur. The common pathogenic fungi include Candida albicans and Aspergillus . And its incidence rate is related to gender, age, existence of basic disease, nutrition, length of hospitalization, and the use of glucocorticoids. According to literature reports, 60-70 % of human infection with avian infl uenza is complicated by liver dysfunction, with slightly increase of ALT and AST. However, in China, almost 100 % of human infection with avian infl uenza shows liver dysfunction, with slight to moderate increase of transaminase. In some cases, the patients may show moderate jaundice. Liver dysfunction mostly occurs 2-3 weeks after the onset. However, liver function failure has not yet been reported in cases with human infection of avian infl uenza. Some patients with avian infl uenza might develop cardiomyopathy with different severity at different stages, which is clinically characterized by chest distress, precordial upset or dull pain, palpitation, and shortness of breath. About 20-40 % of the patients experience bradycardia, slight to moderate increase of myocardial enzymes CPK and LDH, and ECG abnormality. In some serious cases, the patients experience rapid heart rate and decreased blood pressure, which may develop into shock. Some severe cases with human infection of avian infl uenza might develop rapid heart rate, nodal tachycardia, and acute heart failure at day 10-18 after the onset. Death occurs in such patients due to heart failure or peripheral circulatory failure. A large amount of proteinuria (>3 g/L) occurs in some severe patients with avian human infl uenza in the early stage of onset. At the same time, they might also develop oliguria without hematuria, symptoms caused by urinary irritation, and abnormal number of serum creatinine as well as urea nitrogen. In other cases in the early stage of onset, decreased proportion of urine, polyuria, and erythrocytes as well as casts in the urine can also be found. In some patients with avian infl uenza, the conditions may be complicated by myositis, characterized by remarkable tenderness of the involved muscle and swelling muscle with no elasticity. The most commonly involved muscle is at the lower limbs. Some severe cases might also develop myoglobinuria due to rhabdomyolysis, leading to renal failure. Reye syndrome is one of the common complications in children with avian infl uenza, with a high mortality rate. It is clinically characterized by nausea and vomiting, followed by symptoms of involved central nervous system, such as lethargy, coma, or delirium. There are usually no localized neurological signs, with jaundice due to hepatomegaly. Gene detection has simple operational procedures but with high sensitivity, specifi city, and accuracy. The detection result can be rapidly harvested. And it represents the orientation of virus detection for avian infl uenza virus. Quantitative RT-PCR is the best way to detect avian infl uenza virus at the early stage of infection, with results obtained within 4-6 h. Pharyngeal swab can carry more viruses than nasal swab, with a higher positive rate. But negative fi nding by just once detection cannot exclude the possibility of virus infection of avian infl uenza H5N1 virus. Repeated detections are recommended to defi ne the diagnosis. Isolation of avian infl uenza virus from respiratory specimens such as nasopharyngeal secretion and tracheal aspiration is the classical way to defi ne the diagnosis of human infection by avian infl uenza. Double sera should be collected at the early or convalescent stage. Hemagglutination inhibition test, complement fi xation test, or enzyme-linked immunosorbent assay (ELISA) can be performed to detect the antibody of avian infl uenza virus. An at least four times increase of the antibody titer is an indicator for retrospective diagnosis. X-ray, CT scanning, and MR imaging are important ways for the diagnosis of human infection by avian infl uenza and its complication, differential diagnosis, therapeutic assessment, and prognosis analysis. According to the criteria for clinical diagnosis of human infection by avian infl uenza, radiological fi nding of infi ltration shadow at the lungs is important for early diagnosis of human infection by avian infl uenza. Consecutive X-rays can demonstrate the dynamic changes of lesions, which is the important way to assess the progress of the conditions, the therapeutic effect, and the prognosis. The radiological demonstrations should be analyzed based on the stages and clinical types. At the early stage, commonly at day 1-4 after the onset, the imaging demonstrations are characterized by focal fl akes or patches of shadow due to focal consolidation at the lungs. About 90 % of patients with avian infl uenza within 7 days after the onset demonstrate by CT scanning singular or multiple small fl akes of shadow with low-density and poorly defi ned boundary. Most of the shadow is singular with irregular