key: cord-0042880-p9opvoro authors: Lu, Pu-Xuan; Jing, Yuan; Xiao-Hua, Le; Zhou, Bo-Ping; Yu-Xin, Shi; Zhi-Yong, Zhang; Yu-Shen, Zhou; Ying-Ying, Deng; Xian-Gui, Ran; Yang, Ge; Jian, He; Jia-Fu, Lin; Qing-Si, Zeng; Jing-Jing, Li; De-Min, Yan; Xiang-Rong, Huang title: Human Avian Influenza A H5N1, H7N9, H10N8 and H5N6 Virus Infection date: 2015-07-25 journal: Diagnostic Imaging of Emerging Infectious Diseases DOI: 10.1007/978-94-017-7363-8_3 sha: b26e51df745e3d60fb8da985e87a06b0ac2399de doc_id: 42880 cord_uid: p9opvoro Avian influenza is an infectious disease induced by avian influenza viruses in poultry, commonly called genuine fowl plague or European fowl plague. In 1878, a severe disease was fi rstly reported in Italy among chickens, called fowl plague. In 1901, it was confi rmed to be caused by viruses, which were identifi ed as infl uenza A virus in 1955. In 1981, such disease was formally named avian infl uenza on the fi rst international avian infl uenza conference. On May 5, 1997, H5N1 human avian infl uenza was fi rstly found in Hong Kong of China in a 3-year-old child, who died from Reye syndrome and multiple organ failure 10 days after onset of the disease. On May 9, 1997, the US CDC and Rotterdam state infl uenza center of WHO laboratory isolated the H5N1 AIV strain from the bronchial secretions of this 3-year-old boy, which was named "A/HongKong/157/97." This body is the fi rst case of human infected with highly pathogenic avian infl uenza H5N1 virus. In December, there were in total 18 cases of human avian infl uenza confi rmed in Hong Kong, China with 6 cases deceased. By December 31, 2014 , 667 cases of highly pathogenic human avian infl uenza H5N1 were documented around the globe, including 393 deaths with the mortality at 58.92 %. Yuan Jing H5N1 is a segmented negative single-stranded RNA virus belonging to Infl uenzavirus A genus, Orthomyxoviridae family of Mononegavirales order. The typical shape of avian infl uenza virus under electric microscope is spherical in a diameter of 80-120 nm and has a capsid in helical symmetry as well as envelope. The initially isolated strains may appear like fi lament in a diameter of about 20 nm and length of 300-3000 nm. The hemagglutinin protuberance is a homotrimer composed of 3 non-covalently bound protein molecules, and the neural aminase presents with homotetramer made up by head and stem like a mushroom. The structures of the virus are subsequently envelope, matrix protein, and viral core from inside to outside. The surface glycoprotein club-shaped hemagglutinin (HA) and neural aminase (NA) are embedded into the lipid bilayer of the viral envelope together with ion channel protein. Matrix protein binds to the inner surface of viral envelope and associates with the helical ribonucleoprotein of the viral core to form a layer of membrane-like structure to protect the viral core. RNP comprises nucleocapsid protein (NP), three polymerases (PB1, PB2, PA), and eight viral RNA segments. Similar to human infl uenza virus, avian infl uenza virus is sensitive to diethyl ether, chloroform, and acetone and other organic solvents as well as heat and ultraviolet rays. It could be deactivated after exposure to sunlight for 40-48 h and frequently used disinfectants such as sodium hypochlorite, phenolic compounds, quarternary ammonium disinfectants, aquae formalin, and other aldehydes, and iodine compounds could rapidly destroy the infectivity of the viruses. Under general conditions, infl uenza viruses could survive for 30 days under 0 °C, under 22 °C for 4 days, and under 56 °C for 3 h. Besides, it could be deactivated after half an hour under 60 °C and killed after merely 1 min under over 100 °C. However, under natural conditions, viruses in feces possess tremendous resistance due to protection from organics. HA on the envelope of infl uenza virus, as an attachment protein, could combine with the sialic acid residues of host cell receptors at the top of the globular head, which is key to the viral infection. However, infl uenza virus could only recognize specifi c sialic acid molecules on host cell membranes. Neu5Acα2-6Gal binding on the membrane of human respiratory tract mucous cells is key to infection of humans by avian infl uenza virus. Hyaluronic acid (HA) of the virus combines with host cell receptors and by pinocytosis mediated by such receptors and then enters coated pits which further internalizes HA into coated vesicle. Then the coated vesicle with viruses generates endosome which combines with lysosome to form endosomic lysosome. The acidic pH value inside endosome lysosome changes HA structure and decreases the aggregation force of trimer to expose segment N of HA and fuse with plasma membrane. Besides, the low pH value activates M2 ion channel and facilitates H+ to enter virion, thus decreasing pH