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Original article
Disease severity and clinical outcomes of community acquired pneumonia caused by non- influenza respiratory viruses in adults: a multicenter prospective registry study from CAP- China Network
Fei Zhou, Yimin Wang, Yingmei Liu, Xuedong Liu, Li Gu, Xiaoju Zhang, Zenghui Pu, Guoru Yang, Bo Liu, Qingrong Nie, Bing Xue, Jing Feng, Qiang Guo, Jianhua Liu, Hong Fan, Jin Chen, Yongxiang Zhang, Zhenyang Xu, Min Pang, Yu Chen, Xiuhong Nie, Zhigang Cai, Jinfu Xu, Kun Peng, Xiangxin Li, Pingchao Xiang, Zuoqing Zhang, Shujuan Jiang, Xin Su, Jie Zhang, Yanming Li, Xiuhong Jin, Rongmeng Jiang, Jianping Dong, Yuanlin Song, Hong Zhou, Chen Wang, Bin Cao
Please cite this article as: Zhou F, Wang Y, Liu Y, et al. Disease severity and clinical outcomes of community acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicenter prospective registry study from CAP-China Network. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.02406-2018).
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.
Copyright ©ERS 2019 Title page
Short Title: Illness severity and clinical outcomes of CAP caused by non-influenza respiratory viruses
Fei Zhou1, 2, 3, Yimin Wang1, 2, 3, Yingmei Liu1, 2, 3, Xuedong Liu4, Li Gu5, Xiaoju Zhang6,
Zenghui Pu7, Guoru Yang8, Bo Liu9, Qingrong Nie10, Bing Xue11, Jing Feng12, Qiang
Guo13, Jianhua Liu14, Hong Fan15, Jin Chen16, Yongxiang Zhang17, Zhenyang Xu18, Min
Pang19, Yu Chen20, Xiuhong Nie21, Zhigang Cai22, Jinfu Xu23, Kun Peng24, Xiangxin Li25,
Pingchao Xiang26, Zuoqing Zhang27, Shujuan Jiang28, Xin Su29, Jie Zhang30, Yanming
Li31, Xiuhong Jin32, Rongmeng Jiang33, Jianping Dong34, Yuanlin Song35, Hong Zhou36,
Chen Wang1, 2, 3, Bin Cao1, 2, 3,* and CAP-China network
1 Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, National Clinical
Research Center of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
2 Clinical Center for Pulmonary Infections, Capital Medical University.
3 Tsinghua University-Peking University Joint Center for Life Sciences.
4 Department of Respiratory Medicine, Qingdao Municipal Hospital Group, Jiaozhou Road, Qingdao City,
Shandong Province, China.
5 Department of Infectious Diseases, Beijing Chao-Yang Hospital, Capital Medical University, No 8,
Gongti Road, Chaoyang District, Beijing, China.
6 Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, China.
7 Department of Infectious diseases, YanTai Yu Huang-Ding Hospital, No. 20, Yu Huangding east Road,
Yantai, China.
8 Department of Pulmonary and Critical Care Medicine, Weifang No. 2 People's Hospital, Yuanxiao Street,
Weifang City, Shandong Province, China.
9 Department of Respiratory and Critical Care Medicine, Linzi District People’s Hospital, Shandong, China.
10 Department of Respiratory and Critical Care Medicine, Liangxiang Hospital, No. 45, Gongchen Road,
Fangshan District, Beijing, China.
11 Department of Respiratory Medicine, Chuiyangliu Hospital Affiliated to Tshinghua University, No. 2,
Chui Yangliu south Road, Beijing, China.
12 Department of Respiratory Medicine, Tianjin Medical University General Hospital, Tianjin, China.
13 Department of Respiratory, Emergency and Critical Care Medicine, First Affiliated Hospital of Soochow
University, China.
14 Department of Respiratory, Beijing Huairou Hospital of University of Chinese Academy of Science,
China.
15 Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichan University, China.
16 Department of Respiratory, Fuxing Hospital, Capital Medical University, China.
17 Department of Pulmonary and Critical Care Medicine, Daxing Hospital Affiliated to Capital Medical
University, China.
18 Department of Pulmonary and Critical Care Medicine, Beijing Luhe Hospital, Capital Medical
University, China.
19 Department of Respiratory, First Hospital of Shanxi Medical University, China.
20 Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University,
China.
21 Department of Respiratory, Xuanwu Hospital Capital Medical University, China.
22 Department of Respiratory, The Second Hospital of Hebei Medical University, China.
23 Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, China.
24 Department of Respiratory, Beijing No.6 Hospital, China.
25 Department of Pulmonary and Critical Care Medicine, Beijing Changping Hospital, China.
26 Department of Pulmonary and Critical Care Medicine, Peking University Shougang Hospital, China.
27 Department of Respiratory, Beijing Shijingshan Hospital, China.
28 Department of Pulmonary and Critical Care Medicine, Shandong Province Hospital, China.
29 Department of Respiratory, Nanjing General Hospital of Nanjing Military Command, PLA, China.
30 Department of Respiratory, Beijing Tiantan Hospital, Capital Medical University, China.
31 Department of Pulmonary and Critical Care Medicine, Beijing Hospital, China.
32 Department of Respiratory, Beijing Pinggu Hospital, China.
33 The National Clinical Key Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical
University, China.
34 Department of Infectious diseases, Beijing Haidian hospital, Haidian section of Peking University Third
Hospital, China.
35 Department of Respiratory, Zhongshan Hospital, Fudan University, China.
36 Department of Respiratory, Beijing electric power Hospital, China.
FZ, YMW, YML, XDL, LG, XJZ, ZHP, GRY and BL contributed equally.
* Correspondence to: Dr. Bin Cao ([email protected]) at Department of Pulmonary and Critical Care
Medicine, China-Japan Friendship Hospital; National Clinical Research Center of Respiratory Diseases;
Clinical Center for Pulmonary Infections, Capital Medical University; Tsinghua University-Peking
University Joint Center for Life Sciences.
Take home Message: The high incidence of complications in non-influenza viral pneumonia and similar impact of non-influenza viruses relative to influenza virus on disease severity and outcomes suggest more attention should be given to CAP caused by non-influenza viruses.
Disease severity and clinical outcomes of community acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicenter prospective registry study
from CAP-China Network
Abstract
Although a wide knowledge of influenza viral pneumonia have been established, the significance of non-influenza respiratory viruses in community acquired pneumonia
(CAP) and their impact on clinical outcomes remains unclear, especially in non-immunocompromised adult population. Hospitalised immunocompetent patients with CAP were prospectively recruited from 34 hospitals in Mainland China. Respiratory viruses were detected by molecular methods. Comparisons were conducted between influenza and non-influenza viral-infection groups. In total, 915 of 2336 adult patients with viral infection were enrolled in the analysis with influenza virus (28.4%) most frequently detected, followed by respiratory syncytial virus (3.6%), adenovirus (3.3%), human coronavirus (3.0%), parainfluenza virus (2.2%), human rhinovirus (1.8%), and human metapneumovirus (1.5%). Non-influenza viral infections accounted for 27.4% of viral pneumonia. Consolidation was more frequently observed in patients with adenovirus infection. The occurrence of complications such as sepsis (40.1% vs 39.6%, p
= 0.890) and hypoxemia (40.1% vs 37.2%, p = 0.449) during hospitalization in influenza group didn’t differ from that of non-influenza group. Compared with influenza viral infection, the multivariable-adjusted odds ratios and 95% confidence intervals (CIs) of
CURB-65 >3, PaO2/FiO2 <200 mmHg, and occurrence of sepsis or hypoxemia for non-influenza viral infection were 0.87 (0.26-2.84), 0.72 (0.26-1.98), 1.00 (1.63-1.58), and 1.05 (0.66-1.65), respectively. The hazard ratio and 95% CI of 90-day mortality was
0.51 (0.13-1.91). The high incidence of complications in non-influenza viral pneumonia and similar impact of non-influenza viruses relative to influenza virus on disease severity and outcomes suggest more attention should be given to CAP caused by non-influenza viruses.
Keywords non-influenza viruses, community acquired pneumonia, complications, outcomes
Abbreviations:
CAP Community acquired pneumonia
ICU Intensive care unit
NP Nasopharyngeal
ETA Endotracheal aspirates
BALF Bronchoalveolar lavage fluid
PCR Polymerase Chain Reaction
UTM Universal transport medium
IFV Influenza virus
CoV Human coronavirus
AdV Adenovirus
HMPV Human metapneumovirus
RSV Respiratory syncytial virus
PIV Parainfluenza virus
HRV Human rhinovirus
MP Mycoplasma pneumoniae
CP Chlamydia pneumoniae
LP Legionella pneumophila
ARDS Acute Respiratory Distress Syndrome
COPD Chronic obstructive pulmonary disease
WBC White blood cell
AST Aspartate transaminase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
BUN Blood urea nitrogen
PCT Procalcitonin
HR Heart rate
PI Principle investigators
IQR Inter quartile range
OR Odds ratio
HR Hazard ratio
Introduction
Community acquired pneumonia (CAP) is the leading cause of death worldwide among communicable diseases[1]. The development of molecular-diagnostic techniques has markedly improved the ability of virus identification, with numerous studies having reported a high prevalence of viral infections in patients with CAP[2]. A recent meta-analysis incorporating 31 observational studies showed that the proportion of viral infection was 24.5% in hospitalized patients with CAP, with influenza virus most frequently identified, followed by human rhinovirus (HRV), respiratory syncytial virus
(RSV) and human coronavirus (CoV)[2].
