PLoS ONE: Clinical = Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A = (H5N1) Virus Infection in China

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Clinical Characteristics of = 26 Human=20 Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in=20 China

Hongjie Yu¹^#,=20 Zhancheng Gao²^#^*,=20 Zijian Feng¹^#,=20 Yuelong Shu³^#,=20 Nijuan Xiang¹,=20 Lei Zhou¹,=20 Yang Huai¹,=20 Luzhao Feng¹,=20 Zhibin Peng¹,=20 Zhongjie Li¹,=20 Cuiling Xu³,=20 Junhua Li⁴,=20 Chengping Hu⁵,=20 Qun Li⁶,=20 Xiaoling Xu⁷,=20 Xuecheng Liu⁸,=20 Zigui Liu⁹,=20 Longshan Xu¹⁰,=20 Yusheng Chen¹¹,=20 Huiming Luo¹²,=20 Liping Wei¹³,=20 Xianfeng Zhang¹⁴,=20 Jianbao Xin¹⁵,=20 Junqiao Guo¹⁶,=20 Qiuyue Wang¹⁷,=20 Zhengan Yuan¹⁸,=20 Longnv Zhou¹⁹,=20 Kunzhao Zhang²⁰,=20 Wei Zhang²¹,=20 Jinye Yang²²,=20 Xiaoning Zhong²³,=20 Shichang Xia²⁴,=20 Lanjuan Li²⁵,=20 Jinquan Cheng²⁶,=20 Erdang Ma²⁷,=20 Pingping He²⁸,=20 Shui Shan Lee²⁹,=20 Yu Wang¹,=20 Timothy M. Uyeki³⁰,=20 Weizhong Yang¹^*

1 Office for Disease Control and = Emergency=20 Response, Chinese Center for Disease Control and Prevention (China CDC), = Beijing, China, 2 = Department of=20 Respiratory Medicine, Peking University People's Hospital, Beijing, = China, 3 State Key Laboratory for = Infectious=20 Disease Prevention and Control, National Institute for Viral Disease = Control and=20 Prevention, China CDC, Beijing, China, 4 Hunan Provincial Center for Disease = Control and=20 Prevention, Changsha, China, 5 Xiang=20 Ya Hospital of Central South University, Changsha, China, 6 Anhui Provincial Center for Disease = Control and=20 Prevention, Hefei, China, 7 Anhui=20 Provincial Hospital, Hefei, China, 8=20 Sichuan Provincial Center for Disease Control and Prevention, Chengdu, = China, 9 Huaxi Hospital, Sichuan = University,=20 Chengdu, China, 10 = Fujian Provincial=20 Center for Disease Control and Prevention, Fuzhou, China, 11 Fujian Provincial Hospital, Fuzhou, = China, 12 Guangdong Provincial = Center for=20 Disease Control and Prevention, Guangzhou, China, 13 Third Affiliated Hospital, = Guangzhou Medical=20 College, Guangzhou, China, 14 Hubei=20 Provincial Center for Disease Control and Prevention, Wuhan, China, 15 Hankou Union Hospital, Hubei = Province, Wuhan,=20 China, 16 Liaoning = Provincial Center=20 for Disease Control and Prevention, Shenyang, China, 17 First Affiliated Hospital, China = Medical=20 University, Shenyang, China, 18=20 Shanghai Center for Disease Control and Prevention, Shanghai, China, 19 Ninth Affiliated Hospital, Shanghai = Transportation University, Shanghai, China, 20 Jiangxi Provincial Center for = Disease Control=20 and Prevention, Nanchang, China, 21=20 First Affiliated Hospital, Nanchang University, Nanchang, China, 22 Guangxi Provincial Center for = Disease Control=20 and Prevention, Nanning, China, 23=20 First Affiliated Hospital, Guangxi Medical University, Nanning, China, = 24 Zhejiang Provincial = Center for=20 Disease Control and Prevention, Hangzhou, China, 25 First Affiliated Hospital, Zhejiang = University, Hangzhou, China, 26=20 Shenzhen Center for Disease Control and Prevention, Shenzhen, China, 27 Xinjiang Uygur Autonomous Region = Center for=20 Disease Control and Prevention, Urumqi, China, 28 Department of Epidemiology and = Biostatistics=20 School of Public Health, Health Science Center, Peking University, = Beijing,=20 China, 29 Centre for = Emerging=20 Infectious Diseases, Chinese University of Hong Kong, Hong Kong Special=20 Administrative Region, China, 30=20 Influenza Division, National Center for Immunization and Respiratory = Diseases,=20 Centers for Disease Control and Prevention, Atlanta, Georgia, United = States of=20 America