value inside the virus. Therefore, the direct interaction between M1 and NP is damaged to free RNP, thus resulting in uncoating of the virus. Thereafter, the genome of the virus is released into the cell plasma and again transported to the nucleus. Both the transcription and repli-cation of the infl uenza virus RNA segments take place in the host cell nuclei, and RNP must enter the cell nuclei. Yuan Jing It has been proved that the avian infl uenza subtypes able to infect humans are H5N1, H7N9, H10N8, H5N6, H9N2, H7N7, H7N2, and H7N3, of which H5N1 presents with relatively strong infectiveness and causes severe conditions and high mortality. Besides, in 2013, patients infected with H7N9 avian infl uenza also manifested relatively severe conditions and high mortality. Avian infl uenza viruses have been confi rmed widely distributed in many poultry (including the turkeys, chicken, guinea fowl, pigeons, geese, and ducks) and wild fowl (including wild ducks, swans, and various kinds of sea birds) with diseases induced by avian infl uenza viruses in domesticated chicken and turkey most severe. Besides, there exists silent infection in domesticated poultry which could prolong several months. The poultry infected by avian infl uenza or carrying avian infl uenza virus such as chicken, ducks, geese, and pigeons, particularly chicken, serve to be the important source of infection. The secretions and excretions, feathers, tissue organs, and fowl eggs may also carry viruses. The infl uenza A virus could also be seen in humans, horses, pigs, monkeys, domestic cats, rats, tigers, and American leopards, and occasionally in ferret-polecat, seal, whales, and other mammals. In 1970, Kundin found H3N2 subtype antibodies in pigs and isolated similar virus. Whether human could spread infection needs to be further consolidated, and whether patients with human avian infl uenza are source of infection has not been determined. Besides, human avian infl uenza H5N1 and H7N9 are also reported in individual interpersonal infection case. Avian infl uenza viruses is mainly disseminated through the feces and excretions of infected poultry, contaminated drinks, drinking water, egg holders, chicken embryos, gassoluble gels, poultry eggs, transportation tools, and other channels. This virus could spread the infection through human respiratory tract, digestive tract, gas-soluble gel, as well as skin damages and eye conjunctiva, particularly respiratory tract and digestive tract. Direct contact with infected poultry or indirect contact with viral pollutants is also regarded as the main route of infection; viral secretions, feces, and any subjects contaminated by poultry corpses could also transmit the epidemic; direct contact with the viral strains could also spread this disease. Considering human avian infl uenza cases already detected, patients of any case could be infected irrespective of gender. There could be epidemic in all the four seasons, but mainly in the alternate season between winter and spring as well as between autumn and winter, so frequently upon sudden attack of cold current and drastic change of temperature. Generally, human avian infl uenza is seldom reported in summer but could also occur sporadically such as the fi rst case of avian infl uenza H5N1 in Shenzhen of China in June. The newly emerging human avian infl uenza H7N9 in 2013 in China also mainly occurred in February to March. Human avian infl uenza develops mainly in the vast village areas in various countries in the world. In China, the highly pathogenic human avian infl uenza epidemic is mostly documented in rural areas and surrounding areas of provincial capitals. Meanwhile intimate contact with dead poultry and their secretions and excretions provide main conduit for dissemination of human avian infl uenza. Among patients with human avian infl uenza, children and the young people occupy a relatively high proportion, and the ratio between the male and female is at 7: 14, with the latter remarkably higher than the before. Besides, farmers and rural students or children take a large proportion. However, for avian infl uenza H7N9, the middle old-aged account for a relatively high proportion. Infl uenza virus belongs to infl uenza virus genus of orthomyxovirus family and is an enveloped, negative singlebranded and segmented RNA virus. Infl uenza virus falls into type A, type B, and type C in light of the antigen of nucleoprotein (NP). Infl uenza virus type A could be further divided into subtypes according to the antigen difference of hemagglutinin (HA) and neuraminidase (NA) embedded in the lipid bilayer outer membrane. Avian infl uenza virus (AIV) of different types or subtypes demonstrates varying pathogenicity due to the difference in viral genome structure and sequence expressing protein polypeptide. Some mutant