Previous studies have established the clinical features, complications, and outcomes associated with influenza viral pneumonia[3, 4]. However, most data concerning non-influenza viral pneumonia was derived from case reports and cases series, since non-influenza respiratory viruses were most frequently known as the causative of upper–respiratory tract infections[3]. Additionally, a majority of studies focusing on non-influenza respiratory viruses in adults with pneumonia were conducted in populations with limited generalizability to CAP patients, such as immunocompromised or frail elderly patients, residents of long-term facilities, cases with underlying lung diseases, or critically ill people[5-11]. Therefore, the significance of non-influenza respiratory viruses in pneumonia and their specific impact on clinical outcomes has not been established in immunocompetent adult patients with CAP.
Here, we performed a national, prospective, multicentre study in order to evaluate the impact of non-influenza respiratory viruses compared with influenza virus on disease severity, proportion of patients achieving clinical stability within the first 3 days at the
hospital, complications, intensive care unit (ICU) admission, length of hospital stay and
90-day mortality in immunocompetent adult patients with CAP.
Methods
Study setting and design
The CAP-China study, a prospective multicenter observational study, was conducted in 34 hospitals from 10 provinces of mainland China (Figure 1), with all of the hospitals located in urban areas (Table S1). From 1 October 2015 to 30 June 2017
(Figure S1), patients with CAP admitted to emergency department, general wards, or
ICUs were screened for enrollment. Written informed consent was obtained from all patients or their caregivers before enrollment. The study was approved by the institutional review board of China-Japan Friendship Hospital and was registered at “ClinicalTrial.gov”
(ID: NCT02492425).
Study population
Patients aged ≥14 years and hospitalized for CAP were enrolled on admission. CAP was diagnosed according to the guideline published by the American Thoracic Society in
2007[12].
Patients were excluded if one of the following criteria was met: 1) hospitalization within the previous 90 days or enrolled in this study within the previous 30 days; 2) being immunocompromised: cancer with neutropenia (absolute neutrophil count < 500/mm3), hematological malignancies, solid malignancies receiving chemotherapy during the previous 3 months, solid organ or bone-marrow transplant, active graft-versus-host disease, bronchiolitis obliterans, human immunodeficiency virus infection, immunoglobulin deficiency, using immunosuppressive agents, or current treatment with
systemic corticosteroids (≥20 mg of prednisone per day or its equivalent) for >30 continuous days before illness onset; 3) receipt of a tracheotomy, insertion of a percutaneous endoscopic gastrostomy tube, or presentation of cystic fibrosis; 4) had a clear alternative diagnosis at the end of follow-up that included lung cancer, pulmonary tuberculosis, interstitial lung disease, pulmonary embolism, pulmonary edema, or allergic bronchopulmonary aspergillosis.
During the study period, 2718 hospitalized CAP patients were eligible for enrollment. A total of 382 cases were excluded for refusal to consent (n = 69), failing in sampling (n = 158), being immunocompromised (n = 37), final diagnosis of tuberculosis or non-pneumonia illness (n = 58), or being lost to follow-up (n = 60). Of the 2336 participants enrolled in the CAP-China study, 1421 were negative for viral detection.
Finally, a total of 915 patients with positive viral detection were included in this analysis.
Data collection and quality control
Before study initiation, all local principal investigators and study staff received extensive training on the protocol. Trained staff interviewed patients (or their caregivers) within 24 h after enrollment, with demographic information, comorbidities, clinical manifestations, vital signs, laboratory results and microbiology data, antimicrobial use, complications, and outcomes collected using a standardized case-report form. During a
90-day follow up period, all-cause death was recorded by telephone interview. All information was uploaded into an electronic database (www.chinapneumonia.cn) by trained clinical research coordinators, and systematic data checks were performed automatically online in order to detect the logical errors or extremes. For each case, 10%
of the data were selected at random and were checked against the original medical record by clinical research associates in order to confirm accuracy and completeness.
Specimen collection and testing
Two nasopharyngeal (NP) swabs were obtained from all patients (n = 2332) immediately upon entry to emergency department, general wards, or ICUs. One was collected for rapid influenza-antigen testing on site, and the other was placed in universal transport medium and stored at −80°C for polymerase chain reaction (PCR) analysis in the central laboratory. On-site urine-antigen tests for Streptococcus pneumoniae and
Legionella pneumophila were performed in all patients within 24 h after admission.
Blood for cultures was obtained from 610 patients with temperature ≥38.5°C within 48 h on admission, with 73.4% of them having received empirical antibiotics treatment. A total of 1229 patients had qualified sputum or endotracheal aspirate (ETA) collected within 48 h after admission, with 868 of these patients having already received empirical
CAP antibiotics. On-site Gram staining and bacterial cultures were performed according to routine microbiological guidance. Sputum, ETA and bronchoalveolar lavage fluid
(BALF) samples were stored at −80°C until PCR testing in the central laboratory.
Pathogen detection
Viral etiology was considered positive if one of the criteria was met: 1) detection of respiratory virus in sputum, ETA, BALF, or NP swabs, by real-time PCR[13] (TaqMan
Array Microfluidic Cards, Applied Biosystems, Foster City, CA, USA), including RSV, influenza virus types A and B (IFV), parainfluenza virus (PIV), HRV, CoV, human metapneumovirus (HMPV), and adenovirus (AdV); 2) positive antigen for IFV
(Clearview Exact Influenza A& B; Alere, Waltham, MA, USA).
Bacterial or atypical pathogens were considered positive if one of the following criteria was met: 1) positive bacterial culture from blood or pleural fluid; 2) positive urinary antigen for L. pneumophila (Binax Now; Trinity Biotech, Bray, Ireland) or S. pneumoniae (Binax Now; Emergo Europe, Amsterdam, The Netherlands); 3) detection of
Mycoplasma pneumoniae or Chlamydia pneumoniae in sputum, BALF, ETA, or NP swabs by real-time PCR[14] (Zhijiang, Shanghai, China); 4) detection of L. pneumophila in sputum, BALF, or ETA by real-time PCR[14] (Zhijiang, Shanghai, China); 5) bacteria with moderate to heavy growth (>3+ growth) in qualified sputum or ETA, or quantified culture in BALF of ≥104 CFU/mL. In this study, qualified samples were defined as >25 leukocytes and <10 epithelial cells per magnified field (100×).
Definitions
[15] Hypoxemia was defined as PaO2/FiO2 <300 mmHg . Sepsis was diagnosed based on the revised criteria defined by the 2014 task force[16] (sequential organ failure
[17] assessment score ≥ 2). Pneumonia severity was assessed by CURB-65 and PaO2/FiO2.
Clinical stability was defined according to American Thoracic Society guideline published in 2007[12]. Viral and bacterial co-infection was defined as detection of both virus and bacteria[18]. Viral and M. pneumoniae/C. pneumoniae co-infection was defined as detection of both virus and atypical pathogens. Mixed viral infection was defined as detection of ≥2 viruses.
Statistical analysis
Viral CAP patients were classified into three groups: influenza viral-infection group, non-influenza viral-infection group and mixed viral-infection group. For the influenza or non-influenza viral-infection group, only one virus was detected. Clinical features,
CURB-65 ≥3 and PaO2/FiO2 <200 mmHg on admission, 24-h and 72-h clinical stability, hypoxemia and sepsis during hospitalization, ICU admission, invasive ventilation and
90-day mortality were compared between influenza and non-influenza viral-infection groups. Further comparisons were performed in different viral infection groups (IFV,
CoV, HMPV, HRV, AdV, PIV, RSV, and mixed viral infection). Continuous variables were described as medians (interquartile range), and categorical variables were presented as number (percentage). The normality of data distribution was assessed, and a
Mann-Whitney U test was used for non-normally distributed variables. A χ2 test was used to compare categorical variables, and a multivariable-adjusted logistic regression model was used to estimate the effect of different viruses on disease severity (CURB-65 ≥3 and
PaO2/FiO2 <200 mmHg on admission) and complications (sepsis and hypoxemia during hospitalization). Multivariable-adjusted Cox regression was conducted to estimate the association between viral etiology and 90-day mortality. All data were analyzed with
SPSS (v.19.0; IBM Corp, Armonk, NY, USA). A two-sided p < 0.05 was considered statistically significant. Bonferroni correction was used for multiple comparisons.
Results
Patient characteristics
The median age of the 915 patients with viral infection was 59.0 (36.0–72.0) years and 55.2% were male (Table 1). A total of 426 (46.6%) patients had comorbidities, with cardiovascular disease most commonly observed (31.3%), followed by diabetes (14.6%) and chronic obstructive pulmonary disease (COPD) (4.5%). The most common symptoms of patients with viral infection were cough (93.0%), fever (81.3%) and sputum
(81.3%), and >~33% of patients had dyspnea. There were 151 patients that had received
antiviral therapy in the emergency room or on admission, among which 98.7% represented empirical treatment. Neuraminidase inhibitors were the most commonly used antivirals (86%), followed by ganciclovir (9%), acyclovir (7%), and ribavirin (2%). The median length of hospital stay in patients with viral infection was 10 (8–14) days, and the
90-day mortality was 3.1%.