Abstract
Background While=20 human cases of highly pathogenic avian influenza A (H5N1) virus = infection=20 continue to increase globally, available clinical data on H5N1 cases are = limited. We conducted a retrospective study of 26 confirmed human H5N1 = cases=20 identified through surveillance in China from October 2005 through April = 2008.
Methodology/Principal=20 Findings Data=20 were collected from hospital medical records of H5N1 cases and analyzed. = The=20 median age was 29 years (range 6=E2=80=9362) and 58% were female. Many = H5N1 cases=20 reported fever (92%) and cough (58%) at illness onset, and had lower = respiratory=20 findings of tachypnea and dyspnea at admission. All cases progressed = rapidly to=20 bilateral pneumonia. Clinical complications included acute respiratory = distress=20 syndrome (ARDS, 81%), cardiac failure (50%), elevated aminotransaminases = (43%),=20 and renal dysfunction (17%). Fatal cases had a lower median nadir = platelet count=20 (64.5=C3=9710⁹ cells/L vs 93.0=C3=9710⁹ = cells/L, p =3D 0.02),=20 higher median peak lactic dehydrogenase (LDH) level (1982.5 U/L = vs 1230.0=20 U/L, p =3D 0.001), higher percentage of ARDS (94% [n =3D 16] vs = 56% [n =3D 5],=20 p =3D 0.034) and more frequent cardiac failure (71% [n =3D 12] vs = 11% [n =3D=20 1], p =3D 0.011) than nonfatal cases. A higher proportion of patients = who received=20 antiviral drugs survived compared to untreated (67% [8/12] vs 7% = [1/14],=20 p =3D 0.003).
Conclusions/Significance The=20 clinical course of Chinese H5N1 cases is characterized by fever and = cough=20 initially, with rapid progression to lower respiratory disease. = Decreased=20 platelet count, elevated LDH level, ARDS and cardiac failure were = associated=20 with fatal outcomes. Clinical management of H5N1 cases should be = standardized in=20 China to include early antiviral treatment for suspected H5N1 = cases.

Citation: Yu H, Gao Z, Feng Z, Shu Y, Xiang N, et = al. (2008)=20 Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian = Influenza=20 A (H5N1) Virus Infection in China. PLoS ONE 3(8): e2985.=20 doi:10.1371/journal.pone.0002985

Editor: Joel Mark Montgomery, U.S. Naval Medical = Research=20 Center Detachment/Centers for Disease Control, United States of = America

Received: January 24, 2008; = Accepted: July=20 19, 2008; Published: August 21, 2008

This is an open-access article distributed under the terms of the = Creative=20 Commons Public Domain declaration which stipulates that, once placed in = the=20 public domain, this work may be freely reproduced, distributed, = transmitted,=20 modified, built upon, or otherwise used by anyone for any lawful = purpose.

Funding: This study was supported by grants from the = Ministry of Science and Technology of China (2004BA519A17, 2004BA519A71 = and=20 2006BAD06A02), and the China-U.S. Collaborative Program on Emerging and=20 Re-emerging Infectious Diseases. The funders had no role in study = design, data=20 collection and analysis, decision to publish, or preparation of the=20 manuscript.

Competing interests: The authors have declared that = no=20 competing interests exist.

* E-mail: gaozhancheng5446@163.com = (ZG); yangwz@chinacdc.cn (WY)

# These authors contributed equally to = this work.=20

Introduction As=20 of July 13, 2008, 385 confirmed human cases of infection with highly = pathogenic=20 avian influenza A (H5N1) virus with 243 deaths had been reported from 15 = countries since November, 2003 [1].=20 Although largely a panzoonotic among poultry and wild birds, = avian-to-human=20 transmission of H5N1 virus has resulted in most human cases [2],=20 with rare instances of limited, non-sustained human-to-human H5N1 virus=20 transmission [3]=E2=80=93[5].=20 The continuing propagation of highly pathogenic H5N1 viruses among = poultry [6]=20 and migratory birds [7],=20 [8]=20 poses a continuing and potentially escalating threat to human = populations.=20 Preparedness for a possible H5N1 pandemic requires not only enhanced = prevention=20 efforts but also a heightened awareness of the clinical characteristics = of H5N1=20 cases among physicians.
To=20 date, limited H5N1 clinical data are available in case reports and = limited case=20 series from Hong Kong Special Administrative Region (SAR), China in 1997 = [9]=20 and 2003 [10],=20 and Vietnam [11],=20 [12],=20 Thailand [13]=E2=80=93[15],=20 Indonesia [4],=20 [16],=20 Cambodia [17],=20 Azerbaijan [18],=20 [19],=20 and Turkey [20]=20 during 2004=E2=80=932006. These observational studies described = symptoms, signs, and=20 laboratory findings at hospital admission. Few data are available on the = clinical characteristics of cases throughout the course of H5N1 disease. = Data on=20 the natural history of H5N1 disease may allow risk stratification and=20 identification of prognostic factors for outcomes of H5N1 virus = infection. We=20 describe the natural history and report the clinical characteristics at = illness=20 onset, hospital admission, and throughout hospitalization for 26 H5N1 = cases=20 identified by surveillance between October 2005 and April = 2008.

