key: cord-016369-tnvlafa2
authors: Lu, Puxuan; Zhou, Boping; Yuan, Jing; Yang, Guilin
title: Human Infected H5N1 Avian Influenza
date: 2016-06-23
journal: Radiology of Influenza
DOI: 10.1007/978-94-024-0908-6_10
sha: 
doc_id: 16369
cord_uid: tnvlafa2

Avian influenza is an infectious disease caused by avian influenza virus, which is also known as avian plague or European avian plague.

reported, and the patients aged 1-60 years, with the same H5N1 virus strain isolated from their respiratory secretions. In December, 1997, AIV H5N1 was isolated in samples collected from a market selling alive poultry. By killing sick poultry in a large-scale, human infection was then rapidly controlled. In the year of 1997, a total of 18 cases human infected H5N1 avian infl uenza were reported, with 5 cases of death.

Since the fi rst occurrence of human infected H5N1 avian infl uenza in HongKong in 1997, a total of 667 cases have been defi nitively diagnosed globally, with 393 cases of death by Dec. 31, 2014 . And the death rate was 58.92 %. WHO warned that human infected H5N1 avian infl uenza may be one of the most potentially life-threatening diseases and should be highly concerned across the world.

The infected poultry by AIV H5N1 or the poultry carrying AIV H5N1, such as chicken, duck, goose, and dove, particularly chicken, are important sources of its infection. Wild aquatic birds (mostly with in apparent infection) play an important role in natural spread of the disease. Birds, such as swallow, chukar, bar-headed goose, crow, sparrow, and heron, may also act as the source of its infection. And migration of migrant birds also contributes to the transmission of AIV. Evidence is still needed to prove whether human is also a source of its infection. and excretions. Otherwise, human can also be infected after exposure to the contaminated environment by AIV. After such direct contact or exposure, the virus particles are inhaled into and attached to human upper respiratory tract for further invasion.

Transmission via direct or indirect contact refers to human infection of H5N1 avian infl uenza after close contact to feces of poultry/animal infected by AIV H5N1. Via direct or indirect contact, the virus can be inoculated into human upper respiratory tract, conjunctival mucosa or skin wound by itself.

The data from the cases with human infected H5N1 avian infl uenza indicated that human infected H5N1 avian infl uenza affects any age group and children under the age of 12 years shows a higher incidence with no gender difference. In addition, the patients from such an age group commonly experience serious conditions.

In addition, human infected H5N1 avian infl uenza can also spread via other routes of transmission, including gastrointestinal tract, skin wound, conjunctiva, aerosol, and blood. It may also spread vertically or in laboratory, traffi c vehicle, and hospital.

In the early stage of human infected H5N1 avian infl uenza, the patients commonly experience common infl uenza like symptoms, including fever with a body temperature persistently above 39 °C with accompanying runny nose, nasal obstruction, cough, sore throat, headache, muscular soreness and general malaise. And some patients may experience gastrointestinal symptoms including nausea, abdominal pain, and diarrhea of watery loose stools. In serious cases, the patients show persistent high fever that rapidly progresses into obvious pneumonia, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary hemorrhage, pleural effusion, multiple organ failure, disseminated intravascular coagulation (DIC), shock, and Reye syndrome. Secondary bacterial infection may also occur to complicate the disease that progresses into septicemia, with a mortality of up to above 50 %.

Due to virus infi ltration, the lung of patients with human infected H5N1 avian infl uenza is demonstrated with fl akes of opacity that is predominantly exudates by chest X-ray or chest CT scan, namely the ground glass opacity and lung consolidation. In serious cases, the lesions in lungs progress rapidly, radiologically demonstrated as large ground glass opacity and lung consolidation. In the advanced stage, both lungs are shown with diffuse consolidation.

Human infected H5N1 avian infl uenza is radiologically characterized by:

1. Early increased density opacity and ground glass opacity in upper lung fi eld In the early stage after onset, the upper lung fi eld is demonstrated with fl akes of increased density opacity and ground glass opacity, which are the radiological signs of human infected avian infl uenza.

The invasion of H5N1 avian infl uenza virus to human lung tissues causes an extensive range of lesions, with diffuse and exudative lesions in multiple lobes and multiple segments of both lungs. At the peak of their progression, most of lung fi elds in both lungs are involved, with large fl akes of cloudy dense mass like opacity or even white-lung sign.

