Chinese Medical Journal 2011;124(11):1662-1666
Sixty-two severe and critical patients with 2009 influenza A (H1N1) in Shanghai, China

LIU Li,  ZHANG Ren-fang,  LU Hong-zhou,  LU Shui-hua,  HUANG Qin,  XIONG Yan-ying,  XI Xiu-hong,  ZHANG Zhi-yong

LIU Li (Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

ZHANG Ren-fang (Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

LU Hong-zhou (Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

LU Shui-hua (Department of Respiratory Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

HUANG Qin (Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

XIONG Yan-ying (Department of Respiratory Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

XI Xiu-hong (Department of Respiratory Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China)

ZHANG Zhi-yong (Department of Radiology, Shanghai Public Health Clinical Center, Shanghai 201508, China)

Correspondence to:LU Hong-zhou,Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai 201508, China (Tel: 86-21-37990333. Fax:86-21-57248758. E-mail:luhongzhou@fudan.edu.cn)
Keywords
influenza A virus, H1N1 subtype; critical cases; pneumonia
Abstract
Background  Pandemic influenza A (H1N1) emerged rapidly in China in May 2009. Preliminary comparisons with seasonal influenza suggest that pandemic 2009 influenza A (H1N1) disproportionately affects younger ages and causes generally mild disease. To characterize disease progress, comorbidities, and treatment outcomes among consecutive severe and critically ill patients in a hospital served as a reference center for the care of patients with H1N1 in Shanghai, China.
Methods  A retrospective study on 62 severe and critically ill patients with 2009 influenza A (H1N1) was conducted in Shanghai Public Health Clinical Center. Demographic data, symptoms, comorbidities, disease progression, treatments, and clinical outcomes were collected for analysis.
Results  Sixty-two severe or critically ill patients were admitted to the hospital with confirmed 2009 influenza A (H1N1) infection. The median age of the study cohort was 40 years old with a range from 18 years to 75 years, and 67.7% were males. All patients presented with fever and respiratory symptoms. At presentation, 34 patients (54.8%) had comorbidities such as smoking (29.0%), hypertension (29.0%) and hepatitis B virus infection (9.7%). The median time from symptom onset to hospital admission was 6 days (interquartile-range 3–14 days) and 23 critically ill patients were admitted to Intensive Care Unit after admission. All the patients received neuraminidase inhibitors (oseltaminir), while 60 patients (96.7%) were treated with antibiotics, and 39 (62.9%) with corticosteroids. Twenty-three critical cases received noninvasive mechanical ventilation on the first day of admission, and 3 of them ultimately required invasive ventilation. Four death reports (6.5%) were filed within the first 14 days from the onset of critical illness with the primary causes of severe acute respiratory distress syndrome, hypoxemia, or complications, secondary infection and sepsis, pyopneumothorax and stroke.
Conclusions  Severe illness from 2009 influenza A (H1N1) infection in Shanghai occurred among young individuals. Critical cases were associated with severe hypoxemia, multisystem organ failure, and a requirement for mechanical ventilation. Most patients had a good prognosis.
Although initial reports suggested that illness associated with pandemic 2009 influenza A (H1N1) infection might be mild compared with the 1918 influenza pandemic, data on the clinical features and populations at risk of complications from H1N1 infection are still emerging. Since May 10, 2009, the first case of H1N1 infection reported in China, the H1N1 virus has rapidly spread throughout the country with a total of 4328 cases reported by the end of 2009. The first life-threatening critical case was reported in Guangzhou in southern China on August 13, 2009. Since then the critical illness from H1N1 infection has resulted with 326 deaths in China until December 7, 2009.1 By December 21, 2009, there have been 2717 cases reported in Shanghai, the largest city in China, with 81 critical cases and six deaths.2
 
On October 12, 2009, a new edition of diagnosis and treatment guideline of influenza A (H1N1) was published by the Ministry of Health in China to define the criterion of diagnosis and treatment of H1N1 infection.3 We conducted a retrospective study in Shanghai Public Health Clinical Center, a national reference center in Shanghai, on 62 patients who developed severe or critical illness from confirmed H1N1 infection. The objectives of the present study was to help the early identification of individuals at risk of becoming critically ill who may benefit from targeted interventions including vaccination and antiviral therapy, to determine the pandemic health care resource planning, and to provide H1N1-associated morbidity and mortality data in different jurisdictions and in disease virulence over time.4
 
METHODS
 
We retrospectively studied 62 severe and critically ill patients with confirmed H1N1 infection, defined as positive by specific PCR for H1N1 virus in Shanghai, China admitted between November 11, 2009, and January 5, 2010 to our hospital, a national reference center for the care of patients with influenza A (H1N1). For all cases, data including demographics, race/ethnicity, clinical presentation and course, comorbidities, laboratory and radiographic findings, were collected for analysis.
 