shape. In some cases, pulmonary markings are subject to increase and thickness with predominately peripheral distribution. In the large fl ake of consolidation shadow, air bronchus sign is demonstrated. A small quantity of effusion can be demonstrated in the pleural cavity. Most patients experience aggravation of the conditions 14 days after the onset. Initially, the small fl akes of shadows may turn into large fl ake of multiple or diffuse lesions, which develop from unilateral occurrence to bilateral occurrence, from singular lung fi eld to multiple lung fi elds. In severe cases, obvious changes can be demonstrated within 1-2 days after the onset. The severe cases develop diffuse infi ltrative lesions at unilateral lung or bilateral lungs in large fl akes of ground-glass opacity and pulmonary consolidation shadow, with inner air bronchus sign. With the progress of conditions, diffuse consolidation shadows are demonstrated at the lungs, possibly with white lung sign at both lungs. The lesions of pneumonia in the cases of human infected avian infl uenza are gradually absorbed within 15-30 days, and the lesions of most patients can be completely absorbed. However, in rare cases, the lesions are partially absorbed with development of fi brosis or proliferation of pulmonary interstitial tissues. Obvious proliferation of pulmonary interstitial tissues may occur 30-40 days after the onset, fi rstly occurring as thickening of interlobular septum and intralobular interstitium as well as subpleural arc shape linear shadow. The fl akes of shadow at the lungs shrink with increased density, with following occurrence of high-density cord-like or honeycomb-like shadow. In some serious cases, pulmonary interstitial proliferation causes shrinkage of lung volume and shift of mediastinum towards the affected lung. Pulmonary interstitial proliferation may extensively exist at the lungs, characterized by thickening of interlobular septum, intralobular septum, and interstitium as well as subpleural arch shape linear shadow. Pulmonary interstitial fi brosis is characterized by honeycomb-like shadow and referred bronchiectasis. After the conditions remain stable, the lesions begin to be absorbed, with decreased range and decreased density. In some cases, despite no abnormal fi ndings by X-ray, CT scanning still demonstrates light ground-glass opacity, which may remain for a long period of time. Therefore, regular CT scanning is recommended to demonstrate lesions that fail to be demonstrated by X-ray. Chest X-ray demonstrations of human infected avian infl uenza are characterized by their rapid change, which is also an important difference from common pneumonia and other atypical pneumonia. At the early and progressive stages, the lung lesions are subject to rapid changes during a short period of time (the shortest period being 12 h), with expansion, perfusion, and migration of the lesions. The shape, range, and location of the lesions may also be subject to changes. The absorption of lesions generally occurs 14 days after the onset, but in rare mild type of cases, it may occur at day 7 after the onset, with decreased range and density of lesions. For those with favorable therapeutic effect, the large fl akes of shadow at the lungs can be signifi cantly changed within 1 day. ARDS is the main cause of death in patients with avian infl uenza. In severe cases, diffuse alveolar consolidation and ground-glass opacity can be demonstrated at the lungs. Preliminary observations demonstrate that in the cases of death extensive pulmonary consolidation and white lung sign are commonly demonstrated during the progressive stage. A boy aged 6 years complained of fever and cough for 15 days, which aggravated with accompanying chest distress, shortness of breath, headache, and muscle soreness for 1 week. He lived in a region with deaths of diseased chicken and ducks and he had a history of intake of diseased chicken and duck. Real-time PCR of pharyngeal swab and RT-PCR demonstrated positive nucleic acids of avian infl uenza virus H5N1. His mother died from respiratory failure on the day when the boy experienced the onset 7 days after her complaint of high fever and cough. The cases complicated by pneumonia are radiologically demonstrated with fl akes of shadow at the lungs. In severe cases, the conditions progress rapidly, with ground-glass opacity, pulmonary consolidation shadow, and accompanying small quantity of pleural effusion (Figs. 18.6 , 18.7 , 18.8 , and 18.9 ). In the cases with ARDS, the lesions are extensively distributed. A female patient aged 67 years developed fever with a body temperature fl uctuating between 38.7 and 39.0 °C for about 1 week after she returned home from Zhejiang, China. She had no remarkable cough with sputum. By routine blood test, WBC 3.68 × 10 9 /L and N 58.1 %. By routine urine microscopy, erythrocytes 15-20/HP. At a local hospital, she was suspected to have viral