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Clinical features of three avian influenza H7N9 virus‐infected patients in Shanghai

Clinical features of three avian influenza H7N9 virus‐infected patients in Shanghai A H7N9 – ARDS – clinical features – fibrosis – Introduction: Since February 2013, a novel reassortant H7N9 virus associated with secondary invasive bacterial infections human deaths, but no apparent outbreaks in poultry and wild birds has emerged in eastern China. Correspondence Objectives: The potential reemergence of H7N9 during next year’s influenza season Min Zhou, Professor, Department of demand a further understanding of this important disease. Respiratory Medicine, School of Medicine, Methods: Between March 1 and April 30, 2013, we obtained and analyzed clinical, Ruijin Hospital, Shanghai Jiao Tong University, Ruijin ER Road, 200025 Shanghai, China. epidemiologic and radiologic features, and virologic data from three laboratory- Tel: +86 021-64370045*680805 confirmed patients of A H7N9 infection admitted in Shanghai Ruijin Hospital. Fax: +86 021-64674301 Results: All patients were middle to old aged (mean age 62 years) and overweight email: [email protected] (mean body mass index 31) patients. Two patients were exposed to poultry directly or indirectly in food market. They presented with fever and rapidly progressive Received: 17 May 2013 pneumonia that did not respond to antibiotics. Time between onset of symptoms Revision requested: 26 October 2013 and onset of respiratory failure (days) were 7–11 days. Two patients presented Accepted: 02 December 2013 secondary invasive bacterial infections. All patients died on day 7 to day 86 after the DOI:10.1111/crj.12087 onset of symptoms. Conclusions: Cross species poultry-to-person transmission of this new reassortant Authorship and contributorship avian influenza H7N9 virus can result in severe and fatal respiratory disease like Xiao Fei Wang, Guo Chao Shi, Huan Ying acute respiratory distress syndrome (ARDS) in humans. Reduplicate chest imaging Wan, Shao Guang Hang, Hong Chen, Wei examination is suggested for risky patients with fever and dyspnea. Secondary Chen, Hong Ping Qu were responsible for invasive bacterial infections and pneumothorax can cause severe and fatal conse- data collection. Xiao Fei Wang, Bao Hui Han were responsible for manuscript writing and quence. Old age, obesity and presence of comorbidity may be associated with editing. All authors have seen and approved increased mortality. Pulmonary fibrosis can be seen at late stage of the disease. the final version of the manuscript. Please cite this paper as: Wang XF, Shi GC, Wan HY, Hang SG, Chen H, Chen W, Ethics Qu HP, Han BH and Zhou M. Clinical features of three avian influenza H7N9 The study protocol was approved by the virus-infected patients in Shanghai. Clin Respir J 2014; 8: 410–416. Coordinating Ethics Committee of Ruijin Hospital. Conflict of interest The authors have stated explicitly that there *Co-correspondence author: Shanghai Chest are no conflicts of interest in connection with Hospital, Shanghai Jiao Tong University. this article. Influenza A subtype H7 virus is a recognized common time reverse transcriptase–polymerase chain reaction virus that can cause infection in poultry, which occurs (rt-PCR) assays and confirmed to be H7N9 positive. worldwide. However, Mainland China has just experi- enced the first outbreak of novel reassortant avian- origin influenza H7N9 virus infection in humans (1). Case history We obtained and analyzed the clinical, epidemio- Case 1 logic, laboratory and radiologic features from three patients admitted in Ruijin Hospital. Respiratory The first case occurred in a 67-year-old obese woman specimens were tested for influenza by means of real- with hypertension and diabetes who had traveled to 410 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients B1 B2 B3 B4 Figure 1. Chest imaging of case 1. (A) Computed tomography scan on d9 of symptoms; (B1) X-ray on d7 of symptoms; (B2), X-ray on d14 of symptoms; (B3) X-ray on d15 of symptoms; (B4) X-ray on d20 of symptoms. Zhe Jiang Province with the family a week before hos- day 2 of hospitalization were confirmed to be positive pitalization. No direct exposure to poultry was noticed, for H7N9 by means of rt-PCR. The patient stayed 14 and nobody else in the family was sick. Fever and head- days in the ICU; pulmonary infiltrations rapidly ache developed in this patient just after her return. She extended to both lungs (Fig. 1B), and clinically she was admitted to Shanghai Orient Hospital on March continued worsening despite the antiviral and anti- 25. On admission, she had oral temperature of 38.7°C. biotic treatment (oseltamivir 150 mg twice a day The chest was clear to auscultation, and the blood test through nasogastric tube + imipenem 500 mg q6h was normal. The patient presented no amelioration in iv + linezolid 600 mg q12h iv). The patient finally died spite of intravenous administration of vidarabine and on April 13. Microbiology laboratory reported that cefotiam with standard dose, so she came to our emer- the blood culture of this patient was positive for gency on March 27. Computed tomography scan Burkholderia cepacia 3 days after her death. showed consolidation in the right upper lobe (Fig. 1A) while total white cell count (5.35 × 10 /L) and Case 2 neutrophiles (3.65 × 10 /L) remained normal, but serum creatine kinase increased (CK 582 IU/L). Intra- Patient 2 was a 64-year-old male who weighs 90 kg, venous ciprofloxacin 400 mg once a day was added to with a body mass index (BMI) of 33. He had 10 years’ the regimen. However, the gas analysis realized on history of hypertension and 5 years’ history of diabe- March29onroomair presentedaseverehypoxia tes. He went to the emergency of our hospital on April (PaO : 6.05kPa), and her pulse oxygen saturation 3 for persisted fever to 39°C despite the use of fluctuated between 78% and 82% despite the use paracetamol. The blood test was normal (white cell 9 9 of biphasic positive airway pressure (BiPAP). So the count 5.62 × 10 /L, lymphocyte count 