viruses could even surmount genus and order barriers to infect humans, such as H5N1, H7N7, H9N2, and H7N9, among which H5N1 or H7N9 infection could induce severe conditions and high mortality. HA on the outer membrane of infl uenza virus type A plays critical roles in the pathogenesis of AIV. HA, as the main component of envelope spike, is key to viral attachment and transmembrane process and could stimulate generation of neutralizing antibody and cellular immunity to ward off viral infection and disease. In the course of infection, HA, could be hydrolyzed into peptide chain HA1 and HA2, with the former able to combine with host cell receptors and the latter as a critical subunit to mediate fusion of the virus and host cell membranes. Therefore, the infl uenza virus could integrate with host cell receptors mediated by HA1 and fuse with cell membrane mediated by HA2 to promote release of ribonucleoprotein (RNP). Another important component of highly pathogenic AIV infecting human body cells may be NS1 protein, which could inhibit interferon (IFN) and tumor necrosis factor-alpha (TNFα). Fas signal pathway may mediate cell apoptosis related to infl uenza virus infections. The infl ammatory reaction factors may mediate the systematic infl ammatory reaction syndrome in severe patients, acute respiratory distress syndrome, and multiple organ failure, while corticosteroids may delay or decrease such reactions, suggesting that immune injury may participate in pathogenesis of human avian infl uenza. Highly pathogenic human avian infl uenza is induced by human avian infl uenza virus H5N1 and H7N9 characteristic of acute respiratory system lesions and with high mortality. In light of domestic and foreign literature reports, its main pathological changes could be summarized as severe lung disease, toxic changes, and secondary infections of immune organs and other viscera. Main causes of death include (1) progressive respiratory failure incurred by pulmonary diffusive alveolar injury; (2) complication with multi-organ damages such as liver, kidneys, and heart; and (3) immunosuppression and secondary infections. Lung tissues are revealed swollen and heavier, with the left lung up to 770-2250 g and right lung 785-800 g (both lungs 1550-1950 g). Both lungs present with dark red color and distinct consolidation, particularly at the lower lobes of the lungs. There may be slight adhesions between the lungs and parietal pleura. Lung sections demonstrate notable congestion and edema as well as exudation of light red bubbly blood-stained fl uids. Trachea and bronchi are viewed with congestion at mucosa and light red bubbly secretions inside the lumen. The pleural cavity is observed with slight light yellow effusions. Early phase: It manifests diffuse alveolar injury at both lungs, typical of acute disseminated exudative disease. The alveolar spaces are full of pinkish exudates and infl ammatory cells of varying amount, including mainly lymphocytes, monocytes, plasma cells, and macrophages as well as a few neutrophilic granulocytes. The alveolar spaces could also be seen with exfoliated, degenerated, and necrotic alveolar epithelial cells. Part of the alveolar spaces are found with bleeding and fi brin as well as hyaloid membrane. Alveolar type II epithelial proliferation is also observable. No inclusion bodies are observed in megakaryocytes and nucleus or plasma. Part of the alveolar septum become lightly thicker with vascular dilatation, congestion, and infl ammatory cell (type similar to that inside alveolar space) infi ltration but without intravascular fi brinous thrombi. Middle phase (disease course over 10 days): it presents changes of proliferation phase. Diffuse alveolar damages and alveolar epithelial reactive proliferation are seen but cellular changes related to virus absent. Alveolar space is seen with fi brinous exudation, bleeding, formation, and mechanization of hyaloid membrane. Interstitium is detected with vascular congestion, reactive fi broblast proliferation, and light lymphocyte infi ltration. Part lung tissues are found with fungal infections. Advanced phase (disease course over 3 weeks): it presents changes of fi brosis. Part alveolar epithelium is revealed with necrosis and exfoliation as well as reactive proliferation (Figs. 3.1 and 3.2 ) but without viral inclusion body in epithelial cells. Alveolar spaces are observed with effusion of plasma fl uid, fi brin, red cells, and neutrophilic granulocytes, formation of hyaloid membrane, organization of squamous epithelia, and mechanization of exudates ( Fig. 3.3 ). Part alveoli are detected with collapse or compensatory emphysema. Pulmonary interstitium is seen with fi brosis and occasional presence of lymphocytes, plasma cells, and reactive hemophagocytes. Pulmonary interstitial capillaries are viewed