Radiologically, the lesions are demonstrated with rapid changes. A lesion that is initially found in one lung fi eld may rapidly develop to involve the upper, middle and lower lung fi elds within 24-48 h, radiologically demonstrated as involvement of the whole lung lobe. 4. Concurrently involved pulmonary parenchyma and interstitium Due to necrosis and shedding of pulmonary alveoli, the pulmonary alveoli contain less gas but are fi lled with exudates such as various serous fl uids, fi brin, erythrocytes, and neutrophilic granulocytes. In addition, hyaline membrane obviously forms in the alveolar space. Therefore, the lesions of human infected H5N1 avian infl uenza are radiologically demonstrated as alveolar exudates and lung consolidation, with the involved exudative lesions overlapping with pulmonary interstitium. After the exudative lesions are absorbed, grid like, fl akes, strips and patches of opacity is shown, which resemble to the radiological signs of viral pneumonia.

The lesions are slowly absorbed. After the invasive assisting mechanical ventilation is retrieved with subsequent normal body temperature, breathing rate and WBC count, the both lungs are still radiologically demonstrated with strips, fl akes, grid like, and patches of consolidation opacity, indicating inconsistency between chest radiology and clinical symptoms due to long-term progression of the lesions. That is to say, the absorption of lesions in lung lags behind clinical manifestations. In adult patients, the pleura is involved in different degrees, with a small quantity of pleural effusion isolateral to the primary lesion as well as bilateral pleural thickening and adhesion. During the absorption stage, multiple lesions of lobular paraseptal emphysema are revealed, with no obvious signs of hilar and mediastinal lymphadenectasis.

Case 1

[ Brief Medical History ] A 31-year-old male truck driver experienced fever, cough and shortness of breath since Jun. 3, 2006. After he paid a clinic visit in a local hospital, a diagnosis was made to be common cold and he received corresponding therapy. At 0:30 a.m. on Jun. 10, 2006, he was hospitalized due to aggravated condition. By physical examination, the body temperature was 39.2-40 °C, heart rate 127/min, breathing rate 32/min and blood pressure 116/80 mmHg. He showed a typical development, moderate nutrition, active position and slight unconsciousness. In addition, he showed eye conjunctival congestion and edema, identically sized and round pupils and obvious cyanosis in oral lips. By percussion, the left lung fl atness; by auscultation, coarse breathing sound of both lungs that attenuated at the right lung. At d 15 prior to the onset, his wife ever went to buy an alive chicken at a market and brought it back home after having it killed on site. His wife and daughter showed no signs of pneumonia. By routine blood test, WBC 4.20 × 10 9 /L, N 0.75, L 0.24, HGB 127 g/L, RBC 4.84 × 10 12 /L, PLT 132 × 10 9 /L. By blood glass analysis, pH 7.426, PaO 2 63 mmHg, PaCO 2 34 mmHg, SO 2 % 92 %. By blood biochemistry, GLU 7.87 mmol/L, BUN 2.8 mmol/L, Cr 88 μmol/L, ALT 30U/L, and AST 66U/L. T cell count in peripheral blood was 5/μl. Etiologically, RT-PCR by QIAGEN One Step RT-PCR kit was performed to examine his tracheal secretions. The examination report indicated that the target segments of H5 and N1 were amplifi ed. Throat swab for RNA of H5N1 (PCR) twice were positive. All the above fi ndings indicated the existence of H5N1 avian infl uenza virus.

[ Radiological demonstration ] See Fig. 10 .1

[ Diagnosis ] Human infected H5N1 avian infl uenza complicated by pneumonia.

[ Discussion ] Following the fi rst case of human infected H5N1 avian infl uenza reported in HongKong in 1997, 6 cases of death were subsequently reported. By Dec. 31, 2014, a total of 40 cases was reported in China, with 27 cases of death, and the mortality was up to 67 %. The high death rate indicated strong virulence of avian infl uenza virus H5N1 and the rapid progression of the disease. Chest radiological examinations are of great importance for our understandings about its radiological demonstrations, which facilitate its diagnosis, differential diagnosis and treatment.