We classified patients according to case definition developed by the Ministry of Health of China. The symptoms in severely ill patients included: (1) sustained high fever over 3 days, (2) violent cough with purulent sputum or blood in sputum and chest pain, (3) increased respiratory frequency, dyspnea and cyanosis, (4) altered mental status, such as unresponsiveness, lethargies, restlessness or seizures, (5) severe vomiting or diarrhea with dehydration, (6) signs of pneumonia in chest X-ray or CT scan, (7) rapid increase in cardiac enzymes including creatine kinase (CK) or creatine kinase isoenzyme (CK-MB), and (8) aggravation of basic illness. Critical cases were defined when one of the following condition occurred: (1) respiratory failure, (2) septic shock causing by severe infection, (3) multiple organ dysfunction syndrome, or (4) requirement of intensive care.
 
As a part of the standardized case report form, race/ethnicity data such as nationality were collected from the medical records. Comorbidities were considered absent in cases for which records stated that the patient was previously healthy or had no underlying medical conditions or when there was no direct reference to the condition.
 
Descriptive data included frequency analysis (percentages) for categorical variables and mean ± standard deviation (SD) or medians and interquartile ranges (IQRs) for continuous variables.
 
RESULTS
 
Between November 11, 2009 and January 31, 2010, 62 severe or critically ill patients were admitted to the hospital with confirmed H1N1 infection. All patients had a median age of 40 years (range 18–75) (Figure). Forty-two patients were males (67.7%) and there were 3 foreign patients. None of these patients were health care workers. There were three pregnant patients. All patients presented with symptoms including fever (62, 100%), respiratory complaints (cough, dyspnea, or wheeze; 62, 100%), generalized weakness (29, 46.8%), and headache (23, 37.1%). Only six patients had gastrointestinal symptoms of nausea, vomiting, or diarrhea. Eighteen patients had blood in their sputum and 11 of them were critically ill (Table 1)
 

view in a new window
Figure. Age distribution of 62 severe patients with confirmed 2009 influenza A (H1N1).
 

view in a new window
Table 1. Characteristics of critically ill patients with confirmed 2009 influenza A (H1N1) infection
 
The median number of comorbid conditions was 1 (IQR 1–3). At presentation, comorbidities were present in 34 patients (54.8%). The most common individual ones were ever smoker (29.0%), hypertension (29.0%) and hepatitis B (9.7%). The median body mass index (BMI) was 26.1 kg/m2 and 14 patients (22.6%) had BMI greater than 30 kg/m2.
 
The median time from symptom onset to hospital admission was 6 days (IQR 3–14 days) and a total of 23 critically ill patients were admitted to the Intensive Care Unit (ICU) after admission. None of the patients had ever received a seasonal influenza or H1N1 vaccination in the past 2 years. All the patients had abnormal chest radiograph or CT scan. Approximately 56.0% patients had bilateral infiltrate with 4-quadrant involvement and the lesions of 19 patients were present in lower lungs. Five patients had pleural effusion at the onset of critical illness. All the patients received oseltaminir, 60 patients (96.7%) were treated with antibiotics, and 39 (62.9%) with corticosteroids.
 
Creatine kinase was mildly elevated on the day 1 of hospitalization in all the patients (median 199 U/L, IQR 54–7708 U/L). The mean leukocyte count was normal at admission and remained in the normal range for the first week. Eighty-five point five percent patients had mildly to moderately elevated alanine transaminase or aspartate transaminase. Six patients had microbiologic evidence of a secondary bacterial infection, confirmed by bacterial cultures from a sterile site (3 blood samples and 3 sputum samples), in whom resulted with 2 death. The pathogens identified were Acinetobacter Baumanni and Methicillin resistant Staphylococcus aureus.
 