3.43 × 10 /L, patient was transferred to specialist intensive care unit platelet count 94 × 10 /L) with increased serum CK (ICU) on March 31, where the intubation was done. level (CK 537IU/L); the X-ray showed patchy consoli- Specimens obtained from nose and throat swabs by the dation of upper lobe of her right lung (Fig. 2A). Intra- Centers for Disease Control and Prevention (CDC) on venous levofloxacin, 500 mg once a day + cefoxitin, 2 g The Clinical Respiratory Journal (2014) � ISSN 1752-6981 411 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. AB Case 3 Patient 3 was a 54-year-old man with no underlying health problems. He had bought a killed chicken in the food market 5 days before the sickness. He came to our emergency on April 9 for persisting high fever after 3 days’ antivial treatment (ribavirin). The first X-ray (Fig. 3A) was taken in emergency and showed consoli- dation in right middle lobe; 1 day later, the lesions extended rapidly to right lower lobe and left middle lobe (Fig. 3B). Like the first two cases, the hemogram was Figure 2. Chest radiographs of case 2 patient. (A) X-ray on d3 normal whereas CK increased to 2758 IU/L and PaO of symptoms; (B) X-ray on d7 of symptoms. decreased to 5.13 kPa. The patient was intubated on April 10, and he was laboratory confirmed to be the third case of A H7N9 virus infection on the same day. twice a day were prescripted, however the patient Two weeks later, he was successfully extubated and now showed up at the emergency again on April 7 for sequentially supported by BiPAP Vision (Respironics, breathlessness. Auscultation revealed fine moist in Murrysville, PA, USA) with stable vital signs. The the lower lung fields. Sequential chest X-rays showed rt-PCR result of his throat swabs turned negative of extensive involvement of the right lung, with new infil- H7N9 after 21 days’ use of oseltamivir (150 mg twice a trates appearing on the left (Fig. 2B). The arterial gas day through nasogastric tube from April 10 to April 30). analysis showed a severe hypoxia (PaO 5.47 kPa, SaO Repeated sputum cultures of the patient were positive 2 2 61%) on room air, requiring noninvasive ventilation for Stenotrophomonas maltophilia since April 27, but the with BiPAP. We noticed the elevation of C-reactive blood cultures remained sterile. The patient became protein (73 mg/L) and CK (537 IU/L) at the same apyrexic on May 4 with antibiotherapy of cefepime (2 g time. After throat swab samples were taken, oral q12h iv). Generalized coarse reticulation of the right oseltamivir (150 mg twice a day) was immediately lung was noted on the chest radiograph realized on May added to the regimen. However, the patient showed 5 (Fig. 3C), which may explain why the patient still rely no amelioration with BiPAP, and unfortunately he on BiPAP support with high concentration of oxgen died in the course of intubation. Reports from CDC therapy (fraction of inspiration oxygen 80%). The confirmed this patient to be H7N9 positive; inter- patients had been relatively stable with BiPAP until May rogation of the family revealed that the patient went 18, when his dyspnea gradually worsened. Bedside chest to the food market every day when he was healthy, radiograph (Fig. 3D) showed right-sided pneumotho- which is believed to be the source of infection for this rax as was suspected, and an intercostal chest drain was patient. inserted the same day. The patient suffered of refractory AB C D Figure 3. Chest radiographs of case 3. (A) X-ray on d3 of symptoms; (B) X-ray on d4 of symptoms; (C) X-ray on d29 of symptoms; (D) X-ray on d42 of symptoms. 412 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients Table 1. Demographic, epidemiologic, and imaging characteristics and treatment and clinical outcome of three patients infected with A H7N9 virus Characteristic Case 1 Case 2 Case 3 Age (year) 67 64 54 Sex F M M Occupation Retired Retired Retired BMI 35 33 26 Underlying illness Hypertension, diabetes Hypertension, diabetes None Exposure to live poultry None Yes (probably indirect) Yes Time between onset of symptoms 14 7 8 and initiation of oseltamivir (days) Time between onset of symptoms 11 7 8 and onset of respiratory failure (days) Time between onset of 31 1 respiratory failure and need for mechanical ventilation (days) Time between mechanical 14 1 78 ventilation and death (days) Major symptom Fever, dyspnea Fever, dyspnea Fever, dyspnea Hemogram at presentation Normal Normal Normal CK (IU/L) at presentation 582 537 2758 Initial affected lobe on X-ray Upper lobe of right lung Upper lobe of right lung Middle lobe of right lung Complications Sepsis shock (Burkholderia Unknown Secondary bacterial cepacia) pneumonia (Stenotrophomonas maltophilia) and pneumothorax Antibiotics given Cefotiam, ciprofloxacin, Levofloxacin, cefoxitin, Cefuroxime, cefotaxime, imipenem–cilastatin, imipenem–cilastatin cefepime, vancomycin, vancomycin, moxifloxacin, meropenem linezolid, caspofungin Days after onset of symptoms on Days 11–23 (40 mg every Day 7 (40 mg every 12 h) Days 6–26 (40 mg every which intravenous 24 h days 11–13; 40 mg 24 h days 6–9; 40 mg methylprednisolone given every 8 h days 14–17; every 8 h days 10–12; (dosage) 40 mg every 24 h days 40 mg every 12 h days 18–23) 13–15; 40 mg every 24 h days 15–20; 20 mg every 24 h days 21–26) Days after onset of symptoms on Days 17–25 (10 g every Day 7 (5 g every 24 h) Days 10–26 (20 g every which intravenous 24 h) 24 h) immunoglobulin given (dosage) Outcome Died on April 13 of sepsis Died on April 7 in course Died on June 26 of choc of intubation refractory pneumothorax BMI, body mass index; CK, creatine kinase. hypoxia because of the persisting pneumothorax and Table 1). Two patients were exposed to live poultry finally died on June 26. directly or indirectly in the food market while the other patient got a trip outside Shanghai; the presumed incu- bation period was about 1 week. All of the patients Results were overweight to obese, with BMI ranging from 26 to 35 (mean 31). None of the patients had upper res- We identified three patients with mean age of 62 piratory tract