Methods National=20 surveillance system and case definitions In=20 China, all suspected H5N1 cases are reported to the Chinese Center for = Disease=20 Control and Prevention (China CDC, Beijing, China) through a national=20 surveillance system, which is based upon reporting of hospitalized cases = of=20 pneumonia of unknown origin, and by enhanced 1-month surveillance for = cases of=20 influenza-like illness at all health-care facilities within a 3-km = radius after=20 the occurrence of a suspected or confirmed H5N1 poultry outbreak with = high bird=20 mortality.
A=20 case of pneumonia of unknown origin was defined as a patient with all of = the=20 following criteria without specific laboratory diagnosis: fever = (temperature=20 =E2=89=A538=C2=B0C); radiological evidence of pneumonia or acute = respiratory distress=20 syndrome (ARDS); normal white blood cell count (WBC; range = 4=E2=80=9310=C3=9710⁹=20 cells per L), leukopenia (WBC <4=C3=9710⁹ cells per L), or = lymphopenia=20 (lymphocyte count <0.8=C3=9710⁹ cells per L) at clinical = presentation;=20 and absence of clinical improvement after treatment with broad-spectrum=20 antibiotics. A case of influenza-like illness was defined as a patient = with=20 fever (temperature =E2=89=A538=C2=B0C) and cough or sore throat, in the = absence of any other=20 confirmed diagnosis.
A=20 confirmed case of H5N1 was defined as a patient with pneumonia or = influenza-like=20 illness and laboratory evidence of H5N1 virus infection diagnosed by = viral=20 isolation or reverse transcriptase (RT) PCR by testing respiratory = specimens, or=20 a four-fold or greater increase in H5N1 antibody titre in paired acute = and=20 convalescent sera.
Case-patients All=20 suspected H5N1 case-patients were interviewed by staff of the local CDC, = and=20 respiratory specimens, and acute- and convalescent-phase sera were = obtained if=20 available for laboratory investigations following the WHO protocol [21].=20 Respiratory specimens were tested by conventional [22]=20 and real-time RT-PCR [23]=20 to detect H5-specific viral RNA in biosafety level (BSL) 2 facilities at = the=20 National Influenza Center (NIC) of China CDC, and were inoculated into = amniotic=20 and/or allantoic cavities of specific pathogen free (SPF) embryonated = chicken=20 eggs for viral isolation [24]=20 in enhanced BSL 3 facilities at the NIC. H5N1 antibody testing was = performed on=20 sera at the NIC by microneutralization (MN) assay [25]=20 in a BSL-3 laboratory, and modified hemagglutination-inhibition (HI) = assay using=20 horse red blood cells [26]=20 in BSL-2 conditions.
In=20 mainland China, 30 confirmed human H5N1 cases have been identified to = date. We=20 included 26 laboratory-confirmed H5N1 cases identified by surveillance = in 12=20 provinces in China between October 2005 and April 2008. Our analyses = included=20 limited data from 2 case reports [27],=20 [28]=20 and 6 urban cases reported previously in a brief epidemiological = dispatch [29].=20 Of the 26 cases, H5N1 virus infection was confirmed by both virus = isolation and=20 RT-PCR in 20 (77%) cases, one (4%) case by virus isolation only, three = (11%) by=20 RT-PCR and serology, and two (8%) by serology only. Twenty-four cases in = southern China were infected with clade 2.3.4 H5N1 viruses, and two = cases from=20 northern China had clade 2.2 H5N1 virus infections [2].=20 We excluded four H5N1 cases, including 2 military cases with unavailable = clinical data and 2 cases in a cluster with limited person-to-person=20 transmission reported elsewhere [5].
Clinical=20 investigations A=20 trained team from the China CDC interviewed all confirmed H5N1 cases or = their=20 proxies, and collected clinical data through review of hospital medical = records.=20 A standardized form was used to collect information on demographic=20 characteristics and clinical data, including clinical findings, blood = chemistry=20 testing and chest radiograph results performed during clinical = management,=20 complications, treatments, and outcomes. Data were collected during = field=20 investigations by China CDC staff, and was part of a continuing = public-health=20 outbreak investigation and determined by the Ministry of Health to be = exempt=20 from institutional review board assessment in China.
We=20 used the following definitions: cardiac failure was defined as requiring = use of=20 inotropic agents; respiratory failure was defined as the need for = assisted=20 ventilatiory support; ARDS was defined as clinical deterioration with = severe=20 arterial hypoxaemia and diffuse bilateral infiltrates on chest = radiograph;=20 disseminated intravenous coagulation (DIC) was defined as elevated = prothrombin=20 time (PT) with elevated activated partial thromboplastin time (APTT), = and=20 decreased fibrinogen (FIB) level with thrombocytopenia; liver function=20 impairment was defined as aminotransferase (ALT or AST) levels =E2=89=A5 = 2=C3=97 upper range=20 of normal values; renal dysfunction was defined as creatinine level=20 >178mmol/L for adults or =E2=89=A5 2=C3=97 upper limit of normal for = age. High-dose=20 corticosteroid use was defined as =E2=89=A5250 mg hydrocortisone or = equivalent=20 intravenous (IV) administration daily. For children <13 years old, = high-dose=20 corticosteroid use was defined as =E2=89=A55 mg hydrocortisone or = equivalent=20 IV/kg/day.
Statistical=20 analysis Medians=20 and interquartile ranges (IQRs) were calculated for continuous = variables, and=20 compared between fatal and nonfatal cases using Wilcoxon rank sum test. = For=20 categorical variables, percentages of case-patients in each category = were=20 compared using Fisher's exact test. Fatal cases were compared to = nonfatal cases=20 by demographic characteristics, H5N1 virus clade, underlying medical = conditions,=20 medical care practices, haematological and biochemical markers at = admission or=20 during hospitalization, clinical complications, and treatments, in the = bivariate=20 analyses using logistic regression. All statistical tests were two-sided = with a=20 significance level set at =CE=B1 =3D 0.05. Data were analyzed = with SPSS (version=20 13.0, SPSS Inc, Chicago, IL, USA).

Results Twenty-six=20 confirmed H5N1 cases had illness onset beginning in October, 2005 = through=20 February 2008. The median age of the 26 cases was 29 years (range = 6=E2=80=9362) and 58%=20 were female. Five (19%) were children aged <10 years old, one (4%) = was 16=20 years old, and 20 (77%) were adults aged >18 years.
Clinical=20 presentation The=20 earliest reported symptoms and signs of 26 patients at illness onset and = noted=20 at hospital admission are shown in Table=20 1. Many patients reported fever (92%) or cough (58%) initially, but = very few=20 reported upper respiratory symptoms such as rhinorrhea or sore throat. = All=20 patients developed cough a median of 1 day (IQR 1=E2=80=933) from = illness onset, and 85%=20 had sputum production a median of 3 days (IQR 1=E2=80=935.3) after = illness onset. Lower=20 respiratory tract signs and symptoms such as tachypnea and dyspnea = increased=20 substantially from illness onset to hospital admission. Most patients = (88%) had=20 tachypnea a median of 5 days (IQR 4=E2=80=937) from illness onset and = 46% reported=20 dyspnea a median of 6.5 days (IQR 4.5=E2=80=938.5) from illness onset. = Diarrhea was=20 reported in only one adult case at illness onset, and in two cases at = hospital=20 admission, but developed in six patients (one child and five adults) = after=20 hospitalization. The duration of diarrhea in these nine (35%) cases was = a median=20 of 1 day (IQR 1=E2=80=934).