upper respiratory infection and was then treated with anti-viral oral medication. After positive therapy, her temperature still fl uctuated around 39 °C, and she went to the emergency department of our hospital on March 27, 2013. By auscultation, breathing sound at both lungs is rough with a few moist rales. Chest CT scanning indicated consolidation shadow at the right upper lung lobe, which was suspected to be infl ammatory disease. By routine blood test, WBC 5.35 × 10 9 /L and N 68.2 %, and by routine urine microscopy erythrocytes 16-20/HP as well as normal BUN and creatinine. The patient was immediately administered anti-infection and symptomatic supportive treatment. After these therapies, her body temperature failed to return to normal and reached to the highest temperature of 39.5 °C on March 29. She then developed chest distress and cough with rare foamy sputum that is diffi cult to be expectorated. Meanwhile, hypoxemia occurred. Thus, the administered antibiotic was upgraded to Tienam to fi ght against the suspected infection. BiPAP and methylprednisolone were also administered to facilitate ventilation, anti-infl ammation, and bronchial dilation. After the active therapy, the high body temperature slightly decreased but hypoxemia gradually aggravated. By auscultation, breathing sound at both lungs is rough, with moist rales at the right upper A male patient aged 56 years complained of fever for 7 days as well as cough with sputum and chest distress for 3 days. lung. X-ray indicated extensive infl ammation at both lungs and lobar pneumonia at the right upper lung. She was immediately offered SIMV + PSV via tracheal intubation and treated with additional medicine including norvancomycin and acyclovir to fi ght against the infection and virus. Her oxygen saturation fl uctuated between 75 and 80 %, indicating severe conditions. And she was transferred to ICU due to suspected diagnosis of severe pneumonia and respiratory failure. By physical examination, T 37.3 °C, P 66/min, R 20/min, and BP 171/84 mmHg. She was unconscious and had cyanosis at lips and weakened breathing movement at the right side. Percussion demonstrated dullness at the right upper lung while clear sound at the other lung fi elds. The breathing sound was rough at both lungs with moist rales, particularly at the right upper lung. On April 1 after her hospitalization, operational procedures were performed to exclude the possibility of human infected avian infl uenza but demonstrated positive avian infl uenza (H7N9) by local CDC. After consultation of experts, the therapies were modifi ed. On April 2013, she underwent tracheotomy but still treated with mechanical ventilation by a respirator. On April 13, 2013, SpO 2 decreased to 65 % with fl uctuating blood pressure and a minimum of 79/43 mmHg. Her highest body temperature was 40.3. Treated by modifi ed therapies, the heart rate and blood pressure once returned to normal, but fi nally clinical death was declared after emergency rescuing. On April 1, 2013, laboratory tests were performed. By routine blood test, WBC 7.70 × 10 9 /L, GR 90.4 %, LY 5.8 %, HGB 131 g/L, and PLT 162 × 10 9 /L. By blood gas analysis, pH 7.41, PO 2 6.88 kPa, PCO 2 6.22 kPa, and SaO 2 80.5 %. By blood biochemistry, urea 9.5 mmol/L, Cr 57 μmol/L, UA 216 μmol/L, K 3.86 mmol/L, Na 128 mmol/L, Cl 95 mmol/L, Ca 1.98 mmol/L, P 1.51 mmol/L, and CO 2 32.3 mmol/L. On April 13, 2013, by routine blood test, WBC 9.65 × 10 9 /L, GR 93.4 %, LY 2.5 %, HGB 79 g/L, and PLT 79 × 10 9 /L. By blood gas analysis, pH 7.14, PO 2 10.45 kPa, PCO 2 10.00 kPa, and SaO 2 85.3 %. By blood biochemistry, K 6.20 mmol/L, Na 146 mmol/L, Cl 90 mmol/L, Ca 1.88 mmol/L, P 3.88 mmol/L, and CO 2 28.4 mmol/L. By detection of infl ammatory indicators, PCT 0.14 ng/mL and CRP 43 mg/L. Apparent pulmonary interstitial hyperplasia fi rstly causes interlobular septal hyperplasia, intralobular interstitial hyperplasia, and subpleural arch shape linear shadow. The fl akes of shadows at the lungs shrink with increased density, with gradual development of strips and honeycomblike high-density shadow at the lungs. Severe pulmonary interstitial hyperplasia causes reduced lung volume and shift of mediastinum towards the affected lung. Pulmonary interstitial hyperplasia may be extensively found at the lungs, characterized by thickened interlobular septum, thickened intralobular interstitium, and subpleural arch shape line. Otherwise, it can be demonstrated as local irregular high-density patches of and cord-like shadows. Intrapulmonary honeycomb-like shadow and referred bronchiectasis are indicators of pulmonary interstitial fi brosis. Bacterial Infection X-ray or CT scanning demonstrates fl akes of and mass-like shadows at the lungs. Fungal Infection X-ray and CT scanning demonstrate diversifi ed lesions. They may be scattering small nodular shadows at the lungs or patches of shadows at the middle and lower lung fi