symptoms or conjunctivitis. Fever and years including two females and one male (the clinical later onset dyspnea were the major symptoms. The characteristics of these three patients are shown in The Clinical Respiratory Journal (2014) � ISSN 1752-6981 413 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. Table 2. Summary of human infection with avian flu in recent years Subtype of virus Source Year/country Number/clinical manifestation A/H7N7 Gull 1980/United States 3/conjunctivitis A/H7N7 Duck 1996/United Kingdom 1/conjunctivitis A/H5N1 Bird 1997/Hong Kong, China 18/ILI, pneumonia A/H9N2 Chicken 1998/Guang Dong, China 5/ILI, pneumonia A/H9N2 Avian 1999/Hong Kong, China 2/ILI A/H7N2 Avian 2002/North America (Virginia) 1/ILI, serologic diagnostic A/H9N2 Avian 2003/Hong Kong, China 1/ILI A/H5N1 Avian 2003/Hong Kong, China 2/ILI A/H7N7 Avian 2003/Holland 89/conjunctivitis, ILI, pneumonia (including 1 death) A/H5N1 Avian 2003 until now, 15 countries 602/ILI, pneumonia A/H7N2(NY/107) Unknown 2003/North America (New York) 1/pneumonia A/H7N3 Avian 2004/Canada 2/conjunctivitis, ILI; 1 LPAI; 1 HPAI A/H5N2 Avian 2005/Japan (Ibaraki) 13/serologic diagnostic A/H7N2 Avian 2007/United Kingdom (Wales) 1/conjunctivitis, ILI A/H9N2 Unknown 2007/Hong Kong, China 1/ILI A/H10N7 Duck 2004/Eygept (Ismaillia) 2/ILI A/H10N7 Birds from infected areas 2010/Sydney (New South Wales) 7/URI, conjunctivitis HPAI, highly pathogenic avian influenza; ILI, influenza-like infection; LPAI, lowly pathogenic avian influenza; URI, upper respiratory tract infection. hemograms were normal at presentation, and we tions are generally mild, causing conjunctivitis or observed a substantial elevation of CK in all three modest respiratory symptoms, although a fatal case patients. Upper and middle lobe of the right lung are was reported before this A H7N9 virus outbreak (3). the most affected zones at early stage of the disease, Novel influenza viruses of the A H7N9 subtype, which may be related to the inhalation of the virus by characterized by high fever and severe respiratory respiratory tract, and then rapidly extended to both symptoms, have infected 127 and killed 24 people in lungs within 7–15 days (mean 10 days). Antiviral China as of April 30, 2013 and may pose a serious therapy with traditional medications like vidarabine human health risk. An understanding of the source and ribavirin showed no effect on this kind of infec- and mode of transmission of these infections, further tion. Three patients were given 150 mg oral oseltamivir surveillance and appropriate countermeasures are twice daily after throat swab samples were taken, start- urgently required. This novel influenza viruses’ ing a mean of 9.7 days after onset of symptoms. Mean hemagglutinin (HA) and neuraminidase genes prob- time between onset of symptoms and respiratory ably originated from Eurasian avian influenza viruses; failure was 8.6 days. All patients required mechanical the remaining genes are closely related to avian H9N2 ventilation. Combination antibiotic therapy, glucocor- influenza viruses. Several characteristic amino acid ticoids and intravenous immunoglobulin were admin- changes in HA and the polymerase basic 2 protein istered in all three patients. Patient 1 died of sepsis 14 (PB2) RNA polymerase subunit probably facilitate days after intubation while patient 2 died of cardiac binding to human-type receptors and efficient replica- arrest in course of intubation. The third patient had tion in mammals, respectively, highlighting the pan- once been successfully extubated; however, he later demic potential of the novel viruses (4) (Fig. 4). complicated with a pneumothorax in the context of However, unlike other types of avian influenza affect- pulmonary fibrosis and finally died 86 days after the ing human beings, no increase in poultry deaths was onset of symptoms. Secondary invasive bacterial infec- noticed before onset of human infections. Zoonotic tions were found in two of these patients: sepsis choc of infections of A H7N9 virus from birds to humans B. cepacia in patient 1 and bacterial pneumonia of appear to be associated with live poultry markets, like S. maltophilia in patent 3. the last two of our cases. There also have been sporadic reports of human-to-human transmission (5, 6); therefore, the pandemic potential of these novel avian- Discussion origin viruses should not be underestimated. We diag- Human infections with avian-origin influenza virus nosed avian influenza H7N9 in all three patients (who have been observed before (Table 2) (2); most infec- were epidemiologically unlinked); two patients had 414 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients attention to ‘risky’ patients with copresence with of fever and dyspnea with normal white blood cell count and CK elevation, especially in those old and over- weight patients. Virus is not the only germ we face; secondary inva- sive bacterial infections were found in two of our patients, and one result in fatal sepsis. The develop- ment of secondary infection, especially Gram-negative rod infection, can be explained by several factors, such as exposure to high-risk procedures, use of glucocor- ticoids, severity of underlying diseases and frequent use of medical instruments, all of which may facilitate development of nosocomial bacteremia (12), so appro- priate empirical antibiotic treatment may be indicated for initial management of severe A H7N9 virus pneu- monia. Glucocorticoids are used in all of our cases while they are still controversial in the routine treat- Figure 4. Structure of avian influenza virus H7N9. ment of influenza (13–15). Because of the limited number of patients, our experiences are not conclusive; whether the continuous activity of virus replication is histories of wet market exposure to poultry, suggesting associated with glucocorticoid is unknown. Long-term poultry-to-person transmission. Fortunately, no close complication of mechanical ventilation is pneumo- contacts of these three patients are found be infected thorax. Yang and her colleagues (16) find that the till now. incidence