with transparent emboli and DIC as well as occasionally obliteration ( Fig. 3.4 ) . Pulmonary bleeding and secondary infection could also be seen. Lymphocytes decrease and scatters and lymph sinus is found dilated and with focal necrosis. Histiocytes proliferate accompanied by phenomenon of phagocytosis of the hemophagocytes and lymphocytes. The spleen presents with mild enlargement, smooth surface, and dark red color. Microscopy suggests extravasated blood, edema, atrophy of white marrow, and enlargement of red marrow. Peripheral to the white marrow is atypical lymphocytes. Part spleen sinuses are seen with slight infl ammatory cell infi ltration and histiocytosis accompanied by hemophagocytosis. Bone marrow tissues are revealed with reactive histiocytosis and hemophagocytosis. The brain is unveiled with extravasated blood at the surface blood vessels and slight widening of gyrus. Microscopy visualizes wider spaces between the cerebrum, cerebellum, and spinal nerve cells and small blood vessels, as well as extravagated blood in blood vessels. Cardiac chambers are found with dark-brown blood clots. Microscopy indicates degeneration of cardiocyte vacuole and cardiocytes with swelling and loss of striated patterns as well as partial pyknosis. Interstitium manifests light edema and extravagated blood in blood vessels. The surface of the liver is smooth, grayish red, and with homogeneous section. The liver lobule presents normal structure, with slight hydropic degeneration and fat degeneration ( Fig. 3 Interstitium is unveiled with light extravagated blood and part portal area with light lymphocyte infi ltration. The kidney becomes swollen and the renal capsule is easily to be separated. The cortex and medulla are well demarcated with slight blood stasis at the latter. Under the microscope, multiple glomerular capillaries are seen with dilatation and blood stasis, and the renal tubules with necrosis. The blood vessels of renal interstitium are revealed with extravagated blood and thrombosis. Yuan Jing Patients with human avian infl uenza are characterized by decrease of the peripheral blood WBC count, particularly decrease of lymphocytes, which meanwhile is closely related with the occurrence of ARDS and mortality rate. Creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase are mostly found elevated and so are C-reactive protein and myoglobin. Infl uenza viruses infect mainly the epithelial cells of respiratory tract. Positive experiment suggests that this patient or cultured subject has infl uenza virus and could directly conclude infection of the corresponding type or subtype of infl uenza virus. This experiment is superior in specifi city and sensitivity, which are 5-10 times higher than direct immunofl uorescence assay. The sample extract from the test kit is mixed with any clinical specimen to separate virus antigens, which are then dropped on the test membrane already adsorbed with alkaline phosphatase-labeled anti-infl uenza virus A nucleoprotein monoclonal antibody and substrate liquid. The thorough reaction between the antigen and antibody could develop color under the catalysis of enzymes. This method is applicable to quantitative measurement of infl uenza virus A and B in nasal suction liquid, nasal scrubbing liquid, and laryngopharyngeal scrubbing liquid specimens. Competitive block method is adopted to test H5 antibodies in the serum specimen. The coating monoclonal antibodies on the microwell plate of the agent kit are added with serum specimen and antigen reaction liquid, which forms "coating monoclonal antibody-antigen specimen antibody" complex. Then enzyme-marked antibodies are added. If the serum specimen could distinctly inhibit the combination of enzymemarked antibodies with antigens, it suggests the presence of avian infl uenza H5 antibodies. 1. Cutoff value: The Cutoff value = average negative control OD × 0.5 2. Positive judgment: Sample OD value 38°C, and over half of the patients are accompanied with infl uenza-like symptoms such as chilliness, headache, soreness of joints and muscles, fatigue, dry and nonproductive cough, as well as chest pain. Chest X-ray or CT inspections may be manifested as (1) lobular septum thickening and acinar nodular shadows; (2) solitary or multiple patchy ground-glass shadows in the lungs and lesions mostly located at unilateral inferior lung lobe; and (3) patchy pulmonary consolidation shadows with air bronchogram in between or ground-glass shadows at the periphery or other long lobes (Figs. 3.3 , 3.4 , 3.5 , and 3.6 ). The lesions aggravate within 14 days after the onset in most patients. The patchy shadows of the early phase progress into large patchy, multiple, or diffusive lesions in 3-7 days. The lesions may extend from unilateral to bilateral lungs and from single lung lobe to multiple lobes. In progression phase, severe patients manifest multilobar lesions or lesions advancing by over 50 % within 48 h (Fig. 3.7 ) . 