Via systematic examination as well as dynamic observation and analysis, the radiological demonstrations and all the dynamic changes of the lesions were harvest from the patient. The radiological demonstrations are characterized by:

1. On d 7 after onset, the fi rst chest X-ray demonstrated large fl akes of increased density opacity in the left upper and middle lung fi elds. On d 8 after onset, the fi rst chest CT scan demonstrated large consolidation opacity with high density in the apico-posterior and anterior segments of the left lung and in the left lower lung lobe, with air bronchogram inside. The anterior segment of the right upper lung was shown with ground glass opacity. All the fi ndings indicated that ground glass opacity and large consolidation opacity are early signs of human infected avian infl uenza by chest radiology.

virus H5N1 is extensive, demonstrated as diffuse and exudates lesions in both lungs with multiple segments and lobes involved. At the peak of its progression, most of the lung fi elds in both lungs is involved, demonstrated as large cloudy dense mass like opacity and even white-lung sign. 3. Radiologically, the lesions change rapidly. The initial lesions in the left upper and middle lung fi elds can extend into the left lower lung fi eld within 24 h to involve the whole lung. In the following 48 h, the lesions may rapidly extend into the right upper, middle and lower lung fi elds to involve the whole lungs. 4. The lesions are absorbed slowly. In this case, on d 35 after onset, the invasive assisting mechanical ventilation was retrieved, and the patient subsequently showed normal body temperature, breathing rate and WBC count. On d 33 after onset, chest CT scan still showed strips, fl akes, grid like and patches of consolidation opacity with obvious air bronchogram inside. The follow-up CT scan was then performed each year, and the 5th chest CT scan showed interstitial fi brosis in both lungs, demonstrated as lobular septal thickening, sub-pleural arc shape linear opacity, paraseptal emphysema, ground glass opacity, bronchoectasis and small consolidation opacity. 5. The pleura is involved in different degrees. Pleural effusion in a small quantity was demonstrated isolateral to the primary lesions, and bilateral pleura were shown to be thickened with adhesion. The occurrence complications following human infected avian infl uenza is the direct cause of death and should be highly concerned in clinical practice. The common complications and their prognoses are described as the following:

In the most serious stage of the disease, extensive consolidation opacity in both lungs, namely the whitelung sign, indicates the occurrence of ARDS. In this cases, the patient showed the sign of ARDS on d 9 after onset. After invasive mechanical positive pressure ventilation and anti-anoxia therapy were administered, his condition was improved. And multiple organs dysfunction syndrome (MODS) was controlled.

Common pulmonary secondary infections include pseudomonas aeruginosa infection, mycotic infection and other bacterial infections. Since d 10 after onset, the patient was detected for several times with growth of pseudomonas aeruginosa in his phlegm specimens. Particularly on d 20 after onset, his WBC count obviously increased and chest X-ray demonstrated patches uneven opacity in the left lower lung. After polymyxin B and other medications were administered, his pulmonary secondary infection was controlled.

Although his condition was stable with normal vital signs, on discharge his both lungs were shown with irregular grid like, fi brous strips and patches of opacity and accompanying local pleural thickening by thin layer CT scan. These fi ndings indicated existence of pulmonary fi brosis, whose underlying mechanism may be hyperplasia of fi brous tissues and capillaries caused by fi brosis and organization of exudates as well as formation of microthrombosis in pulmonary capillaries based on formation of alveolar hyaline membrane and fi brin exudation. However, the hypothesis needs to be proved by suffi cient evidence and the dynamic changes of pulmonary fi brosis still need to be further studied.

In this case, the patient showed left pleural effusion in a small quantity on d 8 after onset by the fi rst chest CT scan. On d 33 after onset, the second chest CT scan demonstrated absorption of pleural effusion as well as local pleural thickening and adhesion. These fi ndings indicated pleura is involved in patients with human infected avian infl uenza, which has been further proved by autopsy. H5N1 avian infl uenza should be differentiated from the following diseases.

The lung changes of both human infected avian infl uenza and SARS are mainly parenchymal and interstitial lesions, with similar shape, development and outcome. Therefore, their differential diagnosis is challenging, and SARS is an acute respiratory infectious disease caused by novel corona virus. At its early stage, radiology demonstrates pulmonary interstitial changes, predominantly ground glass opacity. During its progressive stage, the lesions are demonstrated as predominantly ground glass opacity and rarely large consolidation opacity. The lung lesions of human infected H5N1 avian infl uenza show rapid changes. In some serious patients, the lesions in lungs may change within several days or even 1 day, with rapid progression from small area to large area, from upper or lower lung to the whole lung, from one lung to both lungs, and from ground glass opacity to consolidation opacity. However, in patients with SARS, the lesions in lungs progress slowly, and some lesions are migratory.