of pneumothorax in serious coronavirus Our patients presented high fevers, lower respiratory [severe acute respiratory syndrome (SARS)-CoV] tract symptoms (especially dyspnea) and radiological patients with noninvasive positive pressure ventilation features of consolidation without upper respiratory is significantly higher than that without receiving MV. tract symptoms. The most striking common preexist- This might be related to viral-related pulmonary inju- ing factor of our patient group was obesity or being ries, intensive cough and high mechanical ventilation overweight, which was previously reported to be a risk pressure. factor for developing acute respiratory distress syn- The outcome of A H7N9 virus infection in human drome (ARDS) in H1N1 infection (7, 8). In another beings is unfavorable, especially in cases present with study, development of ARDS was seen more frequently ARDS. From the imaging evolution of the only survi- in obese patients (9). However, in a large cases study vor, we find that the opacification has largely resolved (10), they did not find that obesity was associated with and replaced by reticulations especially in the initially increased mortality. It is may be because our patients affected lung. The histologic evolution of SARS-CoV are more severe and presented ARDS. The first two infection coincided with the different stages of diffuse patients who died within 1 month were both over 60 alveolar damage: acute, proliferative organizing and and associated with underlying health problems fibrotic stages (17); whether the nrH7N9 infection (hypertension and diabetes). The third patient, the shared the same process is unknown. 54-year-old male with no medical history, has once Concerning the high mortality of these infections, been successfully extubated. Thus, we think that poor early diagnosis is the key for the treatment. Reduplicate prognosis may probably be related with old age (>60 chest imaging examination is suggested for risky years), obesity and presence of comorbidity. All three patients with fever and dyspnea; early use of Oselta- patients received treatment with oseltamivir starting mivir is necessary for suspicion patients. Old age, on day 7–14 of symptoms onsets, probably at the time obesity and presence of comorbidity may be associated of respiratory failure onset. Data related to human with increased mortality. infections with seasonal, pandemic and HPAI H5N1 viruses indicate that the earlier antiviral treatment is References initiated, the greater the clinical benefit (11). However, none of these clinical, radiological or laboratory changes was pathognomonic, which result in the delay 1. Gao R, Cao B, Hu Y, et al. Human infection with a novel of the antiviral treatment. So this reminds us to pay avian-origin influenza A (H7N9) virus. N human The Clinical Respiratory Journal (2014) � ISSN 1752-6981 415 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. infection with a novel avian-origin influenza A (H7N9) acute respiratory distress syndrome. Thorax. 2010;65(1): virus. N Engl J Med. 2013;368(20): 1888–97. 44–50. 2. Reperant LA, Kuiken T, Osterhaus AD. Influenza viruses: 10. Gao H, Lu HZ, Cao B, et al. Clinical findings in 111 cases from birds to humans. Hum Vaccin Immunother. of influenza A (H7N9) virus infection. N Engl J Med. 2012;8(1): 7–16. 2013;368(24): 2277–85. 3. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. 11. Chan PK, Lee N, Zaman M, et al. Determinants of Avian influenza A virus (H7N7) associated with human antiviral effectiveness in influenza virus A subtype H5N1. conjunctivitis and a fatal case of acute respiratory distress J Infect Dis. 2012;206(9): 1359–66. syndrome. Proc Natl Acad Sci U S A. 2004;101(5): 12. Karakoc C, Tekin R, Yesilbag Z, Cagatay A. Risk factors for 1356–61. mortality in patients with nosocomial Gram-negative rod 4. Kageyama T, Fujisaki S, Takashita E, et al. Genetic analysis bacteremia. Eur Rev Med Pharmacol Sci. 2013;17(7): of novel avian A(H7N9) influenza viruses isolated from 951–7. patients in China, February to April 2013. Euro Surveill. 13. Marik PE, Meduri GU, Rocco PR, Annane D. 2013;18(15): 20453–67. Glucocorticoid treatment in acute lung injury and acute 5. Jie Z, Xie J, He Z, et al. Family outbreak of severe respiratory distress syndrome. Crit Care Clin. 2011;27(3): pneumonia induced by H7N9 infection. Am J Respir Crit 589–607. Care Med. 2013;188(1): 114–5. 14. Panesar NS. What caused lymphopenia in SARS and how 6. Qi X, Qian YH, Bao CJ, et al. Probable person to person reliable is the lymphokine status in glucocorticoid-treated transmission of novel avian influenza A (H7N9) virus in patients? Med Hypotheses. 2008;71(2): 298–301. Eastern China, 2013: epidemiological investigation. BMJ. 15. Póvoa P, Salluh JI. What is the role of steroids in 2013;347: f4752. pneumonia therapy? Curr Opin Infect Dis. 2012;25(2): 7. Kumar A, Zarychanski R, Pinto R, et al. Critically ill 199–204. patients with 2009 influenza A(H1N1) infection in 16. Yang L, Li F, Li D, Jia JG, Yang P, Sun JB. Clinical analysis Canada. JAMA. 2009;302(17): 1872–79. of complications after non- invasive positive pressure 8. Davies A, Jones D, Bailey M, et al. Australia and New ventilation and an inquiry into the respiratory treatment Zealand Extracorporeal Membrane Oxygenation (ANZ strategy in patients with SARS. Zhongguo Wei Zhong ECMO) Influenza Investigators. Extracorporeal membrane Bing Ji Jiu Yi Xue. 2004;16(5): 281–3. oxygenation for 2009 influenza A(H1N1) acute respiratory 17. Hsiao CH, Wu MZ, Chen CL, Hsueh PR, Hsieh SW, Yang distress syndrome. JAMA. 2009;302(17): 1888–95. PC, Su IJ. Evolution of pulmonary pathology in severe 9. Gong MN, Bajwa EK, Thompson BT, Christiani DC. acute respiratory syndrome. J Formos Med Assoc. Body mass index is associated with the development of 2005;104(2): 75–81. 416 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Clinical Respiratory Journal Pubmed Central

Clinical features of three avian influenza H7N9 virus‐infected patients in Shanghai

Wang, Xiao Fei; Shi, Guo Chao; Wan, Huan Ying; Hang, Shao Guang; Chen, Hong; Chen, Wei; Qu, Hong Ping; Han, Bao Hui; Zhou, Min