Table=20 1. Signs=20 and symptoms of 26 H5N1 cases at illness onset and at hospital = admission,=20 China.

All=20 case-patients had abnormal chest radiographs at admission; unilateral or = bilateral infiltrates were observed in 10 (38%) and 16 (62%) = case-patients, at a=20 median of 6.5 days (IQR 4=E2=80=937.3) and 7.5 days (IQR 6.3=E2=80=939) = from illness onset,=20 respectively. The 10 case-patients with unilateral infiltrates at = admission all=20 developed bilateral pneumonia (Table=20 2). Chest radiographs showing rapid progression from unilateral to = bilateral=20 pulmonary infiltrates and ARDS in adult and paediatric cases are shown = in Figure=20 1. Radiographic findings included patchy or diffuse infiltrates or=20 consolidation with air bronchograms in multi-segmental or lobular=20 distribution.

Figure=20 1. doi:10.1371/journal.pone.0002985.g001

Table=20 2. Initial=20 chest radiographic findings and progression during hospitalization of 26 = H5N1=20 cases, China.

Laboratory=20 findings Laboratory=20 findings on initial testing, at admission and during hospitalization are = shown=20 in Table=20 3. The prevalence of patients with abnormal haematological findings = at=20 admission [leukopenia (46%), lymphopenia (62%), and moderate = thrombocytopenia=20 (50%)] increased to 92%, 89% and 73%, respectively, during = hospitalization. At=20 admission, the median leukocyte count was 3.5=C3=9710⁹ = cells/L (IQR=20 2.3=E2=80=934.5) and median lymphocyte count was 0.6=C3=9710⁹ = cells/L (IQR=20 0.4=E2=80=931.0). These declined during hospitalization to a median = leukocyte count of=20 2.3=C3=9710⁹ cells/L (IQR 1.5=E2=80=932.8) and median = lymphocyte count of=20 0.3=C3=9710⁹ cells/L (IQR 0.3=E2=80=930.5), after a median of = 8.0 days.

Table=20 3. Laboratory=20 findings of 26 H5N1 cases^* on = initial=20 testing, at hospital admission, and during hospitalization,=20 China.

Abnormal=20 percentage, peak measurement and median days from illness onset of = biochemical=20 markers on initial testing, at hospital admission, and during = hospitalization=20 are shown in Table=20 3. Elevated ALT, AST, creatine kinase (CK), creatine phosphokinase=20 isoenzymes (CPK), lactic dehydrogenase (LDH), and plasma glucose = concentration,=20 and decreased albumin levels were observed in more than half of cases at = admission, and developed in nearly all cases during hospitalization. = Elevated=20 creatine level was observed in 25% of cases during hospitalization. = Seventeen=20 (77%) cases developed proteinuria at a median of 9.0 days (IQR = 7.0=E2=80=9311) after=20 illness onset.

Treatment All=20 cases received empiric treatment with broad-spectrum antibiotics during=20 hospitalization, including ceftriaxone (n =3D 6), moxifloxacin (n =3D 8) = and=20 azithromycin (n =3D 15). Corticosteroids (median methylprednisolone = dosage 1.6 [1]=E2=80=93[5]=20 mg/kg per day IV) were initiated at a median of 6.5 days (IQR = 6.0=E2=80=938.0) from=20 illness onset and administered to 24 (92%) cases for a median of 6 days = (IQR=20 3=E2=80=9313). Of these, 21 (88%) received high-dose = corticosteroids.

Four=20 children received late antiviral treatment. One was treated with = amantadine (100=20 mg per os (po) twice daily (BID) on illness days 10=E2=80=9315) and = ribavirin (200 mg=20 IV/d on illness days 9=E2=80=9316), and one received rimantadine (100 mg = po each day=20 (qD) on illness days 9=E2=80=9311); both cases survived. One child = received oseltamivir=20 (37.5 mg po BID) on illness days 12=E2=80=9314, and one child was = treated with=20 oseltamivir (40 mg po qD) on illness day 10; both died. Eight adults = received=20 late oseltamivir treatment, including two fatal cases =E2=80=93 one = received 75 mg po=20 BID on illness days 8=E2=80=9311, and one received both oseltamivir = (75mg po BID on=20 illness days 11=E2=80=9320) and rimantadine (200mg po qD on illness day = 11). Six adults=20 treated with oseltamivir survived: one was treated with 75 mg/day on = illness=20 days 8=E2=80=9312, four received 75 mg BID on illness days 4=E2=80=9311, = illness days 8=E2=80=9314,=20 illness days 10=E2=80=9314, and illness days 8=E2=80=9312, respectively, = and one was treated=20 with 75mg BID and amantadine (100 mg po BID) on illness days = 8=E2=80=9312.