Among the 915 patients, influenza viral infection, non-influenza viral infection and mixed viral infection was found in 581, 240 and 94 cases respectively. The baseline characteristics of age, symptoms, underlying diseases, and laboratory findings were similar between influenza and non-influenza viral-infection groups, except that leukocytosis was more common in the non-influenza viral-infection group [25.2% vs
16.0%, p = 0.002; 95% confidence interval (CI): 1.23–2.56] and diffuse bilateral pulmonary infiltration was more common in the influenza viral-infection group (36.8% vs 13.8%, p < 0.001; 95% CI: 0.18–0.42) (Tables 1 and S2).
Table 1. Demographic characteristics, underling diseases, clinical features and laboratory findings of hospitalized CAP patients with viral infections Influenza viral Non-influenza Mixed viral Viral infection * Variables infection a viral infection b infection c p value N = 915 N = 581 N = 240 N = 94 Age, median (IQR), years 59.0 58.0 59.0 59.0 0.866 (36.0-72.0) (36.0-72.5) (34.3-72.8) (37.0-72.0) Male, n (%) 505 (55.2) 312 (52.7) 136 (56.7) 57 (60.6) 0.438 Underlying diseases, n (%) Cardiovascular disease 286 (31.3) 181 (31.2) 77 (32.1) 28 (29.8) 0.794 Diabetes 134 (14.6) 82 (14.1) 38 (15.8) 14 (14.9) 0.526 COPD 45 (4.5) 27 (4.6) 13 (5.4) 5 (5.3) 0.641 Chronic renal failure 41 (4.5) 29 (5.0) 9 (3.8) 3 (3.2) 0.441 Asthma 30 (3.3) 20 (3.4) 6 (2.5) 4 (4.3) 0.483 Solid malignancy d 23 (2.5) 14 (2.4) 6 (2.5) 3 (3.2) 0.939 Liver disease 16 (1.7) 12 (2.1) 2 (0.8) 2 (2.1) 0.345 Symptoms, n (%) Fever 744 (81.3) 482 (83.0) 190 (79.2) 72 (76.6) 0.200 Cough 851 (93.0) 535 (92.1) 227 (94.6) 89 (94.7) 0.207 Sputum 744 (81.3) 471 (81.1) 196 (81.7) 77 (81.9) 0.841 Hemoptysis 48 (5.2) 27 (4.6) 10 (4.2) 11 (11.7) 0.763 Myalgia 364 (39.8) 240 (41.3) 91 (37.9) 33 (35.1) 0.368 Chill 352 (38.5) 228 (39.2) 87 (36.2) 37 (39.4) 0.423 Dyspnea 303 (33.1) 195 (33.6) 70 (29.2) 38 (40.4) 0.220 Chest pain 147 (16.1) 99 (17.0) 29 (12.1) 19 (20.2) 0.075 Diarrhea 40 (4.4) 26 (4.5) 11 (4.6) 3 (3.2) 0.946 Laboratory findings on admission, n (%) Leukocytosis e 175/907 (19.3) 92/575 (16.0) 60/238 (25.2) 23 (24.5) 0.002 Granulocytopenia f 44/907 (4.9) 29/575 (5.0) 11/238 (4.6) 4 (4.3) 0.800 Lymphocytopenia g 188/907 (20.7) 120/575 (20.9) 47/238 (19.7) 21 (22.3) 0.719 Anemia h 184/907 (20.3) 114/575 (19.8) 46/238 (19.3) 24 (25.5) 0.871 Thrombocytopenia i 193/907 (21.3) 130/575 (22.6) 47/238 (19.7) 16 (17.0) 0.368 ALT >40, U/L 199/896 (22.2) 135/567 (23.8) 48/237 (20.3) 16/92 (17.4) 0.273 LDH >250, U/L 224/844 (26.5) 194/544 (27.4) 59/218 (27.1) 16/82 (19.5) 0.927 BUN >7, mmol/L 131/903 (14.5) 82/571 (14.4) 35/238 (14.7) 14 (4.6) 0.899 PCT, ng/mL <0.25 568/812 (70.0) 365/509 (71.7) 141/216 (65.3) 62/87 (71.3) 0.25–0.5 70/812 (8.6) 39/509 (7.7) 22/216 (10.2) 9/87 (10.3) 0.520 0.5–1.0 66/812 (8.1) 40/509 (7.9) 22/216 (10.2) 4/87 (4.6) ≥1.0 108/812 (13.3) 65/509 (12.8) 31/216 (14.4) 12/87 (3.8) CRP ≤100, mg/L 68/528 (87.1) 45/344 (86.9) 18/122 (85.2) 5/62 (7.4) 0.642
PaO2/FiO2 <300, mmHg 327/855 (38.2) 204/534 (38.2) 86/234 (36.8) 37/87 (42.5) 0.703
Initial radiographic findings, n (%) Consolidation 395/759 (52.0) 241/478 (50.4) 112/210 (53.3) 42/71 (59.2) 0.481 Ground glass opacity 542/759 (71.4) 351/478 (73.4) 141/210 (67.1) 50/71(70.4) 0.092 Diffuse bilateral pulmonary 225/759 (29.6) 176/478 (36.8) 29/210 (13.8) 20/71 (28.2) < 0.001 infiltration Pleural effusion 36/579 (4.7) 24/478 (5.0) 8/210 (3.8) 4/71 (5.6) 0.487 Received antibiotic treatment 705 (77.7) 461 (79.3) 178 (74.2) 66 (70.2) 0.104 before enrollment, n (%) Received antiviral treatment before 151 (16.5) 107 (18.4) 31 (12.9) 13 (13.8) 0.055 enrollment, n (%) Received antibiotic treatment 904 (98.8) 575 (99.0) 235 (97.9) 94 (100.0) 0.234 during hospitalization, n (%) Received antiviral treatment during 130 (14.2) 97 (16.7) 23 (9.6) 10 (10.6) 0.009 hospitalization, n (%) Viral-bacterial co-infectionj 66 (7.2) 38 (6.5) 15 (6.2) 13 (13.8) 0.878 Viral-MP/CP co-infection 130 (14.2) 87 (15.0) 31 (12.9) 12 (12.8) 0.445 Categorical variables were presented as number (percentage). Continuous variables were presented as median (IQR, inter quartile range). COPD, chronic obstructive pulmonary disease; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; BUN, Blood urea nitrogen; PCT, procalcitonin; CRP, C-reactive protein; MP, Mycoplasma pneumoniae; CP, Chlamydia pneumoniae. a: Patients detected only influenza virus with or without co-infection. b: Patients detected any one of non-influenza viruses with or without co-infection. c: Patients detected any two or more viruses. d: Solid malignancy: including 6 lung cancer, 5 colon cancer, 4 stomach cancer, 4 liver cancer, 2 thyroid cancer, 1 breast cancer and 1 cervical cancer. e: Leukocytosis: Leukocyte count > 10, 000 /mm3. f: Granulocytopenia: Neutrophil < 1500 /mm3. g: Lymphocytopenia: Lymphocyte count < 800 /mm3. h: Anemia: hemoglobin < 120 g/L for men and < 110 g/L for women. i: Thrombocytopenia: platelet count < 150, 000/mm3. j: Viral-bacterial co-infection included typical bacteria and viruses co-infection (n = 57); L. pneumophila and viruses co-infection (n = 9). *: Influenza viral infection group vs non-influenza viral infection group.
Pathogen detection
Among 2336 hospitalized patients with CAP, IFV (28.4%) was most frequently
detected，followed by RSV (3.6%), AdV (3.3%) and CoV (3.0%), and mixed viral
infection was observed in 68 patients (Table 2). AdV infection was found in 4.6%, 4.2%,
1.8%, 1.2% and 1.6% of patients aged 14 to 24 years, 25 to 44 years, 45 to 64 years, 65 to
84 years and ≥85 years respectively (p = 0.002), with the positive rate of other respiratory
viruses similar in different age groups (Table S3). Influenza viral infection was more
common in patients admitted to ICU than patients in general wards (32.9% vs 24.3%, p =
0.023; 95% CI: 1.06–2.18) (Table S4). Typical bacteria were detected in 72 patients with viral infection, with S. pneumoniae and Klebsiella pneumoniae most commonly detected
(Table S5).