4. Pleural effusion is relatively common, particularly in patients with severe pneumonia. The absorption of pleural effusion and lung foci are synchronous generally. After effective treatment in progression phase, the conditions of patients with human avian infl uenza pneumonia are under control and foci begin to be absorbed. The majority foci of patients with human avian infl uenza virus pneumonia free of secondary infections are completely absorbed within 30 days, while the lungs of part of the patients may present with fi brosis or proliferation of lung interstitium. For a few severe patients, the foci absorption is relatively slow, and absorption of lung shadows still takes a relatively long time, even years, resulting in interstitial fi brosis. Imaging presentations in the phase of recovery: (1) The large patchy pulmonary consolidation shadows are gradually absorbed and become smaller and light in color, and the consolidation pulmonary tissues gradually swell. Imaging presentations are characterized by plaque-shaped and striped consolidation shadows. The characteristic dynamic changes of human avian infl uenza virus pneumonia are as follows: ① The foci present with rapid dynamic changes, and the foci in severe pneumonia cases could disseminate to multiple lobes and segments within 48 h. ② Lesions in the early phase and progression phase mainly manifest as consolidation shadows and groundglass shadows. ③ Absorption of the foci is slow. Some patients may present with lung interstitial fi brosis in the lungs several years after discharge (Figs. 3.3 , 3.4 , 3.5 , 3.6 , 3.7 , 3.8 , 3.9 , 3.10 , 3.11 , 3.12 , and 3.13 ). ④ During the course of absorption in recovery phase, the foci in the middle and upper lung lobe are absorbed at an earlier time than those in the dorsal inferior lung lobes and subpleura; and foci fi rstly formed in the early and progression phase are absorbed at a later time. On the contrary, foci that appear at a later time are absorbed more early. ⑤ Chest imaging changes and clinical symptoms and signs are inconsistent, that is a delay of imaging signs of absorption of pulmonary lesions from clinics (Figs. 3.3 , 3.4 , 3.5 , 3.6 , 3.7 , 3.8 , 3.9 , 3.10 , 3.11 , 3.12 , 3.13 , and 3.14 ). The imaging manifestations of human avian infl uenza pneumonia comprise disseminated lung consolidation shadows and ground-glass shadows, and intrapulmonary foci occur at an early time and last a long time. Pulmonary lesions present with rapid progression and could extend rapidly into large patchy and disseminated lesions in a short period. The density change of the lesions, or the mutual transformation between ground-glass change and consolidation density, is also very fast. Besides, imaging signs of acute respiratory distress syndrome may also appear in a short time. Due to the lack of specifi c diagnostic method of human avian infl uenza pneumonia, clinical diagnosis entails comprehensive analysis of several examination methods, including epidemiologic history, laboratory examination, chest imaging, and observation of the effects of antibiotics therapy. The differential diagnosis of human avian infl uenza pneumonia depends on imaging manifestations combined with the patients' history and clinical and laboratory examinations. Clinically the disease must be differentiated from viral pneumonia such as H1N1 and SARS, mainly from the epidemiological history; laboratory examinations, clinical and imaging characteristics; as well as immune impairment. Their common imaging presentations are ground-glass shadows and pulmonary consolidation shadows, with lesions of rapid change and progression. However, human avian infl uenza pneumonia demonstrates the fastest progression of the foci and early lesions mainly at the both inferior lung lobes, but such characteristics are not obvious in the case of H1N1 and SARS. Complication of human avian infl uenza pneumonia is an important factor affecting the prognosis, which should be highlighted. In the course of treatment of human avian infl uenza, antivirus drugs, glucocorticoid steroids, and broad-spectrum antibiotics are administered, and positive airway pressure or tracheal cannula may be applied in some patients. Reasonable use of such procedures is of great signifi cance for raising the successful therapeutic rate of patients with human avian infl uenza pneumonia and lowering mortality rate. However, due to the decrease of the resistance of patients, the drugs and therapies themselves may induce side reactions t and incur corresponding complications. The primary complications of human avian infl uenza pneumonia encompass secondary lung Fig. 3.11 ( an ) The 31-year-old male patient was confi rmed