Two=20 critically ill adult H5N1 cases (31-year-old male, 44-year-old female) = with ARDS=20 were treated with convalescent plasma obtained from one of two fully = recovered=20 H5N1 adult donor cases. Plasma was obtained 129 days after illness onset = from an=20 adult female case and 81 days after illness onset from an adult male = case. Both=20 donors' convalescent plasma tested negative for hepatitis B, hepatitis = C, and=20 HIV, and were separated and heat-inactivated at 56=C2=B0C for 10 h = before=20 transfusion. The male ARDS case received three units (200 mL/unit) of = transfused=20 convalescent plasma from the female donor for 2 days, beginning on = illness day=20 13. His H5N1 viral titre in bronchial-alveolar lavage fluid declined=20 substantially and was undetectable for the next 3 consecutive days after = receipt=20 of the third convalescent plasma dose. The female ARDS case, who had a = history=20 of bronchiectasis, received one unit (200 mL) of transfused convalescent = plasma=20 from the male donor once daily for 3 days, starting on illness day 13. = Further=20 virological testing has not been done for this case. Both cases also = received=20 oseltamivir (75 mg po BID) on illness days 10=E2=80=9314 and days = 8=E2=80=9312, respectively.=20 Both cases recovered fully and were discharged home.

Complications=20 and outcomes Twenty-three=20 (88%) cases required ventilatory support for respiratory failure. ARDS = developed=20 in 21 (81%) cases at a median of 8 days (IQR 7=E2=80=939) after illness = onset. Liver=20 function impairment, renal dysfunction and cardiac failure occurred in 9 = (43%),=20 4 (17%) and 13 (50%) patients.

Seventeen=20 (65%) cases died (2 children, 1 adolescent and 14 adults), including one = pregnant woman at 4 months' gestation [28]=20 after a median of 10 days (IQR 8=E2=80=9320.5). Nine (35%) nonfatal = cases were=20 discharged at a median of 41 days (IQR 31.5=E2=80=9364.0) after illness = onset. Five=20 (24%) of the 21 cases with ARDS survived, including one pregnant woman, = two=20 adults who received convalescent H5N1 plasma, and two other previously = healthy=20 adults. The pregnant woman survived after developing ARDS and = experiencing a=20 spontaneous abortion during mechanical ventilation. Her pulmonary status = subsequently improved and her temperature normalised quickly; the = patient was=20 extubated and recovered completely. All 17 fatal cases had multi-organ = failure,=20 including respiratory failure (94%), cardiac failure (71%), renal = failure (27%)=20 and 24% had disseminated intravenous coagulation (Table=20 4).

Table=20 4. Comparison=20 of demographic and clinical features of 17 fatal and 9 nonfatal H5N1 = cases,=20 China.

In=20 the bivariate analyses, demographic characteristics, year of illness = onset,=20 clade of H5N1 virus infection, and underlying medical conditions were = similar=20 between fatal and nonfatal cases (Table=20 4). Fatal cases had significantly lower median nadir platelet count = during=20 hospitalization (64.5=C3=9710⁹ cells/L vs = 93.0=C3=9710⁹=20 cells/L, p =3D 0.02), higher median peak LDH level during = hospitalization (1982.5=20 U/L vs 1230.0 U/L, p =3D 0.001), higher frequency of ARDS (94% [n = =3D 16]=20 vs 56% [5],=20 p =3D 0.034), more frequent cardiac failure (71% [n =3D 12] vs = 11% [1],=20 p =3D 0.011), and shorter median duration of corticosteroid therapy (4.0 = days=20 vs 12.0 days, p =3D 0.025) compared to cases that survived. A = higher=20 proportion of cases survived that received any antiviral treatment = compared to=20 those that did not receive antivirals (67% [8/12 patients] vs 7% = [1/14=20 patients], p =3D 0.003), with a positive correlation between antiviral = therapy and=20 disease outcome (Gamma coefficient =3D 0.664, p =3D 0.005).

Discussion Our=20 findings suggest that H5N1 disease in Chinese patients generally begins = with=20 fever, cough, and sputum production, and progresses rapidly to lower = respiratory=20 disease. Upper respiratory symptoms of rhinorrhea and sore throat were = less=20 common in China than observed in Hong Kong SAR, China [9],=20 Thailand [13],=20 Turkey [21],=20 Azerbaijan [18],=20 and Egypt [2].=20 Studies suggest that the lower respiratory tract is the major site for = H5N1=20 viral replication, although initial infection may occur in either the = upper or=20 lower respiratory tract [30]=E2=80=93[33].

Diarrhea=20 was present in only two H5N1 cases at admission, but developed in a = quarter of=20 cases during hospitalization. Diarrhea was a common presenting symptom = among=20 H5N1 cases in Vietnam [11],=20 [12]=20 and Thailand [13],=20 but was reported infrequently among cases in Hong Kong SAR, China [9],=20 [10],=20 and Indonesia [4],=20 [16].=20 H5N1 virus and viral RNA have been detected in feces and intestines of = human=20 H5N1 cases [12],=20 [17],=20 [30],=20 [33].=20 Whether the gastrointestinal tract is a primary site for H5N1 virus = infection is=20 currently unknown.

Disease=20 course in Chinese H5N1 cases was rapidly progressive; the median time = from=20 illness onset to death in our case series is consistent with WHO = findings [2].=20 All H5N1 cases presented with pulmonary infiltrates, and all cases = progressed=20 rapidly to bilateral disease. Many cases experienced respiratory = failure, ARDS,=20 and multi-organ failure, with hepatic dysfunction and cardiac failure.=20 Leukopenia and lymphopenia were also common. A recent molecular = pathology study=20 on two cases documented that in addition to the lungs, H5N1 virus = infects the=20 trachea and disseminates to other organs including the brain [30].=20 Our findings are consistent with other reports [11]=E2=80=93[20].=20 The pathogenesis of some clinical complications could be immunologically = mediated, as suggested by high levels of proinflammatory cytokines and=20 chemokines in vitro and cytokine dysregulation in fatal cases in = observational=20 studies [10],=20 [33],=20 [34].