Table 2. The number of patients detected positive for viruses Pathogen identified N Viral detection only One viral infection 645 Influenza A/B 452 Adenovirus 45 Respiratory syncytial virus 45 Human coronavirus 29 Parainfluenza virus 1-4 28 Human rhinovirus 24 Human metapneumovirus 22 Mixed viral infection 68 Viral-bacterial co-infection a 66 Viral-MP/CP co-infection 130 Viral-bacterial-MP/CP co-infection b 6 MP/CP, mycoplasma pneumoniae or chlamydia pneumoniae. a: Viral-bacterial co-infection included typical bacteria and viruses co-infection (n = 57); L. pneumophila and viruses co-infection (n = 9). b: Viral-bacteria-MP/CP co-infection included viruses, typical bacteria and MP/CP co-infection (n = 6)
Comparison of illness severity, complications and clinical outcomes between influenza and non-influenza viral infection
Among 915 patients with viral infection, the proportions of patients with CURB-65
≥3 (4.8% vs 3.8%, p = 0.486; 95% CI: 0.35–1.64) and PaO2/FiO2 <200 mmHg (8.6% vs
5.1%, p = 0.092; 95% CI: 0.30–1.10) on admission, incidence of sepsis (40.1% vs 39.6%, p = 0.890, 95% CI: 0.72–1.33) and hypoxemia (40.1% vs 37.2%, p = 0.449; 95% CI:
0.65–1.22) during hospitalization in the influenza group did not significantly differ from
that in the non-influenza group (Tables 3 and S6). Additionally, there was no significant
difference in ICU admission (8.3% vs 5.4%, p = 0.157; 95% CI: 0.34–1.20), 90-day
mortality (3.8% vs 1.7%, p = 0.174; 95% CI: 0.15–1.26) and the length of hospital stay
(10 vs 10 days, p = 0.986) between the two groups.
Compared with influenza viral infection, the multivariable-adjusted odds ratios and
95% confidence intervals (CIs) of CURB-65 >3 and PaO2/FiO2 <200 mmHg on
admission, occurrence of sepsis and hypoxemia during hospitalization for the
non-influenza viral-infection group were 0.87 (0.26–2.84), 0.72 (0.26–1.98), 1.00
(1.63–1.58), and 1.05 (0.66–1.65) respectively. The hazard ratio and 95% CI of 90-day
mortality was 0.51 (0.13–1.91) (Table 4). Additionally, diabetes and elevated
procalcitonin (PCT) were associated with a higher proportion of CURB-65 ≥3 and sepsis
(Table S7).
Table 3. Disease severity, complications and outcomes of influenza and non-influenza viral infection Influenza viral Non-influenza Mixed viral Variables infection a viral infection b infection c p value* N = 581 N = 240 N = 94 CURB-65 ≥3 on admission, n (%) 28/571 (4.8) 9/238 (3.8) 3 (3.2) 0.486
PaO2/FiO2 <200, mmHg on admission, n (%) 46/534 (8.6) 12/234 (5.1) 4/87 (4.6) 0.092 Complications during hospitalization, n (%) Sepsis 233 (40.1) 95 (39.6) 39 (41.5) 0.890 Hypoxemia d 214/534 (40.1) 87/234 (37.2) 39/87 (44.8) 0.449 ICU admission, n (%) 48 (8.3) 13 (5.4) 2 (2.1) 0.157 Invasive mechanical ventilation, n (%) 30 (5.2) 5 (2.1) 1 (1.1) 0.056 Length of hospital stay, median (IQR), days 10.0 (8.0-14.0) 10.0 (7.0-14.0) 11.0 (8.0-14.3) 0.986 In-hospital mortality, n (%) 16 (2.8) 1 (0.4) 1 (1.1) 0.062 90-day mortality 22 (3.8) 4 (1.7) 2 (2.1) 0.174 Categorical variables were presented as number (percentage). Continuous variables were presented as median (IQR, inter quartile range). ICU: Intensive care unit. a: Patients detected only influenza virus with or without co-infection. b: Patients detected any one of non-influenza viruses with or without co-infection. c: Patients detected any two or more viruses. d: Hypoxemia: PaO2/FiO2 <300 mmHg.
*: Influenza viral-infection group vs non-influenza viral-infection group.
Relationship between viral etiology and disease severity, complications, and
outcomes
On admission, the proportions of patient with CURB-65 ≥3 (p = 0.803) and
PaO2/FiO2 <200 mmHg (p = 0.476) were similar in different viral-infection groups (IFV,
CoV, HMPV, HRV, AdV, PIV, RSV and ≥2 viruses) (Figure 3). No significant
difference was found in demographic characteristics, underlying diseases, respiratory
symptoms, C-reactive protein or PCT between the influenza viral-infection group and any
one of the non-influenza viral-infection groups following Bonferroni correction. Higher
proportions of consolidation on chest radiography (83.7% vs 50.4%, p < 0.001; 95% CI:
2.31–10.98) but a lower rate of diffuse bilateral pulmonary infiltration (4.1% vs 36.8%, p
< 0.001; 95% CI: 0.02–0.304) was found in the AdV group as compared with the IFV
group (Table S8).
Although patients with AdV infection had a higher rate of temperature >37.8°C, the
proportion of patients achieving clinical stability within 24 h (p = 0.205) and 72 h (p =
0.230) after hospitalization was similar irrespective of viral etiology (Figure 4).
During hospitalization, the frequency of hypoxemia was 45.1% in the influenza
viral-infection group, and was similar among different viral infection groups (p = 0.416).
Although the proportion of sepsis was lower in the RSV group than that in the IFV (24.6%
vs 40.1%, p = 0.022; 95% CI: 0.76–0.91), AdV (24.6% vs 46.6%, p = 0.025; 95% CI:
0.18–0.90), HMPV (24.6% vs 46.4%, p = 0.036; 95% CI: 0.14–0.97) and CoV (26.6% vs
48.3%, p = 0.042; 95% CI: 0.14–0.98) groups, the difference was not significant
following Bonferroni correction. Additionally, no significant difference in 90-day
mortality (p = 0.953) or length of hospital stay (p = 0.185) was found between the different viral-infection groups (Figure 3).
Multivariable analysis showed no significant difference in the impact of different non-influenza viruses on risk of CURB-65 ≥3 or PaO2/FiO2 <200 mmHg on admission, occurrence of sepsis or hypoxemia during hospitalization, and 90-day mortality were not significantly different from that of influenza viral infection, after adjustment for confounding factors (p > 0.05 for all) (Table 4).
Table 4. Association of different viruses with CURB-65 ≥3 and PaO2/FiO2 <200 mmHg on admission，occurrence of hypoxemia and sepsis during hospitalization, and 90-day mortality in multivariable analysis
CURB-65 ≥3 on PaO2/FiO2 <200 mmHg on Sepsis during Hypoxemia during 90-day mortality Virus admission admission hospitalization hospitalization OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p HR (95% CI) p IFV Reference - Reference - Reference - Reference - Reference - non-IFVa 0.87 (0.26 - 2.84) 0.811 0.72 (0.26-1.98) 0.519 1.00 (0.63-1.58) 0.993 1.05 (0.66-1.65) 0.842 0.51 (0.13-1.91) 0.314 CoV 0.51 (0.04 -6.64) 0.60 0.36 (0.02 -5.78) 0.469 1.25 (0.46 -3.40) 0.659 1.38 (0.52 -3.66) 0.514 3.33 (0.30 -36.80) 0.327 HMPV 0.88 (0.08 -9.31) 0.916 0.75 (0.07 -8.05) 0.810 1.63 (0.64 -4.19) 0.307 1.45 (0.57 -3.67) 0.436 7.39 (0.54 -10.16) 0.135 HRV 3.74 (0.24 -17.42) 0.344 2.33 (0.22 -24.75) 0.483 1.86 (0.64 -5.40) 0.257 1.81 (0.64 -5.13) 0.265 NA - AdV 0.87 (0.11 -6.71) 0.892 1.29 (0.29 -5.79) 0.742 0.82 (0.37 -1.80) 0.629 0.89 (0.40 -2.00) 0.779 0.10 (0.04 -2.62) 0.170 PIV 2.37 (0.23 -24.05) 0.464 NA - 1.40 (0.53 -3.71) 0.493 1.14 (0.43 -3.03) 0.786 NA - RSV 0.59 (0.06 - 5.77) 0.653 1.11 (0.19 -6.36) 0.905 0.56 (0.23 -1.39) 0.209 0.55 (0.22 -1.38) 0.204 4.60 (0.36 -58.65) 0.240 ≥ 2 viruses 0.66 (0.10- 4.27) 0.661 0.62 (0.15-2.64) 0.618 1.08 (0.52-2.22) 0.838 1.14 (0.57-2.28) 0.713 0.16 (0.01-2.50) 0.190 Note: co-infection, fever, elevated PCT, leukocytosis, lobar consolidation, and all other variables with p < 0.2 in the univariate analysis were included in multivariable regression model, and the variables included in multivariable-adjusted regression analysis were shown in Table S7. IFV, influenza virus types A and B; CoV, human coronavirus; HMPV, human metapneumovirus; HRV, human rhinovirus; AdV, adenovirus; PIV, parainfluenza virus; RSV, respiratory syncytial virus; NA, not available; OR, odds ratio; HR, hazard rate; CI, confidence interval. a: non-IFV, non-influenza viruses including CoV, HMPV, HRV, AdV, PIV and RSV.
Discussion
Here, we performed a large multicenter prospective observational study (conducted in 34 hospitals) in mainland China to systemically investigate the impact of non-influenza respiratory viruses in the adult immunocompetent population, relative to that of influenza virus. Our results indicated that the effect of non-influenza respiratory viruses on illness severity, complications and outcomes in immunocompetent patients with CAP is similar to that associated with influenza-related respiratory diseases.