The Clinical Respiratory Journal , Volume 8 (4) – Jan 10, 2014
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Abstract

A H7N9 – ARDS – clinical features – fibrosis – Introduction: Since February 2013, a novel reassortant H7N9 virus associated with secondary invasive bacterial infections human deaths, but no apparent outbreaks in poultry and wild birds has emerged in eastern China. Correspondence Objectives: The potential reemergence of H7N9 during next year’s influenza season Min Zhou, Professor, Department of demand a further understanding of this important disease. Respiratory Medicine, School of Medicine, Methods: Between March 1 and April 30, 2013, we obtained and analyzed clinical, Ruijin Hospital, Shanghai Jiao Tong University, Ruijin ER Road, 200025 Shanghai, China. epidemiologic and radiologic features, and virologic data from three laboratory- Tel: +86 021-64370045*680805 confirmed patients of A H7N9 infection admitted in Shanghai Ruijin Hospital. Fax: +86 021-64674301 Results: All patients were middle to old aged (mean age 62 years) and overweight email: [email protected] (mean body mass index 31) patients. Two patients were exposed to poultry directly or indirectly in food market. They presented with fever and rapidly progressive Received: 17 May 2013 pneumonia that did not respond to antibiotics. Time between onset of symptoms Revision requested: 26 October 2013 and onset of respiratory failure (days) were 7–11 days. Two patients presented Accepted: 02 December 2013 secondary invasive bacterial infections. All patients died on day 7 to day 86 after the DOI:10.1111/crj.12087 onset of symptoms. Conclusions: Cross species poultry-to-person transmission of this new reassortant Authorship and contributorship avian influenza H7N9 virus can result in severe and fatal respiratory disease like Xiao Fei Wang, Guo Chao Shi, Huan Ying acute respiratory distress syndrome (ARDS) in humans. Reduplicate chest imaging Wan, Shao Guang Hang, Hong Chen, Wei examination is suggested for risky patients with fever and dyspnea. Secondary Chen, Hong Ping Qu were responsible for invasive bacterial infections and pneumothorax can cause severe and fatal conse- data collection. Xiao Fei Wang, Bao Hui Han were responsible for manuscript writing and quence. Old age, obesity and presence of comorbidity may be associated with editing. All authors have seen and approved increased mortality. Pulmonary fibrosis can be seen at late stage of the disease. the final version of the manuscript. Please cite this paper as: Wang XF, Shi GC, Wan HY, Hang SG, Chen H, Chen W, Ethics Qu HP, Han BH and Zhou M. Clinical features of three avian influenza H7N9 The study protocol was approved by the virus-infected patients in Shanghai. Clin Respir J 2014; 8: 410–416. Coordinating Ethics Committee of Ruijin Hospital. Conflict of interest The authors have stated explicitly that there *Co-correspondence author: Shanghai Chest are no conflicts of interest in connection with Hospital, Shanghai Jiao Tong University. this article. Influenza A subtype H7 virus is a recognized common time reverse transcriptase–polymerase chain reaction virus that can cause infection in poultry, which occurs (rt-PCR) assays and confirmed to be H7N9 positive. worldwide. However, Mainland China has just experi- enced the first outbreak of novel reassortant avian- origin influenza H7N9 virus infection in humans (1). Case history We obtained and analyzed the clinical, epidemio- Case 1 logic, laboratory and radiologic features from three patients admitted in Ruijin Hospital. Respiratory The first case occurred in a 67-year-old obese woman specimens were tested for influenza by means of real- with hypertension and diabetes who had traveled to 410 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients B1 B2 B3 B4 Figure 1. Chest imaging of case 1. (A) Computed tomography scan on d9 of symptoms; (B1) X-ray on d7 of symptoms; (B2), X-ray on d14 of symptoms; (B3) X-ray on d15 of symptoms; (B4) X-ray on d20 of symptoms. Zhe Jiang Province with the family a week before hos- day 2 of hospitalization were confirmed to be positive pitalization. No direct exposure to poultry was noticed, for H7N9 by means of rt-PCR. The patient stayed 14 and nobody else in the family was sick. Fever and head- days in the ICU; pulmonary infiltrations rapidly ache developed in this patient just after her return. She extended to both lungs (Fig. 1B), and clinically she was admitted to Shanghai Orient Hospital on March continued worsening despite the antiviral and anti- 25. On admission, she had oral temperature of 38.7°C. biotic treatment (oseltamivir 150 mg twice a day The chest was clear to auscultation, and the blood test through nasogastric tube + imipenem 500 mg q6h was normal. The patient presented no amelioration in iv + linezolid 600 mg q12h iv). The patient finally died spite of intravenous administration of vidarabine and on April 13. Microbiology laboratory reported that cefotiam with standard dose, so she came to our emer- the blood culture of this patient was positive for gency on March 27. Computed tomography scan Burkholderia cepacia 3 days after her death. showed consolidation in the right upper lobe (Fig. 1A) while total white cell count (5.35 × 10 /L) and Case 2 neutrophiles (3.65 × 10 /L) remained normal, but serum creatine kinase increased (CK 582 IU/L). Intra- Patient 2 was a 64-year-old male who weighs 90 kg, venous ciprofloxacin 400 mg once a day was added to with a body mass index (BMI) of 33. He had 10 years’ the regimen. However, the gas analysis realized on history of hypertension and 5 years’ history of diabe- March29onroomair presentedaseverehypoxia tes. He went to the emergency of our hospital on April (PaO : 6.05kPa), and her pulse oxygen saturation 3 for persisted fever to 39°C despite the use of fluctuated between 78% and 82% despite the use paracetamol. The blood test was normal (white cell 9 9 of biphasic positive airway pressure (BiPAP). So the count 5.62 × 10 /L, lymphocyte count 3.43 × 10 /L, patient was transferred to