Five=20 H5N1 cases were younger than 10 years old and one was aged 16-years, in = contrast=20 to other case series [16],=20 [19]=E2=80=93[20]=20 and the WHO finding that the highest frequency of cases was aged = 10=E2=80=9319 years old=20 [35].=20 The age profile of Chinese H5N1 cases may reflect exposure differences = due to=20 traditional social and cultural behaviours. Visiting wet poultry markets = in=20 urban areas and exposure to sick or dead backyard poultry in rural areas = before=20 illness onset are H5N1 risk factors in China (unpublished data, China = CDC).=20 Paediatric cases lived in rural areas of China, and likely had more = exposures to=20 sick/dead backyard poultry than children in urban areas. In rural areas, = young=20 Chinese children are much more likely to play with backyard poultry than = older=20 children. Adults are much more likely to visit poultry markets in urban = areas of=20 China than children and all urban adult H5N1 cases had visited a wet = poultry=20 market prior to illness onset (unpublished data, China CDC).

In=20 contrast to the WHO finding that cases aged 10=E2=80=9319 years old had = the highest=20 case-fatality [2],=20 mortality of H5N1 cases in China was not associated with median age, sex = or=20 underlying medical conditions in the bivariate analysis. Isolates from = 24 cases=20 in southern China were characterized as H5N1 clade 2.3.4 viruses with = consistent=20 genetic and antigenic properties from 2005 through 2008 (unpublished = data, China=20 CDC). There were no significant differences in case-fatality ratios = between=20 years during 2005=E2=80=932008 or between cases with clade 2.2 and clade = 2.3.4 H5N1=20 virus infection. However, fatal outcomes were associated with decreased = platelet=20 counts, increased LDH, ARDS, cardiac failure, and lack of antiviral = treatment in=20 the bivariate analyses. In Thailand [13]=20 and Hong Kong SAR [9],=20 mortality was associated with late presentation, lower admission = leukocyte,=20 platelet, and lymphocyte counts, bilateral pulmonary findings on chest = X-ray,=20 and development of ARDS. Decreased leukocyte and lymphocyte counts, and=20 increased d-dimer levels were associated with fatal outcomes in other = studies [4],=20 [17],=20 [20],=20 [33].

Survival=20 was significantly higher in cases that received any antiviral treatment = than in=20 untreated cases, and 5 of 8 adult cases that received standard = oseltamivir=20 treatment survived even though all were treated late in their illnesses. = However, it should be noted that treatment was uncontrolled and our = findings=20 lack sequential virological data on antiviral susceptibilities or = quantitative=20 H5N1 viral shedding, and favorable outcomes and clinical courses of some = H5N1=20 cases cannot be attributed definitively to antiviral treatment. In = contrast to=20 clade 1 H5N1 viruses isolated in Vietnam and clade 2.1 viruses in = Indonesia [2],=20 the clade 2.3.4 and clade 2.2 H5N1 viruses isolated from cases in China = were=20 susceptible to both M2 inhibitors and neuraminidase inhibitors = (unpublished=20 data, China CDC). These findings suggest roles for either class of = antiviral=20 drugs as well as combination antiviral therapy for H5N1 cases in China = [36],=20 [37].

Very=20 few Chinese H5N1 cases received early antiviral treatment because only = one=20 patient was admitted within two days of illness onset, and no patients = received=20 outpatient antiviral treatment. Antivirals were not administrated to = most=20 Chinese H5N1 cases until they were hospitalized with pneumonia. = Oseltamivir was=20 not available in some hospitals for treatment of some cases that died.=20 Therefore, education of health-care providers about the epidemiological = risk=20 factors and clinical characteristics of H5N1 patients, and wider = availability of=20 antiviral drugs could help facilitate earlier detection and treatment of = H5N1=20 cases in China. Although little data on early versus late oseltamivir = treatment=20 for H5N1 patients are available, current WHO guidance recommends = initiating=20 oseltamivir treatment as early as possible, including consideration of = higher=20 dosing for severe disease and longer treatment duration because of = prolonged=20 viral replication [37].

Although=20 antiviral therapy is the primary treatment, most clinical management of = H5N1=20 disease is supportive. For severely ill Chinese H5N1 patients with ARDS = or=20 multiorgan failure, management has focused on appropriate mechanical=20 ventilation, correction of hypoxemia, fluid management, and treatment of = other=20 complications such as DIC. Corticosteroids were administered empirically = to most=20 H5N1 cases in China. A reduction in the proportion of cases reporting = with fever=20 from illness onset (92%) to hospital admission (69%) may reflect an = early use of=20 corticosteroids or non steroidal anti-inflammatory drugs. Compared to = fatal=20 cases, nonfatal cases in China had a longer duration of corticosteroid=20 treatment. However, we cannot conclude that corticosteroid therapy = resulted in=20 survival and such treatment has not been shown to be effective in H5N1 = patients=20 [2].=20 Furthermore, prolonged or high-dose corticosteroid therapy may result in = serious=20 adverse events, including infection with opportunistic pathogens. Recent = WHO=20 H5N1 treatment guidance recommends against routine use of corticosteroid = treatment [37].