The lesions of human infected H5N1 avian infl uenza are in one lung or both lungs, possibly in upper and lower lung. In serious cases, the lesions are diffuse in both lungs, with more serious condition at the lower lungs. However, in the early stage of SARS, the nodular lesions are commonly located in the subpleural lateral lung fi eld.

Based only on radiological fi ndings, pneumonia induced by H5N1, H1N1 and H7N9 avian infl uenza viruses can hardly be differentiated. And their differential diagnosis is mainly based on epidemiological history and etiological examination.

Pneumonia induced by H1N1, H5N1 and H7N9 avian infl uenza virus is caused by infl uenza A virus, with clinical infl uenza like manifestations. Chest CT scan demonstrates the diseases with ground glass opacity and consolidation opacity of varying sizes. Compared to pneumonia induced by H1N1 avian infl uenza virus, the lesions of pneumonia induced by H5N1 and H7N9 avian infl uenza virus are radiologically demonstrated with a larger range, with more rapid progression and more common air bronchogram. The lesions of pneumonia induced by H5N1 avian infl uenza virus show the more rapid progression, followed by H7N9 and then H1N1.

By chest CT scan, pneumonia induced by H5N1 avian infl uenza virus is demonstrated with large ground glass opacity and consolidation opacity in both lungs that distribute extensively and progress rapidly. In some cases, the lesions are migratory, with slow absorption and obvious pulmonary interstitial fi brosis. Its mortality rate is around 60 %. Pneumonia induced by H7N9 avian infl uenza virus is radiologically demonstrated with initial lesions in bilateral middle and lower lungs that are predominantly ground glass opacity and consolidation opacity. These lesions show rapid progression and relatively slow absorption. And its mortality rate is about 36 %. Pneumonia induced by H1N1 avian infl uenza virus is radiologically demonstrated as multiple fl akes of ground glass opacity as well as patches and large fl akes of high density consolidation, possibly with lobar or segmental atelectasis and pleural effusion. And its mortality rate is about 6 %.

[ Brief Medical History ] A 26-year-old woman, being pregnant for more than 2 months, reported a history of fever since Feb. 11, 2006, with a body temperature of above 38.5 °C and the highest body temperature of up to 40 °C. She also experienced cough with a little phlegm as well as diarrhea early after onset. In a local hospital, routine blood test showed WBC count 6.1 × 10 9 /L, GR% 74.9 % and LY% 15.6 %. Chest X-ray indicated pneumonia at the right lower lung. By physical examination, breathing sound at the right lower lung was low and no other obvious positive signs. On d 7 after onset, Feb. 18, 2006, she was transferred to another hospital due to persistent fever, aggravated cough with more phlegm, chest distress and diffi culty breathing. By inquiries of her epidemiological history, she reported a defi nitive history of contact to sick/dead chicken in her home 7 days prior to the onset, Feb. 4, 2006. By routine blood test, WBC count 3.30 × 10 9 /L, N 0.83, L 0.15 and PLT 56 × 10 9 /L. Blood biochemistry showed AST 90U/L, CK 74U/L, and LDH 537U/L. By blood gas analysis, pH 7.426, PaO 2 25.1 mmHg, PaCO 2 51 mmHg, HCO 3 19.4 mmol/, and SO 2 % 92 %. Respiratory secretions examination on d 9 after onset (specimens collected 1 day ago), Feb. 20, 2006, the virus nucleic acid positive for H5N1 avian infl uenza virus. By reexamination by national parallel laboratory, the fi nding was still positive, with H5N1 avian infl uenza virus isolation positive.

The patient experienced dyspnea and rapid progression on d 7 after onset, and the condition further progressed into ARDS on d 8 after onset. Because the simplex oxygen supplying therapy failed to maintain oxygenation, noninvasive mechanical ventilation was ordered on d 9 after onset to maintain continuous positive airway pressure (CPAP) with settings of 10 cm H 2 O, FiO 2 45%, and an elevated SaO 2 to 90-93 %. But the noninvasive mechanical ventilation was discontinued due to shortness of breath and frequent cough of the patient. Subsequently, invasive nasotracheal intubation for ventilation was performed on that day. Tracheotomy was then performed for invasive ventilation 3 days after nasotracheal intubation.