specialist intensive care unit platelet count 94 × 10 /L) with increased serum CK (ICU) on March 31, where the intubation was done. level (CK 537IU/L); the X-ray showed patchy consoli- Specimens obtained from nose and throat swabs by the dation of upper lobe of her right lung (Fig. 2A). Intra- Centers for Disease Control and Prevention (CDC) on venous levofloxacin, 500 mg once a day + cefoxitin, 2 g The Clinical Respiratory Journal (2014) � ISSN 1752-6981 411 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. AB Case 3 Patient 3 was a 54-year-old man with no underlying health problems. He had bought a killed chicken in the food market 5 days before the sickness. He came to our emergency on April 9 for persisting high fever after 3 days’ antivial treatment (ribavirin). The first X-ray (Fig. 3A) was taken in emergency and showed consoli- dation in right middle lobe; 1 day later, the lesions extended rapidly to right lower lobe and left middle lobe (Fig. 3B). Like the first two cases, the hemogram was Figure 2. Chest radiographs of case 2 patient. (A) X-ray on d3 normal whereas CK increased to 2758 IU/L and PaO of symptoms; (B) X-ray on d7 of symptoms. decreased to 5.13 kPa. The patient was intubated on April 10, and he was laboratory confirmed to be the third case of A H7N9 virus infection on the same day. twice a day were prescripted, however the patient Two weeks later, he was successfully extubated and now showed up at the emergency again on April 7 for sequentially supported by BiPAP Vision (Respironics, breathlessness. Auscultation revealed fine moist in Murrysville, PA, USA) with stable vital signs. The the lower lung fields. Sequential chest X-rays showed rt-PCR result of his throat swabs turned negative of extensive involvement of the right lung, with new infil- H7N9 after 21 days’ use of oseltamivir (150 mg twice a trates appearing on the left (Fig. 2B). The arterial gas day through nasogastric tube from April 10 to April 30). analysis showed a severe hypoxia (PaO 5.47 kPa, SaO Repeated sputum cultures of the patient were positive 2 2 61%) on room air, requiring noninvasive ventilation for Stenotrophomonas maltophilia since April 27, but the with BiPAP. We noticed the elevation of C-reactive blood cultures remained sterile. The patient became protein (73 mg/L) and CK (537 IU/L) at the same apyrexic on May 4 with antibiotherapy of cefepime (2 g time. After throat swab samples were taken, oral q12h iv). Generalized coarse reticulation of the right oseltamivir (150 mg twice a day) was immediately lung was noted on the chest radiograph realized on May added to the regimen. However, the patient showed 5 (Fig. 3C), which may explain why the patient still rely no amelioration with BiPAP, and unfortunately he on BiPAP support with high concentration of oxgen died in the course of intubation. Reports from CDC therapy (fraction of inspiration oxygen 80%). The confirmed this patient to be H7N9 positive; inter- patients had been relatively stable with BiPAP until May rogation of the family revealed that the patient went 18, when his dyspnea gradually worsened. Bedside chest to the food market every day when he was healthy, radiograph (Fig. 3D) showed right-sided pneumotho- which is believed to be the source of infection for this rax as was suspected, and an intercostal chest drain was patient. inserted the same day. The patient suffered of refractory AB C D Figure 3. Chest radiographs of case 3. (A) X-ray on d3 of symptoms; (B) X-ray on d4 of symptoms; (C) X-ray on d29 of symptoms; (D) X-ray on d42 of symptoms. 412 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients Table 1. Demographic, epidemiologic, and imaging characteristics and treatment and clinical outcome of three patients infected with A H7N9 virus Characteristic Case 1 Case 2 Case 3 Age (year) 67 64 54 Sex F M M Occupation Retired Retired Retired BMI 35 33 26 Underlying illness Hypertension, diabetes Hypertension, diabetes None Exposure to live poultry None Yes (probably indirect) Yes Time between onset of symptoms 14 7 8 and initiation of oseltamivir (days) Time between onset of symptoms 11 7 8 and onset of respiratory failure (days) Time between onset of 31 1 respiratory failure and need for mechanical ventilation (days) Time between mechanical 14 1 78 ventilation and death (days) Major symptom Fever, dyspnea Fever, dyspnea Fever, dyspnea Hemogram at presentation Normal Normal Normal CK (IU/L) at presentation 582 537 2758 Initial affected lobe on X-ray Upper lobe of right lung Upper lobe of right lung Middle lobe of right lung Complications Sepsis shock (Burkholderia Unknown Secondary bacterial cepacia) pneumonia (Stenotrophomonas maltophilia) and pneumothorax Antibiotics given Cefotiam, ciprofloxacin, Levofloxacin, cefoxitin, Cefuroxime, cefotaxime, imipenem–cilastatin, imipenem–cilastatin cefepime, vancomycin, vancomycin, moxifloxacin, meropenem linezolid, caspofungin Days after onset of symptoms on Days 11–23 (40 mg every Day 7 (40 mg every 12 h) Days 6–26 (40 mg every which intravenous 24 h days 11–13; 40 mg 24 h days 6–9; 40 mg methylprednisolone given every 8 h days 14–17; every 8 h days 10–12; (dosage) 40 mg every 24 h days 40 mg every 12 h days 18–23) 13–15; 40 mg every 24 h days 15–20; 20 mg every 24 h days 21–26) Days after onset of symptoms on Days 17–25 (10 g every Day 7 (5 g every 24 h) Days 10–26 (20 g every which intravenous 24 h) 24 h) immunoglobulin given (dosage) Outcome Died on April 13 of sepsis Died on April 7 in course Died on June 26 of choc of intubation refractory pneumothorax BMI, body mass index; CK, creatine kinase. hypoxia because of the persisting pneumothorax and Table 1). Two patients were exposed to live poultry finally died on June 26. directly or indirectly in the food market while the other patient got a trip outside Shanghai; the presumed incu- bation period was about 1 week. All of the patients Results were overweight to obese, with BMI ranging from 26 to 35 (mean 31). None of the patients had upper res- We identified three patients with mean age of 62 piratory tract symptoms or conjunctivitis. Fever and years