Two=20 cases with ARDS survived after receiving passive immunotherapy with = transfused=20 convalescent plasma from surviving H5N1 cases. This is compelling, but = since=20 passive immunotherapy and other treatments were administered in an = uncontrolled=20 manner, no definitive conclusions can be made about the benefit of such=20 treatment [38].=20 A third Chinese H5N1 case survived after receiving post-vaccination = plasma from=20 an H5N1 vaccine clinical trial participant and combination antiviral = treatment=20 [5].=20 A meta-analysis of studies of convalescent plasma treatment during the = 1918=20 influenza pandemic [39],=20 evidence from animal experiments [40]=E2=80=93[42],=20 and the limited experience in three Chinese H5N1 cases suggest that = passive=20 immunotherapy may be a viable option for the treatment of H5N1. Further = research=20 is needed to investigate the efficacy and effectiveness of passive = immunotherapy=20 with H5N1 convalescent plasma treatment for H5N1 patients, including = cases with=20 severe complications such as ARDS.

Our=20 study was limited to available data for H5N1 cases identified through=20 surveillance during the study period. Due to the small number of H5N1 = cases, the=20 study was too underpowered to compare differences between fatal and = nonfatal=20 cases. National surveillance and laboratory testing might not have = identified=20 all H5N1 cases that occurred, especially if the cases were clinically = mild.=20 Clinical management was uncontrolled, H5N1 viral shedding data, = immunological=20 and pathological data were not available, and any differences in = outcomes cannot=20 be interpreted to be due to the use of antiviral drugs, corticosteroids, = or=20 other uncontrolled treatments.

To=20 improve clinical management of H5N1 patients in China, physicians should = be=20 educated about the natural history of H5N1 disease and epidemiological = risk=20 factors, and therapy should be standardized based upon current knowledge = [37].=20 Early antiviral treatment and expanded testing should be considered for=20 suspected H5N1 patients, with wider availability of antiviral = medications at all=20 health care facilities. In the absence of any definitive treatment for = H5N1,=20 preventive education to reduce risk behaviours for H5N1 exposures (e.g. = avoiding=20 direct contact with sick or dead poultry) must be emphasized more=20 strongly.

Acknowledgments

We=20 thank the provincial health bureaus of Hunan, Anhui, Sichuan, Fujian, = Guangdong,=20 Hubei, Liaoning, Shanghai, Jiangxi, Guangxi, Zhejiang and Xinjiang for=20 assistance in coordinating field investigations and provision logistics = support,=20 and the Ministry of Health in China for generously facilitating this = study. We=20 thank Chin-Kei Lee from the WHO Beijing Office for helping us prepare = the=20 article. The views expressed in this article are those of the authors = and do not=20 represent the official policy of the China CDC or US CDC.

Author Contributions

Wrote the paper: HY = TU. Designed=20 the protocal of investigation, set up the field clinical investigation,=20 contacted all investigators: HY ZG ZF YS WY. Responsible for the virus=20 isolation, microneutralisation, hemagglutination inhibition assay, RT = PCR, and=20 real-time RT PCR testing, including the experimental design and analysis = of=20 data: YS CX. Participated in collection and management of data: NX LZ YH = LF ZP=20 ZL JL CH QL XX XL ZL LX YC HL LW XZ JX JG QW ZY LZ KZ WZ JY XZ SX LL JC = EM PH=20 SSL YW. Provided technical assistance for the clinical investigations = and helped=20 to review the data: TU.