In the GLIMP[19] and EPIC studies[20], viral CAP diagnosis was 37.2% in Asia and
23% in the United States, similar to our results (39.2%). Studies of adult CAP in China from 2001 and 2005 showed that bacterial etiology (atypical and other bacteria) was much higher than viral causes (30.3%–53.1% vs 10.6%–19.0%)[21-25]. Whereas, recent
CAP etiology studies from 2009 and 2016 in China revealed an increased detection of viral infections (21.1% vs 34.9%) and a decline of bacterial infection (7.8%-24.8%)[14,
26-29], which is similar to the trends reported in European countries and the United
States[30]. The use of new molecular diagnostic methods rather than paired serum-antibody titers might explain the higher rate of viral detection. According to the recent epidemic surveillance data, with the exception of IFV, the primary causes of non-influenza viral pneumonia in China were AdV, RSV, CoVs, PIV, HRV and
HMPV[14, 26, 29, 31-34], with these representing the main focus of this study.
Non-influenza viruses accounted for nearly one third of the patients with viral pneumonia in this study. However, HRV was uncommon as compared to the EPIC study[20], where it was the most common viral pathogen. According to the recent research[35] and meta-analysis[36], HRV was the most common virus isolated from patients
with COPD, with detecting in 23.0% of exacerbated cases. However, only 5.1%
(120/2336) of the patients in our cohort had COPD as compared with 42% (968/2320) in the EPIC study[20] and 26% (759/3149) in the GLIMP study[19]. This difference might be due to the younger age (median 59.0 vs 69.0 years) and fewer current/former smokers
(31.3% vs 42.3%) among our patients[19]. Additionally, Radovanovic et al[19] found a higher prevalence of HRV in North America relative to other continents, including Asia,
Europe, Africa and Oceania (26.7% vs 2.8%; p < 0.001), suggesting that climate, geographical position and local epidemiologic trends might also influence the prevalence of viruses.
Consistent with previous studies, we observed similar clinical features among the different viral-infection groups[37]. Although diffuse bilateral infiltrates were more common in influenza-infection cases, further analysis showed that the difference only remained significant between influenza- and AdV-infection groups following Bonferroni correction. As previously reported[38, 39], AdV infection was more commonly observed in young adults and more frequently appeared as consolidation than other viruses. The high rate of elevated LDH associated with AdV infection might reflect the possibility of hepatitis[40]. Moreover, we found a high proportion of hypoxemia associated with HMPV and HRV infection. However, none of the clinical factors was specific enough to reliably discriminate between pneumonia caused by influenza and other viral pathogens.
Our data showed that the severity of pneumonia caused by non-influenza viruses was similar to that caused by influenza virus, which agrees with reports by Gilca[41] and
Bjarnason[42]. Previous studies had reported that the spread of virus into the bronchial epithelium could induce respiratory airway injury and release of cytokines. Although the
induced cytokine profiles might vary by virus, they converge on a common end pathway and result in similar diffuse alveolar damage[43, 44]. In the present study, we found that comorbidities but not the type of viruses were independently associated with sepsis and hypoxemia in patients with viral pneumonia. For elderly hospitalized patients with respiratory symptoms, RSV, HMPV, and PIV were even associated with a higher mortality[45-48] and more complications[47, 49] as compared with influenza.
The impact of bacterial co-infection on disease severity and mortality had been reported in patients with viral infections[18, 49, 50]. However, detecting all of the concomitant bacterial infection was difficult due to the limitations in traditional methods, few molecular-diagnostic tests approved for bacteria identification[51] and the high rate of pre-sampling antibiotic use. According to a previous study[52], a PCT threshold of ≥0.5 ng/mL resulted in a specificity of 72.5% for bacterial identification. Additionally, fever, leukocytosis and lobar consolidation have also been used to predict bacterial pneumonia[30]. After adjusting for viral–bacterial co-detection, elevated PCT, leukocytosis, fever and lobar consolidation in multivariate analysis, non-influenza viral-infection group was still confirmed to be comparable with influenza virus group regarding disease severity, complications and mortality
Our study offers critical insights into and recognition of non-influenza viruses among patients requiring admission to hospitals and potentially ICUs. In some random control trials (RCTs)[53, 54] and observational studies[55-58], rapid recognition of viruses was not associated with reducing the proportion of antibiotic use, early de-escalation or decreased hospital stay. However, the duration of antibiotic use was reduced in patients with influenza-like illness[55], asthma and infective exacerbation of COPD[53]. We recently
completed an RCT study (NCT03391076), which demonstrated that timely virus detection via PCR contributes to a decreased duration of antibiotics treatment in hospitalized CAP patients[59]. Furthermore, success has been achieved in patients with decreased antibiotic prescription rate along with increased antiviral use following detection of influenza virus by rapid point-of-care testing[60]. Recognizing the role of non-influenza viruses will promote the rapid development of antivirals, as the same story of anti-influenza drug development, such as balozavir [61] pimodivir[62], and favipiravi[63].
Additionally, more novel antivirals are currently undergoing preclinical trials, including
DAS181 for influenza[64], HMPV[65] and PIV[66]; GS5806, ALS-8176, AK0529 for
RSV[67] and Cidofovir for adenovirus[68]. Timely diagnosis of viral etiology might help clinicians to optimize the use of antivirus and antibiotics in the era of targeted therapy.
There were some limitations in our study. First, viruses identified from NP swabs cannot easily differentiate lower and upper respiratory tract infections. In this study, only patients with radiologically confirmed pneumonia were enrolled, and those with only upper respiratory tract infection had been excluded. Second, bacterial etiology (atypical and other bacteria) was lower than that reported in previous studies (30.3% to
53.1%)[21-25] in China from 2001 to 2005[69]. This might be explained by increased pre-sampling antibiotic use, relatively lower prevalence of comorbidities, and less severe disease, resulting in lower bacterial detection in our study. Third, PCR test was not used to detect typical bacterial pathogens, as it has not been recommended by the Infectious
Diseases Society of America guidelines[51]. Fourth, we did not include immunosuppressed patients in this study. Therefore, our results cannot be generalised to that patient subset.
Conclusions
These findings suggest that complications were common in patients with non-influenza viral pneumonia and the impact of non-influenza viruses on clinical outcomes were comparable with that of influenza virus in immunocompetent adult patients with CAP. The increasing recognition of the significant role of non-influenza respiratory viruses might promote the development of CAP management procedures for immunocompetent adult patients.
Acknowledgements
BC, FZ, YMW, LG, YML, BL and CW conceived of the project. BC and FZ performed the analysis and drafted the paper, and all authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published. All authors agree to be accountable for the all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. None of the material has been published or is under consideration elsewhere, including the Internet. BC takes full responsibility for the data and analysis. All authors declare that they have no competing interests. We appreciate all the physicians from the 34 hospitals who participated in CAP-China.
Funding
This study was supported by grants from the National Science Fund for
Distinguished Young Scholars (grant number 81425001/H0104), the Innovation Fund for
Medical Sciences from the Chinese Academy of Medical Sciences (2018-I2M-1-003), the
National Key Technology Support Program from the Ministry of Science and Technology
(2015BAI12B11) and from the Beijing Science and Technology Project
(D151100002115004).
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Figure 1. Patients were enrolled from five of the seven geographical locations in mainland China.
Including Beijing, Tianjin, Hebei and Shanxi provinces in North China; Shanghai, Shandong and Jiangsu provinces in East China; Henan province in Central China; Sichuan province in Southwest China; Liaoning province in Northeast China.
Figure 2. Study flow chart.
CAP, community-acquired pneumonia; ABPA, allergic bronchopulmonary aspergillosis
Figure 3. The illness severity on admission, complications during hospitalization and outcomes of hospitalized CAP patients with viral infections.
A) On admission, the proportion of patients with CURB-65 ≥3 (p = 0.803) and PaO2/FiO2 <200 mmHg (p
= 0.476) was comparable in differences viral-infection groups. B) During hospitalization, no differences of incidence of sepsis (p = 0.406) and hypoxemia (p = 0.416) were found among different viral-infection groups. C) The 90-day mortality (p = 0.953) and the length of hospitalization (p = 0.185) had no statistically significant difference among different viral infection groups.
CAP, community acquired pneumonia; IFV, influenza virus types A and B; CoV, human coronavirus;
HMPV, human metapneumovirus; HRV, human rhinovirus; AdV, adenovirus; PIV, parainfluenza virus; RSV, respiratory syncytial virus.
Figure 4. The proportion of patients achieved clinical stability on 24 h and 72 h after hospitalization and the day before discharge.
The proportion of patients achieved clinical stability was similar irrespective of viral etiology within 24 h
(P = 0.205) and 72 h (P = 0.230) after hospitalization.