elds. Otherwise, the lesions are demonstrated as mass-like or cavity-like shadows or fused lesions into large fl akes of shadows in a large range. Pneumothorax is manifested as shedding of visceral pleura away from the chest wall. By X-ray, it is demonstrated as hairlike linear shadow parallel to the chest wall and no lung markings exterior to the linear shadow. CT scanning demonstrates transparent areas without lung markings at the peripheral thoracic cavity as well as compression and insuffi cient expansion of the lung. Demonstrations of mediastinal emphysema by X-ray include vertical gas strip between the heart shadow and the paratracheal soft tissue shadow and linear shadow parallel to the mediastinum form by elevated mediastinal pleura supported by a thin layer of gas. Lateral X-ray demonstrates that the thymus and vascular shadows in the anterior mediastinum are surrounded by gas. Flow of gas at the tangent line in involved subcutaneous soft tissue is demonstrated as cystic or strips of gas containing shadow, with the skin being abnormally elevated and thickened. In the cases with gas gathering at the surface of the pectoralis major, characteristic strips of transparent shadows resembling to fan-shaped distributed muscular fi bers are demonstrated at the upper lung fi elds. CT scanning demonstrates gas density linear shadow around the mediastinum and shift of mediastinal pleura towards the lung fi eld. Gas in the mediastinum fl ows along the cervical fascia space to the neck and thoracic subcutaneous tissue, thus producing subcutaneous gas density shadow. The diagnosis can be defi ned based on the contact history, clinical manifestations, and laboratory fi ndings. The contact history plays a critical role in the diagnosis of human infected avian infl uenza. Large quantities of viruses are excreted along with saliva, nasal secretions, and feces from the infected poultry. Direct contact to infected poultry or contact to the utensils contaminated by their feces or secretions is believed to be the main route for spreading avian infl uenza virus. The following epidemiological data facilitates the diagnosis of human infected avian infl uenza: 1. One week prior to the onset, the patients visited the epidemic focus. 2. One week prior to the onset, the patients had close contact to secretions or excretions from infected poultry. 3. One weeks prior to the onset, the patients lived nearby an area with the cases of avian infl uenza or traveled at an epidemic region. 4. The patients have a history of close contact to patients with avian infl uenza. 5. Some patients may have no defi ned epidemiological history of avian infl uenza. For those with no direct epidemiological data, the patients should be carefully inquired about contact history to water contaminated by avian infl uenza. 6. Human infection of avian infl uenza spreads from chicken, duck, goose, and other poultries, especially chickens. Therefore, outbreak of avian infl uenza, especially in chickens, is prior to the outbreak of its human infection. This is an important clue and basis for the diagnosis of human infected avian infl uenza. The incubation period of human infected avian infl uenza generally lasts for 1-7 days, commonly 2-4 days but may be as long as 8 days. The interval of its occurrence in family members is about 2-5 days, maximally 8-17 days but may be as long as 21 days. Different subtypes of avian infl uenza virus can cause variant clinical symptoms after they infect human. Avian infl uenza H5N1 has an acute onset with its early symptoms resembling to common infl uenza. It is characterized by fever persisting for 1-14 days with a body temperature over 39 °C and maximally 41 °C and accompanying rhinorrhea, nasal obstruction, cough, sore throat, headache, muscle soreness, and general upset. In some cases, the patients may develop digestive symptoms including nausea, abdominal pain, diarrhea, and watery stool. Persistent high fever may occur in severe patients, with rapid progress of the conditions into apparent pneumonia, acute lung injury, and acute respiratory distress syndrome. The total WBC count is normal or lower than normal, especially with decreased absolute lymphocyte count. The platelet count is normal or is subject to slight to moderate decrease. The decreases of leukocytes, platelets, and lymphocytes, particularly the decrease of lymphocytes, are related to the severity of clinical symptoms and the mortality rate. Respiratory specimens from patients are collected to detect the antigens of nucleocapsid protein (NP) or matrix protein (M1) or subtype H by immunofl uorescence assay or enzymelinked immunosorbent assay (ELISA). Avian infl uenza virus can be isolated from the respiratory specimen from patients. The serum-specifi c antibody of positive avian infl uenza virus like H5N1 or at least four times increase of antibody titer of avian infl uenza virus subtype strains in paired serum from the early and convalescent stages facilitates diagnosis. The severe type is demonstrated with: 1. Diffuse distribution of lung lesions, commonly with large fl ake of or multiple patches of fused shadows at most of unilateral lung or multiple lobes and segment of bilateral lungs. The diffuse lesions can be demonstrated at the early stage, which persist for a long period of time. 2. Rapid progress of the lesions, with signifi cant development of the lesions with a short period of time. The focal lesions at the early stage rapidly expand to large fl ake of diffuse shadow. The density of shadow changes also rapidly, with rapid mutual transformation between groundglass opacity and consolidation. 