with avian infl uenza H7N9 pneumonia. ( a ) On the third day after onset of the disease, chest X-ray shows patchy shadows of increased density at mesial margin of the right inferior lung fi eld. ( b ) On the 5th day of the disease onset, chest X-ray visualized large patchy shadows of increased density in the middle and inferior lung fi elds of both lungs. ( ce ) On the 5th day after the onset of the disease, chest CT demonstrated groundglass shadows and consolidation shadows scattering at both lungs. Besides, among the consolidation shadows of the right lower lung, air bronchogram was visualized. ( fh ) On the 8th day after the onset of the disease, chest CT revealed extensive ground-glass shadows and consolidation shadows, with the foci increased in number and progressing obviously. ( ik ) On the 11th day after the onset of the disease, after effective treatment, chest CT re-examination disclosed a slight amount of ground-glass density shadows and cord-like and small patchy shadows, indicating entry into recovery phase. ( ln ) On the 15th day after the onset of the disease, chest CT re-examination demonstrated cordshaped and small patchy shadows, lobular septum thickening, subpleural curvature shadows, bronchiolar dilation, and pleural limited thickening and adhesion at both lungs ( df ) On the 34th day after the onset of the disease, both lungs were found with extensive consolidation shadows and ground-glass shadows; the left lung presented mainly consolidation shadows and air bronchogram. There were shrinkage of left inferior lobe and aggregation of lung texture. ( gi ) On the 96th day after the onset, both lungs were visualized with patchy inhomogeneous consolidation shadows and cord-like shadows, with patchy ground-glass shadows seen peripheral to consolidation shadows at both lungs. ( jl ) On the 286th day after the onset of the disease, CT revealed that foci of both lungs were predominated by pulmonary interstitial changes such as fi brous cord-like and latticed shadows, with con-current ground-glass shadows. Absorption of the foci slowed down distinctly. ( mo ) 2 years after onset of the disease, CT unveiled fi brous strip and latticed shadows in both lungs, and patchy ground-glass shadows at the left superior lung and bilateral inferior lungs. Compared with the chest CT presentations 1 year before, the foci were slightly absorbed. Human avian infl uenza virus may attack the human immunity system directly and compromise immunity. Large doses of glucocorticoids are administered during treatment which could undermine the immunity. Some patients may still need such treatment as positive airway pressure or bronchial intubation and central venous indwelling catheter, which create conditions for secondary infection. Meanwhile, abundant use of broad-spectrum antibiotics could disturb the normal bacterial fl ora. The most frequent and severe is a complication with Acinetobacter baumannii infection. Acinetobacter baumannii is highly capable of acquiring drug tolerance and clone dissemination, and Acinetobacter baumannii with multiple drug tolerance and broad drug tolerance is one of the most important pathogen of human avian infl uenza. Acinetobacter baumannii may induce nosocomial pneumonia, bloodstream infection, abdominal infection, central nervous system infection, urinary system infection, cutaneous soft tissue infection, and myelitis. The diagnosis may be concluded based on following evidences: (1) besides clinical symptoms, signs and imaging presentations consistent with pneumonia, new or sustained or aggravated lung exudates, infi ltration, and consolidation are detected (Fig. 3.15 ). (2) Host factors including underlying disease, immune status, application of antibacterial medicines in early period, and duration of mechanical ventilation (3). Sputum culture for over two times shows growth of pure Acinetobacter baumannii or dominant growth of Acinetobacter baumannii ; or blood culture demonstrates with growth of Acinetobacter baumannii . All patients with avian infl uenza suffer from different degrees of lung fi brosis and lung impairment, and the majority of patients need assisted respiration such as artifi cial assisted ventilation of the ventilator and tracheotomy intubation, which could heighten intrapulmonary pressure by different degrees. However, as patients with human avian infl uenza manifest varying degrees of infl ammatory exudation from lung tissues, the occlusive fi brosis inside bronchioli may lead to rupture of alveolar elastic fi bers, which may on one hand damage lung air exchange and on the other hand lower lung compliance. Under the condition of increased intrapulmonary pressure, pneumothorax and mediastinal and subcutaneous emphysema are more likely to occur. Imaging presentations: CT suggests air-density linear shadows encircling