Table S1. The details of hospitals participating in this study
Province, Location Teaching Grade of Number of Hospital City in China Hospital hospital patients enrolled China-Japan Friendship Hospital Beijing North Yes Tertiary 240 Beijing Chao-Yang Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 134 Beijing Changping Hospital Beijing North Yes Tertiary 42 Daxing Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 56 Tianjin Medical University General Hospital Tianjin North Yes Tertiary 90 Peking University Shougang Hospital Beijing North Yes Tertiary 40 Beijing No.6 Hospital Beijing North No Secondary 44 Fuxing Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 63 Beijing Haidian section of Peking University Third Hospital Beijing North Yes Tertiary 18 Beijing Huairou Hospital of University of Chinese Academy of Science Beijing North Yes Secondary 89 Beijing Pinggu Hospital Beijing North Yes Tertiary 24 Chuiyangliu Hospital Affiliated to Tshinghua University Beijing North Yes Tertiary 97 Beijing Luhe Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 54 Beijing electric power Hospital Beijing North Yes Tertiary 4 Fudan University Zhongshan Hospital Shanghai East Yes Tertiary 8 The Second Hospital of Hebei Medical University Hebei North Yes Tertiary 48 Henan Provincial People’s Hospital Henan Central Yes Tertiary 112 Liangxiang Hospital, Fangshan District, Beijing Beijing North Yes Tertiary 98 Qingdao municipal Hspital Shandong East Yes Tertiary 188 Shandong Province Hospital Shandong East Yes Tertiary 36 First Hospital of Shanxi Medical University Shanxi North Yes Tertiary 53 Shanghai Pulmonary Hospital Shanghai East Yes Tertiary 45 Beijing Ditan Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 20 Beijing Shijingshan Hospital Beijing North Yes Secondary 39 West China Hospital, Sichan University Sichuan Southwest Yes Tertiary 74 The First Afflicted Hospital of Soochow University Jiangsu East Yes Tertiary 90 Beijing Tiantan Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 34 Beijing Hospital Beijing North Yes Tertiary 33 Xuanwu Hospital Affiliated to Capital Medical University Beijing North Yes Tertiary 50 Yantai Yuhuangding Hospital Affiliated to Qingdao University Shandong East Yes Tertiary 110 Nanjing General Hospital Jiangsu East Yes Tertiary 36 Shengjing Hospital of China Medical University Liaoning Northeast Yes Tertiary 51 Linzi District People’s Hospital Shandong East Yes Tertiary 106 Weifang No.2 People’s Hospital Shandong East Yes Tertiary 110 Definition of Secondary and Tertiary hospital in China: The Secondary hospital was defined as a hospital providing medical, prevention, health care and rehabilitation services to multiple communities (with a radius of population more than 100,000 peoples); the Tertiary hospital was defined as a hospital providing medical service to the whole country beyond cities and provinces, with comprehensive medical, teaching and research ability[1] Table S2. Comparison of Demographic characteristics, underling diseases, clinical features and laboratory findings between patients with influenza and non-influenza viral infections Influenza viral Non-influenza viral a Variables infection infection b OR (95% CI) p value N = 581 N = 240 Age, median (IQR), years 58.0 (36.0-72.5) 59.0 (34.3-72.8) — 0.866 Male, n (%) 312 (52.7) 136 (56.7) 1.13 (0.833 – 1.526) 0.438 Underlying diseases, n (%) Cardiovascular disease 181 (31.2) 77 (32.1) 0.96 (0.694 – 1.323) 0.794 Diabetes 82 (14.1) 38 (15.8) 0.87 (0.575 – 1.327) 0.526 COPD 27 (4.6) 13 (5.4) 0.85 (0.431 – 1.679) 0.641 Chronic renal failure 29 (5.0) 9 (3.8) 1.35 (0.628 – 2.893) 0.441 Asthma 20 (3.4) 6 (2.5) 1.39 (0.551 – 3.506) 0.483
Solid malignancy c 14 (2.4) 6 (2.5) 0.96 (0.366 – 2.536) 0.939 Liver disease 12 (2.1) 2 (0.8) 2.51 (0.557 – 11.299) 0.345 Symptoms, n (%) Fever 482 (83.0) 190 (79.2) 1.28 (0.877 – 1.872) 0.200 Cough 535 (92.1) 227 (94.6) 0.67 (0.353 – 1.257) 0.207 Sputum 471 (81.1) 196 (81.7) 0.96 (0.653 – 1.416) 0.841 Hemoptysis 27 (4.6) 10 (4.2) 1.12 (0.534 – 2.353) 0.763 Myalgia 240 (41.3) 91 (37.9) 1.15 (0.846 – 1.569) 0.368 Chill 228 (39.2) 87 (36.2) 1.14 (0.832 – 1.551) 0.423 Dyspnea 195 (33.6) 70 (29.2) 1.23 (0.884 – 1.702) 0.220 Chest pain 99 (17.0) 29 (12.1) 1.49 (0.958 – 2.331) 0.075 Diarrhea 26 (4.5) 11 (4.6) 0.98 (0.474 – 2.007) 0.946 Laboratory findings on admission, n (%)
Leukocytosis d 92/575 (16.0) 60/238 (25.2) 0.57 (0.391 – 0.836) 0.002 Granulocytopenia e 29/575 (5.0) 11/238 (4.6) 1.10 (0.538 – 2.232) 0.800 Lymphocytopenia f 120/575 (20.9) 47/238 (19.7) 1.07 (0.735 – 1.563) 0.719 Anemia g 114/575 (19.8) 46/238 (19.3) 1.03 (0.705 – 1.512) 0.871 Thrombocytopenia h 130/575 (22.6) 47/238 (19.7) 1.19 (0.817 – 1.726) 0.368 ALT >40, U/L 135/567 (23.8) 48/237 (20.3) 1.23 (0.849 – 1.783) 0.273 LDH >250, U/L 194/544 (27.4) 59/218 (27.1) 1.02 (0.714 – 1.447) 0.927 BUN >7, mmol/L 82/571 (14.4) 35/238 (14.7) 0.97 (0.634 – 1.492) 0.899 PCT, ng/mL <0.25 365/509 (71.7) 141/216 (65.3) 0.25–0.5 39/509 (7.7) 22/216 (10.2) — 0.520 0.5–1.0 40/509 (7.9) 22/216 (10.2) ≥1.0 65/509 (12.8) 31/216 (14.4) CRP ≤100, mg/L 45/344 (86.9) 18/122 (85.2) 1.15 (0.637 – 2.075) 0.642
PaO2/FiO2 <300, mmHg 204/534 (38.2) 86/234 (36.8) 1.06 (0.774 – 1.462) 0.092 Initial radiographic findings, n (%) Consolidation 241/478 (50.4) 112/210 (53.3) 0.89 (0.643 – 1.232) 0.481 Ground glass opacity 351/478 (73.4) 141/210 (67.1) 1.35 (0.951 – 1.924) 0.092 Diffuse bilateral pulmonary 176/478 (36.8) 29/210 (13.8) 3.64 (2.357 – 5.613) < 0.001 infiltration Pleural effusion 24/478 (5.0) 8/210 (3.8) 1.34 (0.590 – 3.022) 0.487 Received antibiotic treatment 461 (79.3) 178 (74.2) 1.34 (0.941 – 1.903) 0.104 before enrollment, n (%) Received antiviral treatment before 107 (18.4) 31 (12.9) 1.52 (0.988 – 2.343) 0.055 enrollment, n (%) Received antibiotic treatment 575 (99.0) 235 (97.9) 2.04 (0.616 – 6.746) 0.234 during hospitalization, n (%) Received antiviral treatment during 97 (16.7) 23 (9.6) 1.89 (1.168 – 3.062) 0.009 hospitalization, n (%)
Viral-bacterial co-infectioni 38 (6.5) 15 (6.2) 1.09 (0.601 – 1.981) 0.878 Viral-MP/CP co-infection 87 (15.0) 31 (12.9) 1.21 (0.782 – 1.864) 0.445 Categorical variables were presented as number (percentage). Continuous variables were presented as median (IQR, inter quartile range). OR: Odds ratio; COPD, chronic obstructive pulmonary disease; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; BUN, Blood urea nitrogen; PCT, procalcitonin; CRP, C-reactive protein; MP, Mycoplasma pneumoniae; CP, Chlamydia pneumoniae a: Patients detected only influenza virus with or without co-infection b: Patients detected any one of non-influenza viruses with or without co-infection c: Solid malignancy: including 6 lung cancer, 5 colon cancer, 4 stomach cancer, 4 liver cancer, 2 thyroid cancer, 1 breast cancer and 1 cervical cancer. d: Leukocytosis: Leukocyte count > 10, 000 /mm3 e: Granulocytopenia: Neutrophil < 1500 /mm3 f: Lymphocytopenia: Lymphocyte count < 800 /mm3 g: Anemia: hemoglobin < 120 g/L for men and < 110 g/L for women. h: Thrombocytopenia: platelet count < 150, 000/mm3. i: Viral-bacterial co-infection included typical bacteria and viruses co-infection (n = 57); L. pneumophila and viruses co-infection (n = 9)
Table S3. The viral etiology according to age in 2336 patients. Pathogen 14–24 yrs (n = 175) 25–44 yrs (n = 568) 45–64 yrs (n = 662) 65–84 yrs (n = 803) ≥85 yrs (n = 128) p value IFV 44 (25.1) 151 (26.6) 164 (24.8) 196 (24.4) 26 (20.3) 0.660 CoV 2 (1.1) 6 (1.1) 12 (1.8) 12 (1.2) 3 (2.3) 0.764 HMPV 1 (1.1) 2 (0.4) 8 (1.2) 15 (1.9) 1 (0.8) 0.145 HRV 4 (2.3) 6 (1.1) 5 (0.8) 14 (1.7) 0 (0.0) 0.171 AdV 8 (4.6) 24 (4.2) 12 (1.8) 10 (1.2) 2 (1.6) 0.002 PIV 3 (1.7) 4 (0.7) 15 (2.3) 11 (1.4) 2 (1.6) 0.262 RSV 5 (2.9) 11 (1.9) 16 (2.4) 21 (2.6) 4 (3.1) 0.899 ≥ 2 viruses 9 (5.1) 21 (3.7) 30 (4.5) 32 (4.0) 2 (1.1) 0.529 IFV, influenza virus types A and B; CoV, human coronavirus; HMPV, human metapneumovirus; HRV, human rhinovirus; AdV, adenovirus; PIV, parainfluenza virus; RSV, respiratory syncytial virus
Table S4. The viral etiology in 2336 patients admitted to non-ICU and ICU ward. Pathogen non-ICU (n = 2190) ICU (n = 146) p value IFV 533 (24.3) 48 (32.9) 0.023 CoV 32 (1.5) 3 (2.1) 0.722 HMPV 27 (1.2) 1 (0.7) 0.722 HRV 28 (1.3) 1 (0.7) 0.720 AdV 51 (2.3) 5 (3.4) 0.579 PIV 35 (1.6) 0 (0.0) 0.166 RSV 54 (2.5) 3 (2.1) 0.800 ≥ 2 viruses 92 (4.2) 2 (1.4) 0.123 IFV, influenza virus types A and B; CoV, human coronavirus; HMPV, human metapneumovirus; HRV, human rhinovirus; AdV, adenovirus; PIV, parainfluenza virus; RSV, respiratory syncytial virus
Table S5. Number of specific bacteria etiology among 915 patients with viral infection enrolled in final analysis and 2336 patients enrolled in CAP-China study. Patients with viral infection Cases enrolled in Bacteria enrolled in final analysis CAP-China study (n = 915) (n = 2336) S.pneumoniae 19 45 K. pneumoniae 18 32 S. aureus 8 12 P.aeruginosa 6 10 H. influenzae 2 7 A.baumannii 3 7 E.coli 2 5 S.maltophilia 4 4 L. pneumophila 9 29 Other bacteriaa 6 10 a: Other bacteria include: Serratia marcescens (n = 1), Klebsiella oxytoca (n = 1), Haemophilus parainfluenzae (n = 1), Enterobacter cloacae (n = 1), Enterobacter aerogenes (n = 1) and Acinetobacter lwoffi (n = 1) isolated from qualified sputum among 915 cases enrolled in final analysis. Serratia marcescens (n = 1), Enterobacter cloacae (n = 4), Enterobacter aerogenes (n = 1), Haemophilus parainfluenzae (n = 1), Klebsiella oxytoca (n = 1) and Acinetobacter lwoffi (n = 1) isolated from qualified sputum; Streptococcus constellatus (n = 1) isolated from blood among 2336 cases enrolled in CAP-China study.