On d 10 after onset, her body temperature returned to normal, but on d 14 after onset, the body temperature rose again to 37.5 °C, with increased peripheral hemogram and yellowish purulent bronchial secretions. A diagnosis of secondary bacterial infection was made and the administered antibiotics were adjusted accordingly. On d 16 after onset, miscarriage occurred. And on d 18 after onset, the invasive ventilation was discontinued, which was given for 10 days. On d 21 after onset, tracheal extubation was performed. And on d 20 after onset, her hemogram returned to normal indicating controlled secondary infection and convalescent stage of the disease. On Mar. 23, 2006 (d 40 after onset) , the patient was discharged according to the criteria in Clinical Guidelines for Human Infected Avian Infl uenza (revised version, 2005) formulated by Ministry of Health, P. R. China.

[ Radiological demonstration ] Fig. 10 .2 .

[ Diagnosis ] Human infected H5N1 avian infl uenza.

[ Discussion ] The patient is characterized by young woman, contact to sick/dead chicken 7 days before onset, initial symptom of fever, and normal WBC count. Her condition rapidly developed into pneumonia within 1 week after onset, and further rapidly into respiratory failure and multiple organs dysfunction.

Chest X-ray showed early exudation opacity in the right lower lung (d 4 after onset), and exudation opacity in bilateral middle and lower lung fi elds (d 6 after onset). On d 11 after onset, chest X-ray showed the most serious conditions, with large consolidation opacity in the right lung and the left middle lung. On d 12 after onset, oxygenation was improved, but slow absorption of the lesions was revealed by both chest X-ray and chest CT scan. On discharge, chest CT scan still demonstrated extensive spots, fl akes and cords like opacity in both lungs.

The case is special in the following aspects:

1. Rapid progression of the condition. On d 6 after onset, chest X-ray demonstrated obvious deterioration of lesions every 3 h. Clinically, the patient experienced dyspnea and blood gas analysis indicated respiratory failure.

At the onset of the symptoms, the patient was pregnant for more than 2 months and miscarriage occurred on d 16 after onset, which was within the expectation of the physicians. Complete curettage of uterine cavity following intraveneous anesthesia was successfully performed to remove fetus and placenta. 3. Blood gas analysis and chest X-ray.

On d 12 after onset, blood gas analysis, routine blood test and biochemical examination indicated improved condition of the patient. And on d 20 after onset, the above examinations indicated normal condition of the patient. However, chest X-ray and chest CT scan still demonstrated slow absorption of the consolidation opacity. On discharge, blood gas analysis indicated normal but chest CT scan demonstrated obvious pulmonary interstitial changes. This case is one of the cured cases of human infected avian infl uenza, with comparatively severe condition and Only on d 14 after onset, the patient experienced re-elevated body temperature to 37.5 °C, with elevated peripheral hemogram and yellowish purulent bronchial secretions. The condition was diagnosed as secondary bacterial infection and the administered antibiotics were adjusted accordingly. On d 20 after onset, the hemogram returned to normal, indicating controlled secondary infection and convalescent stage of the disease. After her discharge, her serum collected at the convalescent stage was collaboratively administered to cure a patient with human infected H5N1 avian infl uenza in Shenzhen, Guangdong, China, which is known as the patient with the most serious condition among patients with H5N1 avian infl uenza.

By radiology, the key points for differential diagnosis are as the following:

Based on early chest CT scan, the lesions are demonstrated as poorly defi ned large fl akes of increased density opacity, which are bilaterally symmetric. In combination to the clinical symptoms of high fever and cough, it should be differentiated from bacterial pneumonia of both lungs. However, the patient reported a history of contact, with normal level of peripheral WBC count. By dynamic observations via radiological examination, the lesions in both lungs progressed rapidly, with extensive involvement in bilateral lung fi elds and concurrent ground glass opacity and pulmonary consolidation opacity. All of these manifestations and fi ndings are in consistency with pneu-monia induced by human infected avian infl uenza. In addition, pneumonia induced by highly pathogenic H5N1 avian infl uenza virus should also be differentiated from SARS, AIDS complicated by PCP, and pneumonia induced by H7N9 avian infl uenza virus. Further differentiation should be comprehensively based on epidemiological history, etiological examination, clinical manifestations, and radiological fi ndings.

Clinical imaging diagnosis of emerging infectious diseases. Beijing: People's Medical Publishing House

Radiological demonstrations of pneumonia induced by highly pathogenic H5N1 avian infl uenza virus

CT demonstrations and their dynamic changes in adult patients with severe pneumonia induced by H5N1 avian infl uenza virus

Radiological features of lung changes caused by avian infl uenza subtype A H5N1 virus: report of two severe adult cases with regular follow-up

Human infected avian infl uenza