In 23 critical cases according to the standard of guideline released by the Ministry of Health of China, moderate dosage of methylprednisolone (3–5 mg/kg) was administered to all the patients for 3 to 5 days. All these patients received noninvasive mechanical ventilation on the first day of admission, and 3 of them ultimately required invasive ventilation. The median (IQR) PaO2 to FiO2 ratio of day 1 of hospitalization was 84 (53–199) mmHg; the median (IQR) FiO2 value of day 1 of hospitalization was 61% (43%–100%) and the median positive end-expiratory pressure (PEEP) of day 1 of hospitalization was 6 cmH2O (Table 2). Pneumothorax occurred in 3 patients receiving noninvasive ventilation with one death. Two patients with invasive ventilation died.
 

view in a new window
Table 2. Organ dysfunctions over time among 23 critically ill patients from day 1 to day 14 of hospitalization
 
Among 4 deaths associated with H1N1 infection within the first 14 days from the onset of critical illness, the primary causes included severe acute respiratory distress syndrome and hypoxemia, or complications, secondary infection and sepsis, pyopneumothorax, and stroke.
 
Fifty-five patients discharged with a mild to moderate abnormal chest CT scan. All these patients took a follow-up chest CT scan 2–3 weeks after discharge. The CT scan of most of these patients (50 of 55) revealed no significant abnormality and only 5 patients had some mild fibrosis lesion.
 
DISCUSSION
 
We retrospectively investigated 62 cases presented in our hospital, a reference center in China, with severe or critical illness from confirmed H1N1. In this study, severe and critical illnesses more likely occurred in young male patients. The histories of smoking and hypertension were the most common comorbidities. Fever and respiratory symptoms such as bloody sputum were harbingers of disease in almost all cases. There was a relatively long period of illness prior to present to the hospital, followed by a short period of acute or severe respiratory deterioration. All cases were in severe conditions at admission and some patients were with moderate to severe oxygenation failure that required for noninvasive or invasive mechanical ventilation. Within 30 days, 4 death (6.5%) cases were reported among these patients.
 
In these data, the median age of patients was similar to that of Canadian patients but older than that of Mexicans. The median age and relatively good health of this critically ill group were different from those with seasonal influenza or severe acute respiratory syndromes (SARS),5 in whom older patients appear more susceptible to severe disease. A potential biological basis for this observation is that patients in this age group have a cross-reactive antibody to H1N1 at much higher rates than younger patients.6
 
The mortality of 6.5% for H1N1 in this study was much lower than the data from other countries such as Mexico and Canada.4,7 The deaths in this study were more directly related to respiratory rather than multiple organ failure. The patients in these 4 death cases were older than 50 years and with comorbidities such as hypertension or diabetes.
 
There was a tendency of female to develop severe H1N1 infection in Canadian and Mexican data; however, most of severe cases in this study were male (76.4%). The difference of male and female susceptibility has not been observed in mild cases with H1N1 infection in China.8 In most infectious diseases and related conditions such as sepsis and septic shock, males represent a larger proportion of cases and have a higher mortality.9,10 The role of pregnancy as a risk factor has been noted in previous influenza pandemics.11,12 There were 3 pregnant women in our patients group, all of whom presented with moderate to severe pneumonia. Two patients in the first trimester took abortion after stabilization of pneumonia and the other in the 37 weeks of pregnancy accepted cesarean immediately after diagnosis confirmed.
 
The most common comorbidities among severely ill patients in our study were a history of smoking, hypertension and diabetes. Unlike other studies, all these comorbidities occurred in a low percentage (about 25%) and only 1 patient in our patients group had lung disease and most of patients were overweight but not obese. The extent to which these comorbidities contribute to severity of disease was unclear because of the limited number of cases. Among critically ill patients, obesity has been shown to be a risk factor for increased morbidity, but not consistently with mortality.13 The association of obesity with severe H1N1 infection has been reported by many others; however, most severely and critically ill patients in our study were overweight but not obese and we did not find a significant difference in BMI between survivors and non-survivors.14,15 The relative absence of serious comorbidities emphasized that relatively healthy adults were the primary population affected by severe H1N1 infection during this outbreak.
 