the mediastinum and shift of the mediastinal pleura toward lung fi eld. Air in the mediastinum escapes along the cervical fascial space to the neck and chest subcutaneous area, thus rendering subcutaneous gas-density imaging signs (Figs. 3.3 , 3.4 , 3.5 , 3.6 , 3.7 , 3.8 , 3.9 , 3.10 , 3.11 , 3.12 , 3.13 , 3.14 , 3.15 , and 3.16 ). a b Fig. 3.15 ( a , b ) The male patient aged 48 years old was diagnosed with avian infl uenza H7N9 severe pneumonia accompanied by Acinetobacter baumannii infection. ( a ) On the 15th day after the onset of the disease, both lungs were revealed with ground-glass-density shadows and the original right inferior lung consolidation shadows were basically absorbed. Avian infl uenza virus H7N9 became negative. ( b ) On the 24th day after onset of the disease, the patient suffered from fever, and culture of deep sputum for two times showed Acinetobacter baumannii . CT visualized consolidation shadows at the right lung and small patchy consolidation shadow at the subpleural area of the left superior lung In the early phase of onset, human avian infl uenza presents with bronchiolar and peripheral parenchymal or interstitial lesions, which may progress into alveolar parenchymal and interstitial lesions, mostly reversible. In the phase of recovery, some cases may advance into pulmonary interstitial proliferation and then into fi brosis. The degree and outcome of lung interstitial proliferation and fi brosis are related to the scope of lung involvement in the climax phase, presence of complications, as well as treatment. The initial signs of lung interstitial proliferation are thickening of lobular septum and intralobular interstitium as well as subpleural curvature shadows. The intrapulmonary patchy become smaller and denser, and high-density cord and honeycomb-like shadows are gradually observable in the lungs. Severe lung interstitial proliferation could make the lungs shrink and mediastinum shift toward the affected side. Lung interstitial proliferation may exist extensively in the lungs, predominated by thickening of interlobular septum and interlobular interstitium as well as subpleural curvature imaging changes. It may also manifest local irregular highdensity plaque and cord-shaped shadows. Intrapulmonary honeycomb-like imaging presentation and traction bronchiectasis are primary signs of lung interstitial fi brosis. CT reveals cord-like, reticular, and honeycomb-shaped shadows. HRCT could better display the meticulous abnormal changes of pulmonary interstitium, such as thickening of lobular septum, intralobular interstitial thickening, subpleural curvation shadow, honeycomb-like shadow, paraseptal emphysema, as well as bronchiolar dilatation (Figs. 3.17 and 3.18 ). TAt present its pathogenesis still remains unclear and it might be associated with the infl ammatory reaction and damage from use of hormones and human avian infl uenza combined with bacterial infection (such as Acinetobacter baumannii infection) or multiple mixed factors on sclerotin and blood vessels. Femoral head aseptic necrosis is typical of degenerative changes due to femoral head blood circulation disturbance, with limping and pain as main symptoms. The affected lower limb is slightly shorter and manifests mild fl exion and adduction. The abduction and intorsion slightly limited. In the early phase of femur head aseptic necrosis, CT demonstrates that the stellate sign formed by femoral trabeculae become deformed or disappeared, visualized as spot or patchy shadows with increased density in the femoral head and tuft-a b Fig. 3.16 ( a , b ) The 34-year-old male patient was diagnosed with avian infl uenza H7N9 severe pneumonia complicated with mediastinal pneumatosis. Coronal imaging visualized remarkable pneumatosis at the neck, mediastinum, and the periphery of the heart and large blood vessels shaped change or mutual fusion at the periphery of stellate sign. In the advanced phase, the femur head becomes fragmented and deformed, and the absorption of sclerotin between fragmented bones presents irregular low-density area, with the stellate sign absent. Based on MRI presentations, aseptic necrosis of the femur head may be divided into the following four phases: Phase I shows homogenous or inhomogeneous low-signal areas adjacent to joints above the femur head on weighted T1 and T2 imaging; phase II manifests wedge-shaped mixed low-signal band; phase III is typical of sequestrum crescent sign and cortical collapse; phase IV manifests phase III signs accompanied by joint degeneration and joint space stenosis. Besides, apart from the most common ischemic necrosis of the femoral head, osteomyelitis is also documented, mostly at the femur, which presents irregular low-signal area on T2 weighed imaging (Fig. 3.19 ). 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