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del._fixKeys(evt);},_fixKeys:function(evt){switch(evt.type){case = "keypress":var c=3D("charCode" in = evt?evt.charCode:evt.keyCode);if(c=3D=3D10){c=3D0;evt.keyCode=3D13;}else{= if(c=3D=3D13||c=3D=3D27){c=3D0;}else{if(c=3D=3D3){c=3D99;}}}evt.charCode=3D= c;del._setKeyChar(evt);break;}return = evt;},_punctMap:{106:42,111:47,186:59,187:43,188:44,189:45,190:46,191:47,= 192:96,219:91,220:92,221:93,222:39},_stealthKeyDown:function(evt){var = kp=3Devt.currentTarget.onkeypress;if(!kp||!kp._listeners){return;}var = k=3Devt.keyCode;var = _1f4=3D(k!=3D13)&&(k!=3D32)&&(k!=3D27)&&(k<48||k>90)&&(k<96||k>111)&&(k<1= 86||k>192)&&(k<219||k>222);if(_1f4||evt.ctrlKey){var = c=3D_1f4?0:k;if(evt.ctrlKey){if(k=3D=3D3||k=3D=3D13){return;}else{if(c>95= &&c<106){c-=3D48;}else{if((!evt.shiftKey)&&(c>=3D65&&c<=3D90)){c+=3D32;}e= lse{c=3Ddel._punctMap[c]||c;}}}}var = faux=3Ddel._synthesizeEvent(evt,{type:"keypress",faux:true,charCode:c});k= 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evt;}});}if(dojo.isSafari){dojo.mixin(del,{_fixEvent:function(evt,_1ff){s= witch(evt.type){case "keypress":var = c=3Devt.charCode,s=3Devt.shiftKey,k=3Devt.keyCode;k=3Dk||_203[evt.keyIden= tifier]||0;if(evt.keyIdentifier=3D=3D"Enter"){c=3D0;}else{if((evt.ctrlKey= )&&(c>0)&&(c<27)){c+=3D96;}else{if(c=3D=3Ddojo.keys.SHIFT_TAB){c=3Ddojo.k= eys.TAB;s=3Dtrue;}else{c=3D(c>=3D32&&c<63232?c:0);}}}return = del._synthesizeEvent(evt,{charCode:c,shiftKey:s,keyCode:k});}return = evt;}});dojo.mixin(dojo.keys,{SHIFT_TAB:25,UP_ARROW:63232,DOWN_ARROW:6323= 3,LEFT_ARROW:63234,RIGHT_ARROW:63235,F1:63236,F2:63237,F3:63238,F4:63239,= F5:63240,F6:63241,F7:63242,F8:63243,F9:63244,F10:63245,F11:63246,F12:6324= 7,PAUSE:63250,DELETE:63272,HOME:63273,END:63275,PAGE_UP:63276,PAGE_DOWN:6= 3277,INSERT:63302,PRINT_SCREEN:63248,SCROLL_LOCK:63249,NUM_LOCK:63289});v= ar = dk=3Ddojo.keys,_203=3D{"Up":dk.UP_ARROW,"Down":dk.DOWN_ARROW,"Left":dk.LE= FT_ARROW,"Right":dk.RIGHT_ARROW,"PageUp":dk.PAGE_UP,"PageDown":dk.PAGE_DO= 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w>=3D0){s.width=3Dw+u;}if(h>=3D0){s.height=3Dh+u;}};dojo._usesBorderBox=3D= function(node){var n=3Dnode.tagName;return = d.boxModel=3D=3D"border-box"||n=3D=3D"TABLE"||n=3D=3D"BUTTON";};dojo._set= ContentSize=3Dfunction(node,_28c,_28d,_28e){if(d._usesBorderBox(node)){va= r = pb=3Dd._getPadBorderExtents(node,_28e);if(_28c>=3D0){_28c+=3Dpb.w;}if(_28= d>=3D0){_28d+=3Dpb.h;}}d._setBox(node,NaN,NaN,_28c,_28d);};dojo._setMargi= nBox=3Dfunction(node,_291,_292,_293,_294,_295){var = s=3D_295||gcs(node);var = bb=3Dd._usesBorderBox(node),pb=3Dbb?_299:d._getPadBorderExtents(node,s),m= b=3Dd._getMarginExtents(node,s);if(_293>=3D0){_293=3DMath.max(_293-pb.w-m= b.w,0);}if(_294>=3D0){_294=3DMath.max(_294-pb.h-mb.h,0);}d._setBox(node,_= 291,_292,_293,_294);};var = _299=3D{l:0,t:0,w:0,h:0};dojo.marginBox=3Dfunction(node,box){var = n=3Dd.byId(node),s=3Dgcs(n),b=3Dbox;return = !b?d._getMarginBox(n,s):d._setMarginBox(n,b.l,b.t,b.w,b.h,s);};dojo.conte= ntBox=3Dfunction(node,box){var = n=3Ddojo.byId(node),s=3Dgcs(n),b=3Dbox;return = !b?d._getContentBox(n,s):d._setContentSize(n,b.w,b.h,s);};var = _2a5=3Dfunction(node,prop){if(!(node=3D(node||0).parentNode)){return = 0;}var = val,_2a9=3D0,_b=3Dd.body();while(node&&node.style){if(gcs(node).position=3D= =3D"fixed"){return = 0;}val=3Dnode[prop];if(val){_2a9+=3Dval-0;if(node=3D=3D_b){break;}}node=3D= node.parentNode;}return _2a9;};dojo._docScroll=3Dfunction(){var = _b=3Dd.body(),_w=3Dd.global,de=3Dd.doc.documentElement;return = {y:(_w.pageYOffset||de.scrollTop||_b.scrollTop||0),x:(_w.pageXOffset||d._= fixIeBiDiScrollLeft(de.scrollLeft)||_b.scrollLeft||0)};};dojo._isBodyLtr=3D= function(){return !("_bodyLtr" in = d)?d._bodyLtr=3Dgcs(d.body()).direction=3D=3D"ltr":d._bodyLtr;};dojo._get= IeDocumentElementOffset=3Dfunction(){var = de=3Dd.doc.documentElement;return = (d.isIE>=3D7)?{x:de.getBoundingClientRect().left,y:de.getBoundingClientRe= ct().top}:{x:d._isBodyLtr()||window.parent=3D=3Dwindow?de.clientLeft:de.o= ffsetWidth-de.clientWidth-de.clientLeft,y:de.clientTop};};dojo._fixIeBiDi= ScrollLeft=3Dfunction(_2af){var = dd=3Dd.doc;if(d.isIE&&!dojo._isBodyLtr()){var = de=3Ddd.compatMode=3D=3D"BackCompat"?dd.body:dd.documentElement;return = _2af+de.clientWidth-de.scrollWidth;}return = _2af;};dojo._abs=3Dfunction(node,_2b3){var _2b4=3Dnode.ownerDocument;var = ret=3D{x:0,y:0};var db=3Dd.body();if(d.isIE||(d.isFF>=3D3)){var = _2b7=3Dnode.getBoundingClientRect();var = _2b8=3D(d.isIE)?d._getIeDocumentElementOffset():{x:0,y:0};ret.x=3D_2b7.le= ft-_2b8.x;ret.y=3D_2b7.top-_2b8.y;}else{if(_2b4["getBoxObjectFor"]){var = bo=3D_2b4.getBoxObjectFor(node),b=3Dd._getBorderExtents(node);ret.x=3Dbo.= x-b.l-_2a5(node,"scrollLeft");ret.y=3Dbo.y-b.t-_2a5(node,"