3. The conditions rapidly develop into acute respiratory distress syndrome, with demonstrations of extensive highdensity shadow at both lungs. The patients commonly experience an acute onset with symptoms of aversion to cold, high fever, headache, dizziness, general soreness, fatigue, and other toxic symptoms. The patients may also experience respiratory symptoms such as sore throat, dry cough, rhinorrhea, and lachrymation. In rare cases, the patients experience poor appetite, abdominal pain, abdominal distension, vomiting, diarrhea, and other digestive symptoms. By peripheral blood test, the total WBC count is normal or lower. Infl uenza virus can be successfully isolated from the nasopharyngeal secretion of patients. An at least four times increase of antibody titer against infl uenza virus can be detected in serum collected at convalescent and acute stages. Direct detection of the infl uenza virus antigen in the epithelial cells at the respiratory tract is positive, and the antigen of infl uenza virus after one generation reproduction by sensitive cells is positive. Infl uenza virus pneumonia commonly occurs in infants and young children, the elderly and the weak, and patients with chronic disease or compromised immunity. Its incubation period is short, commonly lasting for 1-3 days. Typical infl uenza is commonly characterized by acute onset with sudden symptoms of systemic toxic symptoms, such as aversion to cold, chills, high fever, general soreness, severe headache, fl ushed face, congested conjunctiva, and weakness. But the nasal and pharyngeal symptoms are mild or unremarkable. The respiratory symptoms include gradually exacerbated cough with blood-tinged or bloody sputum, shortness of breath, and cyanosis. The fever commonly persists for a short period of time. Severe infl uenza virus pneumonia is demonstrated with obvious pulmonary lesions, commonly with diffuse bubbling and wheezing. By laboratory test, decreased leukocytes, leftward shift of neutrophil nuclei, and relatively increased lymphocytes can be found. Radiological examinations of the chest demonstrate scattering cotton-wool-like lesions at both lungs or lesions of interstitial pneumonia. Etiological test can provide direct evidence to defi nite the diagnosis of infl uenza, but with no value for the early diagnosis. Throat lavage fl uid for virus isolation is inoculated into chick embryo allantois. Agglutination test is then performed with the throat lavage and chick erythrocytes. However, agglutination inhibition test for chick erythrocytes should be simultaneously performed to exclude nonspecifi c agglutination. Such a test has a positive rate of 26-50 %. The serum antibody detection, commonly by agglutination inhibition test of erythrocytes or complement fi xation test, can be performed simultaneously, with a positive rate of 95 %. Contrast detection should be performed at the early stage and 2 weeks after the onset, and an at least four times increase of the antibody titer has diagnostic value. 18.9.2.1 Epidemiological History 1. The patient has a history of close contact to patients with SARS, or he/she is a member of the possibly infected population, or defi nite evidence has found supporting his/ her transmission to others. 2. One weeks prior to the onset, the patients visited or lived at the region with cases of SARS. The disease has an acute onset, with fever as its initial symptom and a body temperature of above 38 °C as well as occasional aversion to cold. The patients may also experience headache, joint pain, muscle soreness, fatigue, and diarrhea. Although upper respiratory catarrh symptoms are commonly absent, cough and chest distress may develop, particularly dry cough with a little sputum and occasional blood-tinged sputum. In severe cases, the patients experience rapid respiration, shortness of breath, or apparent respiratory distress. The lung lesions are not remarkable, possibly with rare moist rales or pulmonary consolidation. The peripheral WBC count is normal or decreases and the lymphocyte count commonly drops. The lungs are demonstrated with fl akes and patches of infi ltrative shadows or grid-like shadow. Some patients show rapid progress of the lesions, with large fl akes of