including two females and one male (the clinical later onset dyspnea were the major symptoms. The characteristics of these three patients are shown in The Clinical Respiratory Journal (2014) � ISSN 1752-6981 413 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. Table 2. Summary of human infection with avian flu in recent years Subtype of virus Source Year/country Number/clinical manifestation A/H7N7 Gull 1980/United States 3/conjunctivitis A/H7N7 Duck 1996/United Kingdom 1/conjunctivitis A/H5N1 Bird 1997/Hong Kong, China 18/ILI, pneumonia A/H9N2 Chicken 1998/Guang Dong, China 5/ILI, pneumonia A/H9N2 Avian 1999/Hong Kong, China 2/ILI A/H7N2 Avian 2002/North America (Virginia) 1/ILI, serologic diagnostic A/H9N2 Avian 2003/Hong Kong, China 1/ILI A/H5N1 Avian 2003/Hong Kong, China 2/ILI A/H7N7 Avian 2003/Holland 89/conjunctivitis, ILI, pneumonia (including 1 death) A/H5N1 Avian 2003 until now, 15 countries 602/ILI, pneumonia A/H7N2(NY/107) Unknown 2003/North America (New York) 1/pneumonia A/H7N3 Avian 2004/Canada 2/conjunctivitis, ILI; 1 LPAI; 1 HPAI A/H5N2 Avian 2005/Japan (Ibaraki) 13/serologic diagnostic A/H7N2 Avian 2007/United Kingdom (Wales) 1/conjunctivitis, ILI A/H9N2 Unknown 2007/Hong Kong, China 1/ILI A/H10N7 Duck 2004/Eygept (Ismaillia) 2/ILI A/H10N7 Birds from infected areas 2010/Sydney (New South Wales) 7/URI, conjunctivitis HPAI, highly pathogenic avian influenza; ILI, influenza-like infection; LPAI, lowly pathogenic avian influenza; URI, upper respiratory tract infection. hemograms were normal at presentation, and we tions are generally mild, causing conjunctivitis or observed a substantial elevation of CK in all three modest respiratory symptoms, although a fatal case patients. Upper and middle lobe of the right lung are was reported before this A H7N9 virus outbreak (3). the most affected zones at early stage of the disease, Novel influenza viruses of the A H7N9 subtype, which may be related to the inhalation of the virus by characterized by high fever and severe respiratory respiratory tract, and then rapidly extended to both symptoms, have infected 127 and killed 24 people in lungs within 7–15 days (mean 10 days). Antiviral China as of April 30, 2013 and may pose a serious therapy with traditional medications like vidarabine human health risk. An understanding of the source and ribavirin showed no effect on this kind of infec- and mode of transmission of these infections, further tion. Three patients were given 150 mg oral oseltamivir surveillance and appropriate countermeasures are twice daily after throat swab samples were taken, start- urgently required. This novel influenza viruses’ ing a mean of 9.7 days after onset of symptoms. Mean hemagglutinin (HA) and neuraminidase genes prob- time between onset of symptoms and respiratory ably originated from Eurasian avian influenza viruses; failure was 8.6 days. All patients required mechanical the remaining genes are closely related to avian H9N2 ventilation. Combination antibiotic therapy, glucocor- influenza viruses. Several characteristic amino acid ticoids and intravenous immunoglobulin were admin- changes in HA and the polymerase basic 2 protein istered in all three patients. Patient 1 died of sepsis 14 (PB2) RNA polymerase subunit probably facilitate days after intubation while patient 2 died of cardiac binding to human-type receptors and efficient replica- arrest in course of intubation. The third patient had tion in mammals, respectively, highlighting the pan- once been successfully extubated; however, he later demic potential of the novel viruses (4) (Fig. 4). complicated with a pneumothorax in the context of However, unlike other types of avian influenza affect- pulmonary fibrosis and finally died 86 days after the ing human beings, no increase in poultry deaths was onset of symptoms. Secondary invasive bacterial infec- noticed before onset of human infections. Zoonotic tions were found in two of these patients: sepsis choc of infections of A H7N9 virus from birds to humans B. cepacia in patient 1 and bacterial pneumonia of appear to be associated with live poultry markets, like S. maltophilia in patent 3. the last two of our cases. There also have been sporadic reports of human-to-human transmission (5, 6); therefore, the pandemic potential of these novel avian- Discussion origin viruses should not be underestimated. We diag- Human infections with avian-origin influenza virus nosed avian influenza H7N9 in all three patients (who have been observed before (Table 2) (2); most infec- were epidemiologically unlinked); two patients had 414 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd Wang et al. Clinical features of 3 confirmed A H7N9 patients attention to ‘risky’ patients with copresence with of fever and dyspnea with normal white blood cell count and CK elevation, especially in those old and over- weight patients. Virus is not the only germ we face; secondary inva- sive bacterial infections were found in two of our patients, and one result in fatal sepsis. The develop- ment of secondary infection, especially Gram-negative rod infection, can be explained by several factors, such as exposure to high-risk procedures, use of glucocor- ticoids, severity of underlying diseases and frequent use of medical instruments, all of which may facilitate development of nosocomial bacteremia (12), so appro- priate empirical antibiotic treatment may be indicated for initial management of severe A H7N9 virus pneu- monia. Glucocorticoids are used in all of our cases while they are still controversial in the routine treat- Figure 4. Structure of avian influenza virus H7N9. ment of influenza (13–15). Because of the limited number of patients, our experiences are not conclusive; whether the continuous activity of virus replication is histories of wet market exposure to poultry, suggesting associated with glucocorticoid is unknown. Long-term poultry-to-person transmission. Fortunately, no close complication of mechanical ventilation is pneumo- contacts of these three patients are found be infected thorax. Yang and her colleagues (16) find that the till