Patients with H1N1 infection-related severe or critical illness experienced symptoms for an average of 6 days prior to hospital admission, and some rapidly worsened and required care in ICU within 1 to 2 days. The critical cases stood out for the presence of dyspnea, bloody sputum and frothy or purulent sputum on cough. Most of patients demonstrated bilateral mixed interstitial or alveolar infiltrates on their chest radiographs.
 
The certain baseline characteristics of severe or critically ill patients with H1N1 may include elevated creatine kinase and elevated transaminase. Elevated creatine kinase levels and rhabdomyolysis have been previously reported to complicated seasonal influenza, although more commonly in children. Data from Mexico suggested a novel finding of possible worse outcomes among patients presenting with an elevated creatine kinase.4 We could not demonstrate if these factors were associated with increased mortality because only 4 deaths with moderate creatine kinase in our study.
 
One report suggested that severe pulmonary damage occurred as a result of primary viral pneumonia.16 Although direct evidence has not been available, this damage also might be attributable to secondary host immune responses (e.g., through cytokine dysregulation triggered by high viral replication). However, bacterial coinfection in the lung not identified by blood culture or bronchoalveolar lavage cannot be excluded. Only 6 patients (9.7%) had a confirmed evidence of bacterial coinfection in our study group. Although the pulmonary compromise was described in this report, the causes of such damage remained largely unclear.
 
Recent evidence suggests that even if initiated late, antiviral treatment can reduce mortality, and current national guidelines recommended that all hospitalized patients with pandemic H1N1 infection should be treated with a neuraminidase inhibitor at standard dosing (75 mg every 12 hours) as soon as possible, and higher doses (150 mg every 12 hours) and longer duration are needed in severe or critically ill patients. All the patients in our study received antiviral treatment (150 mg every 12 hours) 48 hours after onset of symptoms for 5–7 days. Only three of these patients reported mild gastrointestinal side effect. Considering the limited number of cases we reviewed, additional data are needed to prove if the higher doses can improve outcomes in critically ill patients, who may have altered absorption, distribution, metabolism, protein binding, and clearance of many drugs.
 
The Chinese guideline does not specify if corticosteroids should be used. While some studies indicated a possible reduction in hospital mortality and length of stay,17-19 the implementation of extremely heterogeneous treatment regimens that varied widely for timing of initiation (early vs. late), dosage (hydrocortisone equivalent 300–6000 mg/d), and duration (2–36 days) of treatment made any assessment of efficacy unfeasible.20 However, three randomized trials21-23 investigating prolonged low-to-moderate dose corticosteroid treatment in early acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and the finding of recent meta-analyses  have provided a strong support to anti-inflammatory treatment in ALI-ARDS. The two largest studies of severe H1N1 influenza A-associated respiratory failure reported the use of corticosteroids in 51%–69% of patients.4,7 Moderate dosage and short-duration of corticosteroids treatment in our study group resulted with an improvement of symptoms.
 
Patients aged 50 or older who were hospitalized with pandemic H1N1 infection were among those most likely to die. In Mexico, the case-fatality rate was much higher for infected patients older than 50 years than younger ones.24 Other studies showed that comorbidity may contribute to mortality.24,25 However, the death cases in our group had no significant prior disease history albeit all over 50 years old. Despite reports that elderly persons may be “protected” by preexisting immunity, clinicians should closely monitor and promptly treat older hospitalized patients with pandemic H1N1 infection.
 
The strengths of this study included a detailed description of patients severe or critically ill as a result of 2009 H1N1 influenza A. We have highlighted the differences in severity of illness, associations, and outcomes from other recent infectious respiratory outbreaks. These observations of the epidemiological risk factors, typical clinical features, response to therapy, and prognosis should aid in the diagnosis and clinical management of such infections. This study also has limitations. We defined our patients according to the most recent Chinese national guideline, which might be different from other previous studies. The studied population in this study was selected in a major medical center in charge of most of severely and critically ill patients with 2009 influenza A (H1N1) infection in China. This may lead to biased presentation of certain comorbidities and clinical features.
 
In conclusion, we have demonstrated that 2009 influenza A (H1N1) infection-related critical illness predominantly affects young patients with a few major comorbidities. Critical cases in our study were mainly associated with severe hypoxemia and respiratory failure required for mechanical ventilation. Most patients had a good prognosis.
 