shadows commonly at both lungs. And the shadow is absorbed slowly. The pulmonary shadow demonstrated by chest X-ray might be inconsistent to the clinical symptoms and signs. Autopsy and pathological analysis of human death cases from highly pathogenic avian infl uenza A (H5N1) Infl uenza A (H5N1): will it be the next pandemic infl uenza? Are we ready Avian infl uenza A (H5N1) infection in humans The evolution of H5N1 infl uenza viruses in ducks in southern China Induction of proinfl ammatory cytokines in human macrophages by infl uenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Fatal outcome of human infl uenza A (H5N1) is associated with high viral load and hypercytokinemia Two clusters of human infection with infl uenza A/H5N1 virus in the Republic of Azerbaijan H5N1 infl uenza: a protean pandemic threat Current studies on human infection of avian infl uenza Chest X-ray demonstrations of viral pneumonia caused by avian infl uenza A (H5N1) in children Review and implication of prevention again human infection of avian infl uenza in Hong Kong Strategies for the diagnosis and treatment of human infection of avian infl uenza The fi rst clinical report on human infection of avian infl uenza A (H5N1) in Shenzhen, China Chest X-ray imaging of patients with SARS Chest X-ray demonstrations of SARS Radiological demonstrations of viral pneumonia caused by human infection of highly pathogenic avian infl uenza A (H5N1) The fi rst case report of pneumonia due to human infection of avian infl uenza A (H5N1) in mainland China Avian infl uenza A (H5N1) infection in eastern Turkey in 2006 Re-emergence of fatal human infl uenza A subtype H5N1 disease Evaluation of a genetically modifi ed reassortant H5N1 infl uenza A virus vaccine candidate generated by plasmid-based reverse genetics H5N1 virus attachment to lower respiratory tract Antibacterial medication is commonly ineffective to treat SARS. Pulmonary candidiasis is characterized by white foamy thick sputum or cheese-like sputum with fermented stinky odor. Detection of sulfur granules in the sputum facilitates the diagnosis of pulmonary actinomycosis. The accompanying wheezing at the lungs and increased eosinophils in the blood are helpful for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). Pulmonary aspergilloma has characteristic signs by chest X-ray. Allergic bronchopulmonary aspergillosis (ABPA) is demonstrated with migratory infi ltrative lesions at lobes or segments. Otherwise, ABPA can be demonstrated with segmental or lobar atelectasis due to obstructed bronchus by mucus but no shift of interlobar fi ssure. Invasive pulmonary aspergillosis at the early stage may be characterized by localized or multiple infi ltrative lesions or nodular lesions at both lungs. The lesions commonly rapidly expand to integrate into consolidation or cavity. The diagnosis of pulmonary candidiasis can be defi ned based on positive fi ndings of Candida albicans by sputum culture for three consecutive times, fi nding of fungal threads by smear, or proved pathogenicity by animal inoculation. The fi ndings of fl exuous hyphae by smear of bronchofi broscopic extracts or growth of Aspergillus by culture can defi ne the diagnosis of pulmonary aspergillosis. When sulfur granules are observed in sputum or tissues of fi stula wall, the diagnosis of pulmonary actinomycosis can be defi ned. Otherwise, the fi nding of pathogenic microorganism after anaerobic culture and the diagnosis of pulmonary actinomycosis can also be defi ned. 1. The patients have no defi nitive history of close physical contacts or inhaling of respiratory droplets. HIV/AIDS or in patients with HIV/AIDS. 3. The patients experience no typical symptoms, such as acute fever, headache, muscle soreness, joint pain, fatigue, and other infl uenza-like symptoms. 4. Chest X-ray demonstrates slow change of lung shadows.The lung lesions commonly undergo a series of pathological changes including exudation, infi ltration, integration, consolidation, and interstitial fi brosis. At the early stage, symmetric miliary alveolar effusion shadows are demonstrated at both lungs. The lesions further develop into ground-glass opacity. At the middle stage, fl akes of or consolidation shadows are demonstrated, which are actually infi ltration and integration. After timely and appropriate intervention, the pulmonary shadow can be gradually absorbed, possibly with residual cord-like shadows of pulmonary interstitial fi brosis. Otherwise, the patients may die from respiratory failure or multiple organ failure. 5. Antibody against HIV is positive. Human infected avian infl uenza (H7N9) should be differentiated from highly pathogenic avian infl uenza (H5N1), seasonal infl uenza (including infl uenza A H1N1), bacterial pneumonia, SARS, novel coronavirus pneumonia, adenovirus pneumonia, chlamydia pneumonia, and mycoplasma pneumonia. And the differential diagnosis is mainly based on etiological test.