now. incidence of pneumothorax in serious coronavirus Our patients presented high fevers, lower respiratory [severe acute respiratory syndrome (SARS)-CoV] tract symptoms (especially dyspnea) and radiological patients with noninvasive positive pressure ventilation features of consolidation without upper respiratory is significantly higher than that without receiving MV. tract symptoms. The most striking common preexist- This might be related to viral-related pulmonary inju- ing factor of our patient group was obesity or being ries, intensive cough and high mechanical ventilation overweight, which was previously reported to be a risk pressure. factor for developing acute respiratory distress syn- The outcome of A H7N9 virus infection in human drome (ARDS) in H1N1 infection (7, 8). In another beings is unfavorable, especially in cases present with study, development of ARDS was seen more frequently ARDS. From the imaging evolution of the only survi- in obese patients (9). However, in a large cases study vor, we find that the opacification has largely resolved (10), they did not find that obesity was associated with and replaced by reticulations especially in the initially increased mortality. It is may be because our patients affected lung. The histologic evolution of SARS-CoV are more severe and presented ARDS. The first two infection coincided with the different stages of diffuse patients who died within 1 month were both over 60 alveolar damage: acute, proliferative organizing and and associated with underlying health problems fibrotic stages (17); whether the nrH7N9 infection (hypertension and diabetes). The third patient, the shared the same process is unknown. 54-year-old male with no medical history, has once Concerning the high mortality of these infections, been successfully extubated. Thus, we think that poor early diagnosis is the key for the treatment. Reduplicate prognosis may probably be related with old age (>60 chest imaging examination is suggested for risky years), obesity and presence of comorbidity. All three patients with fever and dyspnea; early use of Oselta- patients received treatment with oseltamivir starting mivir is necessary for suspicion patients. Old age, on day 7–14 of symptoms onsets, probably at the time obesity and presence of comorbidity may be associated of respiratory failure onset. Data related to human with increased mortality. infections with seasonal, pandemic and HPAI H5N1 viruses indicate that the earlier antiviral treatment is References initiated, the greater the clinical benefit (11). However, none of these clinical, radiological or laboratory changes was pathognomonic, which result in the delay 1. Gao R, Cao B, Hu Y, et al. Human infection with a novel of the antiviral treatment. So this reminds us to pay avian-origin influenza A (H7N9) virus. N human The Clinical Respiratory Journal (2014) � ISSN 1752-6981 415 © 2013 John Wiley & Sons Ltd Clinical features of 3 confirmed A H7N9 patients Wang et al. infection with a novel avian-origin influenza A (H7N9) acute respiratory distress syndrome. Thorax. 2010;65(1): virus. N Engl J Med. 2013;368(20): 1888–97. 44–50. 2. Reperant LA, Kuiken T, Osterhaus AD. Influenza viruses: 10. Gao H, Lu HZ, Cao B, et al. Clinical findings in 111 cases from birds to humans. Hum Vaccin Immunother. of influenza A (H7N9) virus infection. N Engl J Med. 2012;8(1): 7–16. 2013;368(24): 2277–85. 3. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. 11. Chan PK, Lee N, Zaman M, et al. Determinants of Avian influenza A virus (H7N7) associated with human antiviral effectiveness in influenza virus A subtype H5N1. conjunctivitis and a fatal case of acute respiratory distress J Infect Dis. 2012;206(9): 1359–66. syndrome. Proc Natl Acad Sci U S A. 2004;101(5): 12. Karakoc C, Tekin R, Yesilbag Z, Cagatay A. Risk factors for 1356–61. mortality in patients with nosocomial Gram-negative rod 4. Kageyama T, Fujisaki S, Takashita E, et al. Genetic analysis bacteremia. Eur Rev Med Pharmacol Sci. 2013;17(7): of novel avian A(H7N9) influenza viruses isolated from 951–7. patients in China, February to April 2013. Euro Surveill. 13. Marik PE, Meduri GU, Rocco PR, Annane D. 2013;18(15): 20453–67. Glucocorticoid treatment in acute lung injury and acute 5. Jie Z, Xie J, He Z, et al. Family outbreak of severe respiratory distress syndrome. Crit Care Clin. 2011;27(3): pneumonia induced by H7N9 infection. Am J Respir Crit 589–607. Care Med. 2013;188(1): 114–5. 14. Panesar NS. What caused lymphopenia in SARS and how 6. Qi X, Qian YH, Bao CJ, et al. Probable person to person reliable is the lymphokine status in glucocorticoid-treated transmission of novel avian influenza A (H7N9) virus in patients? Med Hypotheses. 2008;71(2): 298–301. Eastern China, 2013: epidemiological investigation. BMJ. 15. Póvoa P, Salluh JI. What is the role of steroids in 2013;347: f4752. pneumonia therapy? Curr Opin Infect Dis. 2012;25(2): 7. Kumar A, Zarychanski R, Pinto R, et al. Critically ill 199–204. patients with 2009 influenza A(H1N1) infection in 16. Yang L, Li F, Li D, Jia JG, Yang P, Sun JB. Clinical analysis Canada. JAMA. 2009;302(17): 1872–79. of complications after non- invasive positive pressure 8. Davies A, Jones D, Bailey M, et al. Australia and New ventilation and an inquiry into the respiratory treatment Zealand Extracorporeal Membrane Oxygenation (ANZ strategy in patients with SARS. Zhongguo Wei Zhong ECMO) Influenza Investigators. Extracorporeal membrane Bing Ji Jiu Yi Xue. 2004;16(5): 281–3. oxygenation for 2009 influenza A(H1N1) acute respiratory 17. Hsiao CH, Wu MZ, Chen CL, Hsueh PR, Hsieh SW, Yang distress syndrome. JAMA. 2009;302(17): 1888–95. PC, Su IJ. Evolution of pulmonary pathology in severe 9. Gong MN, Bajwa EK, Thompson BT, Christiani DC. acute respiratory syndrome. J Formos Med Assoc. Body mass index is associated with the development of 2005;104(2): 75–81. 416 The Clinical Respiratory Journal (2014) � ISSN 1752-6981 © 2013 John Wiley & Sons Ltd

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Published: Jan 10, 2014

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