Acknowledgements: We thank all the doctors, nurses and research workers in our hospital who treated and took care of these severely and critically ill patients with 2009 influenza A (H1N1) infection.
 
REFERENCES
 
1.  Death of pregnant women with 2009 influenza A (H1N1) infection in China. Beijing: Ministry of Health of People’s Republic of China, 2009. (Accessed December 9, 2009 at http://61.49.18.65/publicfiles/business/htmlfiles/mohbgt/s3582/200912/44871.htm.)
2.  The fifth death case in Shanghai. Shanghai: Shanghai Municipal Health Bureau, 2009. (Accessed December 21, 2009 at http://wsj.sh.gov.cn/website/b/49016.shtml)
3.  Guideline of diagnosis and treatment of patients with 2009 influenza A (H1N1) infection in China. Beijing: Ministry of Health of People’s Republic of China, 2009. (Accessed October 12, 2009 at http://www.moh.gov.cn/publicfiles /business/htmlfiles/H1N1/s10619/200912/45166.htm.)
4.  Domínguez-Cherit G, Lapinsky SE, Macias AE, Pinto R, Espinosa-Perez L, de la Torre A, et al. Critically Ill patients with 2009 influenza A (H1N1) in Mexico. JAMA 2009; 302: 1880-1887.
5.  Fowler RA, Lapinsky SE, Hallett D, Detsky AS, Sibbald WJ, Slutsky AS, et al. Critically ill patients with severe acute respiratory syndrome. JAMA 2003; 290: 367-373.
6.  Centers for Disease Control and Prevention (CDC). Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. Morb Mortal Wkly Rep 2009; 58: 521-524.
7.  Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, et al. Canadian Critical Care Trials Group H1N1 Collaborative. Critically ill patients with 2009 influenza A (H1N1) infection in Canada. JAMA 2009; 302: 1872-1879.
8.  Cao B, Li XW, Mao Y, Wang J, Lu HZ, Chen YS, et al. The National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China. Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N Engl J Med 2009; 361: 2507-2517.
9.  Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: 1589-1596.
10.  Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546-1554.
11.  Abramowitz LJ. The effect of Asian influenza on pregnancy. S Afr Med J 1958; 32: 1155-1156.
12.  Beigi RH. Pandemic influenza and pregnancy: a call for preparedness planning. Obstet Gynecol 2007; 109: 1193-1196.
13.  Goulenok C, Monchi M, Chiche JD, Mira JP, Dhainaut JF, Cariou A. Influence of overweight on ICU mortality: a prospective study. Chest 2004; 125: 1441-1445.
14.  Sakr Y, Madl C, Filipescu D, Moreno R, Groeneveld J, Artigas A, et al. Obesity is associated with increased morbidity but not mortality in critically ill patients. Intensive Care Med 2008; 34: 1999-2009.
15.  Infobase: BMI/overweight/obesity. Geneva: World Health Organization, 2009. (Accessed September 11, 2009 at https://apps.who.int/infobase/compare.aspx?dm=5&countries=124&year=2005&sf1=cd.0701&sex=all&agegroup=15-100.)
16.  Rello J, Rodríguez A, Ibañez P, Socias L, Cebrian J, Marques A, et al. Intensive care adult patients with severe respiratory failure caused by influenza A (H1N1)v in Spain. Crit Care 2009; 13: R148.
17.  Yam LY, Lau AC, Lai FY, Shung E, Chan J, Wong V. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. J Infect 2007; 54: 28-39.
18.  Chen RC, Tang XP, Tan SY, Liang BL, Wan ZY, Fang JQ, et al. Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience. Chest 2006; 129: 1441-1452.
19.  Cheng VC, Tang BS, Wu AK, Chu CM, Yuen KY. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J Infect 2004; 49: 262-273.
20.  Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3: e343.
21.  Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005; 171: 242-248.
22.  Annane D, Sebille V, Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006; 34: 22-30.
23.  Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007; 131: 954-963.
24.  Vaillant L, La Ruche G, Tarantola A, Barboza P. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Eurosurveillance 2009; 14: 19309-19314.
25.  Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A (H1N1) infection in California. JAMA 2009; 302: 1896-1902.
  1. Biomedical Key Research Grant from the Commission of Science and Technology, Shanghai,No. 09DZ1906604;