Table S6. Comparison of disease severity, complications and outcomes between patients with influenza and non-influenza viral infection Influenza viral Non-influenza
Variables infection a viral infection b OR (95% CI) p value N = 581 N = 240 CURB-65 ≥3 on admission, n (%) 28/571 (4.9) 9/238 (3.8) 0.76 (0.354 – 1.641) 0.486
PaO2/FiO2 <200, mmHg on admission, n (%) 46/534 (8.6) 12/234 (5.1) 0.57 (0.298 – 1.104) 0.092 Complications during hospitalization, n (%) Sepsis 233 (40.1) 95 (39.6) 0.98 (0.720 – 1.331) 0.890
Hypoxemiac 214/534 (40.1) 87/234 (37.2) 0.89 (0.645 – 1.215) 0.449 ICU admission, n (%) 48 (8.3) 13 (5.4) 0.63 (0.338 – 1.197) 0.157 Invasive mechanical ventilation, n (%) 30 (5.2) 5 (2.1) 0.39 (0.150 – 1.020) 0.056 Length of hospital stay, median (IQR), days 10.0 (8.0-14.0) 10.0 (7.0-14.0) — 0.986 In-hospital mortality, n (%) 16 (2.8) 1 (0.4) 0.15 (0.019 – 1.120) 0.062 90-day mortality 22 (3.8) 4 (1.7) 0.43 (0.147 – 1.263) 0.174 Categorical variables were presented as number (percentage). Continuous variables were presented as median (IQR, inter quartile range). OR: Odds ratio; ICU: Intensive care unit. a: Patients detected only influenza virus with or without co-infection. b: Patients detected any one of non-influenza viruses with or without co-infection. c: Hypoxemia: PaO2/FiO2 <300 mmHg.
Table S7. Variables associated with CURB-65 ≥3 and PaO2/FiO2 <200 mmHg on admission, occurrence of hypoxemia and sepsis during hospitalization, and 90-day mortality in multivariable analysis
PaO2/FiO2 <200 mmHg on Sepsis during Hypoxemia during CURB-65 ≥3 on admission 90-day mortality Variables * admission hospitalization hospitalization OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p HR (95% CI) p Male NS — NS NS — Time from illness onset NS — NS — — to hospitalization Fever NS NS NS NS — Cough NS NS — — — Sputum production NS NS — — NS Hemoptysis — — NS NS — Dyspnea — 2.33 (1.05-5.19) 0.038 NS 2.38 (1.60-3.56) < 0.001 — Chill — — 1.53 (1.02-2.27) 0.038 1.67 (1.11-2.47) 0.013 — Myalgia — — — — — Diarrhea — — NS NS — Received antibiotic treatment before — — — — — enrollment COPD — — NS NS — Diabetes 3.78 (1.28-11.12) 0.16 — 1.76 (1.04-3.01) 0.037 NS NS Cardiovascular disease NS — 1.95 (1.28-2.97) 0.002 2.30 (1.50-3.51) < 0.001 NS Liver disease — NS NS — NS Chronic renal failure NS NS NS NS — HR ≥125, beats/min 4.57 (1.35-15.48) 0.015 NS NS NS NS Leukocytosis a NS NS 2.69 (1.71-4.23) < 0.001 2.06 (1.29-3.29) 0.002 — Granulocytopenia b — — — NS — Lymphocytopenia c NS 2.64 (1.20-5.77) 0.15 2.23 (1.32-3.79) 0.003 2.22 (1.36-3.64) 0.002 NS Anemia d NS NS NS NS — Thrombocytopenia e NS NS 5.08 (3.10-8.30) < 0.001 NS NS LDH >250, U/L NS 5.87 (2.53-13.65) < 0.001 1.85 (1.17-2.92) 0.009 1.60 (1.01-2.53) 0.044 8.34 (1.69-41.24) 0.009 ALT >40, U/L — NS — NS NS PCT, ng/mL — PCT < 0.25 Reference Reference Reference Reference Reference 0.25 ≤ PCT < 0.5 NS 3.12 (1.05-9.74) 0.041 NS NS NS 0.5 ≤ PCT < 1.0 17.00 (3.77-26.71) 0.001 NS NS 2.29 (1.17-4.51) 0.016 NS PCT ≥ 1.0 9.64 (2.40-28.73) 0.016 3.60 (1.39-9.34) 0.008 NS 2.34 (1.29-4.26) 0.005 NS
PaO2/FiO2 7.45 (2.66-12.9) < 0.001 — — — 15.26 (4.44-52.12) < 0.001 <200, mmHg Treated with NAI — — NS NS NS during hospitalization Treated with systemic corticosteroid during — — NS NS NS hospitalization Consolidation NS NS NS NS NS Ground glass opacity — — NS NS — Diffuse bilateral NS 4.02 (1.84-8.79) 0.001 NS NS NS pulmonary infiltration Pleural effusion NS — NS 2.73 (1.12-6.63) 0.027 — CURB-65 ≥3 — 4.97 (1.71-14.47) 0.003 NS NS 5.863 (2.32-14.84) < 0.001 Pathogen detected Viral detection only Reference Reference Reference Reference Reference Viral-Bacterial NS NS NS NS NS co-detection Viral-MP/CP NS NS NS NS NS co-detection Viral-Bacterial- NS NS NS NS NS MP/CP co-infection NS, not significant; COPD, chronic obstructive pulmonary disease; HR, heart rate; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; PCT, procalcitonin; NAI: neuraminidase inhibitors; MP, Mycoplasma pneumoniae; CP, Chlamydia pneumoniae; OR; odds ratio; HR, hazard ratio. *: Co-infections, fever, elevated level of PCT, leukocytosis, lobar consolidation and all variables that p < 0.2 in the univariate analysis were included in multivariable regression analysis. —: Not included in multivariable regression analysis. a: Leukocytosis: Leukocyte count > 10, 000 /mm3. b: Granulocytopenia: Neutrophil < 1, 500 /mm3. c: Lymphocytopenia: Lymphocyte count < 800 /mm3. d: Anemia: hemoglobin <120 g/L for men and <110 g/L for women. e: Thrombocytopenia: platelet count < 150, 000/mm3.
Table S8. Characteristics of hospitalized patients with viral infection displayed by different viral pathogen IFV CoV HMPV HRV AdV PIV RSV ≥ two viruses N = 581 N = 35 N = 28 N = 29 N = 56 N = 35 N = 57 N = 94 58.0 62.0 67.0 58.0 39.5 56 62.0 59.5 Age, median (IQR), years (36.0-72.5) (46.0-75.0) (53.8-79.8) (34.0-74.0) (29.0-62.8) (50.0-73.0) (33.0-76.0) (37.0-72.0) Male, n (%) 312 (53.7) 21 (60.0) 12 (42.9) 19 (69.5) 37 (66.1) 17 (48.6) 30 (52.6) 57 (60.6) Duration from illness onset to 5.0 (3.0-7.0) 4.0 (2.0-7.0) 3.5 (2.3-6.8) 6.0 (2.5-8.0) 5.0 (3.0-7.0) 4.0 (2.0-7.0) 4.0 (3.0-7.5) 6.0 (3.0-8.5) hospitalization, n (%) Underlying Disease, n (%) Cardiovascular Disease 181 (31.2) 11 (31.4) 12 (42.9) 12 (41.4) 12 (21.4) 14 (40.0) 16 (28.1) 28 (29.8) Diabetes 82 (14.1) 5 (14.3) 4 (14.3) 2 (6.9) 4 (7.1) 10 (28.6) 13 (22.8) 14 (14.9) COPD 27 (4.6) 1 (2.9) 2 (7.1) 4 (13.8) 1 (1.8) 3(8.6) 2 (3.5) 5 (5.3) Chronic renal failure 29 (5.0) 2 (5.7) 2 (7.1) 0 (0.0) 1(1.8) 2 (5.7) 2 (3.5) 3 (3.2) Asthma 20 (3.4) 0 (0.0) 1 (3.6) 1 (3.4) 2 (3.6) 2 (5.7) 0 (0.0) 4(4.3) Solid malignancy a 14 (2.4) 1 (2.9) 2 (7.1) 1 (3.4) 1 (1.8) 0 (0.0) 1 (1.8) 3 (3.2) Liver disease 12 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 1 (2.9) 0 (0.0) 2 (2.1) Symptoms, n (%) Fever 482 (83.0) 26 (74.3) 20 (71.4) 23 (79.3) 49 (87.5) 28 (80.0) 44 (77.2) 72 (76.6) Cough 535 (92.1) 32 (91.4) 28 (100.0) 27 (93.1) 53 (94.6) 33 (94.3) 54 (94.7) 89 (94.7) Sputum productions 471 (81.1) 27 (77.1) 28 (100.0) 22 (75.9) 43 (76.8) 30 (85.7) 46 (80.7) 77 (81.9) Hemoptysis 27 (4.6) 3 (8.6) 3 (10.7) 0 (0.0) 0 (0.0) 2 (5.7) 2 (3.5) 11 (11.7) Myalgia 240 (41.3) 16 (45.7) 8 (28.6) 9 (31.0) 26 (46.4) 14 (40.0) 18 (31.6) 33 (35.1) Chill 228 (39.2) 10 (28.6) 8 (28.6) 10 (34.5) 31 (55.4) 9 (25.7) 19 (33.3) 37 (39.4) Dyspnea 195 (33.6) 8 (22.9) 12 (42.9) 12 (41.4) 15 (26.8) 12 (34.3) 11 (19.3) 38 (40.4) Chest pain 99 (17.0) 6 (17.1) 0 (0.0) 4 (13.8) 9 (16.1) 6 (17.1) 4 (7.0) 19 (20.2) Diarrhea 26 (4.5) 1 (2.9) 0 (0.0) 1 (3.4) 8 (14.3) 0 (0.0) 1 (1.8) 3 (3.2) Laboratory finding on admission, n (%) Leukocytosis b 92/575 (16.0) 11 (31.4) 7 (25.0) 10 (34.5) 14/55 (25.6) 4 (11.4) 14/56 (25.0) 23 (24.5) Leukopenia c 83/575 (14.4) 4 (11.4) 3 (10.7) 2 (6.9) 8/55 (14.5) 3 (8.6) 5/56 (8.9) 10 (10.6) Granulocytopenia d 29/575 (5.0) 0 (0.0) 2 (7.1) 0 (0.0) 4/55 (7.3) 3 (8.6) 2/56 (3.6) 4 (4.3) Lymphocytopenia e 120/575 (20.9) 6 (17.1) 5 (17.9) 7 (24.1) 18/55 (32.7) 2 (5.7) 9/56 (16.1) 21 (22.3) Anemia f 114/575 (19.8) 7 (20.0) 4 (14.3) 8 (27.6) 12/55 (21.8) 3 (8.6) 12/56 (21.4) 24 (25.5) Thrombocytopenia g 130/575 (22.6) 4 (11.4) 4 (14.3) 5 (17.2) 18/55 (44.2) 8 (22.9) 8/56 (14.3) 16 (17.0) LDH >250, U/L 149/544 (27.4) 7/31 (22.6) 3/27 (11.1) 5 (17.2) 23/52 (51.2) 8/30 (26.7) 13/49 (26.5) 16/82 (19.5) ALT >40, U/L 135/567 (23.8) 6 (17.1) 4 (14.3) 5 (17.2) 11/54 (20.4) 10/34 (29.4) 12/ (21.1) 16/92 (17.4) BUN >7, mmol/L 82/571 (14.4) 8 (22.9) 6 (21.4) 8 (27.6) 5/55 (9.1) 3/34 (8.8) 5 (8.8) 14 (14.9) PCT >1, ng/ml 64/509 (12.6) 7/31 (22.6) 4/27 (14.8) 3/25 (12.0) 11/52 (21.2) 1/32 (3.1) 5/46 (10.9) 12/87 (13.8) CRP >100, mg/ml 45/344 (13.1) 1/17 (5.6) 1/12 (8.3) 5/16 (31.2) 4/40 (20.0) 1/16 (6.2) 6/20 (30.0) 5/62(8.1)
PaO2/ FiO2 <300, mmHg 204/534 (38.2) 15/34 (44.1) 13 (46.4) 12/28 (42.8) 20/54 (37.0) 13/34 (38.2) 13/56 (23.2) 37/87 (42.5) Received antibiotic treatment before 461 (79.3) 26 (74.3) 22 (78.6) 17 (58.6) 47 (83.9) 24 (68.6) 42 (73.7) 66 (70.2) enrollment Received antibiotic treatment during 575 (99.0) 34 (97.1) 28 (100.0) 29 (100.0) 55 (98.2) 33 (94.3) 56 (98.2) 94 (100.0) hospitalization Received NAI treatment during 87 (15.0) 2 (5.7) 0 (0.0) 2 (6.9) 9 (16.1) 1 (2.9) 3 (5.3) 8 (8.5) hospitalization Viral-bacterial co-infection 38 (6.5) 0 (0.0) 3 (10.7) 4 (13.8) 3 (5.4) 3 (8.6) 2 (3.5) 13 (13.8) Viral-MP/CP co-infection 87 (15.0) 6 (17.1) 3 (10.7) 1 (3.4) 8 (14.3) 3 (8.6) 10 (17.5) 12 (12.8) Initial radiographic findings, n (%) Consolidation 241/478 (50.4) 19/33 (57.6) 14/26 (53.8) 8/22 (36.4) 41/49 (83.7) 10/32 (31.2) 20/48 (41.7) 42/71 (59.2) Ground glass opacity 351/478 (73.4) 22/33 (66.7) 19/26 (73.1) 17/22 (77.3) 18/49 (36.7) 28/32 (87.5) 37/48 (77.1) 50/71 (70.4) Diffuse bilateral pulmonary infiltration 176/478 (36.8) 4/33 (12.1) 3/26 (11.5) 4/22 (18.2) 2/49 (4.1) 8/32 (25.0) 8/48 (16.7) 20/71 (28.2) Pleural effusion 24/478 (5.0) 3/33 (9.1) 1/26 (3.8) 1/22 (4.5) 1/49 (2.0) 1/32 (3.1) 1/48 (2.1) 4/71 (5.6) IFV, influenza virus types A and B; RSV, respiratory syncytial virus; CoV, human coronavirus; AdV, adenovirus; PIV, parainfluenza; HMPV, human metapneumovirus; HRV, human rhinovirus; COPD, chronic obstructive pulmonary disease; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; PCT, procalcitonin; CRP, C-reactive protein; NAI: neuraminidase inhibitor; MP, Mycoplasma pneumoniae; CP, Chlamydia pneumoniae. a: Solid malignancy: including 6 lung cancer, 5 colon cancer, 4 stomach cancer, 4 liver cancer, 2 thyroid cancer, 1 breast cancer and 1 cervical cancer. b: Leukocytosis: Leukocyte count > 10, 000 /mm3. c: Leukopenia: Leukocyte count < 4, 000 /mm3. d: Granulocytopenia: Neutrophil < 1500 /mm3. e: Lymphocytopenia: Lymphocyte count < 800 /mm3. f: Anemia: hemoglobin <120 g/L for men and <110 g/L for women. 3 g: Thrombocytopenia: platelet count < 150, 000/mm .
300 the number of patients enrolled in CAP-China study in different month the number of patients with viral infection in different month 250
200
150
100
50
0 Oct. Nov. Dec. Jan. Feb. Mar. Apr. May. June. July. Aug. Sept. Oct. Nov. Dec. Jan. Feb. Mar. Apr. May. June.
2015 2016 2017 Figure S1. Monthly distribution of hospitalized patients with CAP enrolled in this study. About 41% of 2336 patients were enrolled during influenza pandemic season (from November to February of next years)