Article:The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09 (6286525)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at Its title is The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09 and the publication date was 2018-12-07. The initial author is Chandini Raina MacIntyre.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.

Converted JATS paper:

Journal Information

Title: BMC Infectious Diseases

The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09

  • Chandini Raina MacIntyre
  • Abrar Ahmad Chughtai
  • Michelle Barnes
  • Iman Ridda
  • Holly Seale
  • Renin Toms
  • Anita Heywood

Publication date (epub): 12/2018

Publication date (pmc-release): 12/2018

Publication date (collection): /2018



The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the pandemic of influenza A(H1N1)pdm09.


A systematic review was conducted to identify relevant literature in which clinical outcomes of pandemic influenza A(H1N1)pdm09 infection were described. Published studies (between 01/01/2009 and 05/07/2012) describing cases of fatal or hospitalised A(H1N1)pdm09 and including data on bacterial testing or co-infection.


Seventy five studies met the inclusion criteria. Fatal cases with autopsy specimen testing were reported in 11 studies, in which any co-infection was identified in 23% of cases (Streptococcus pneumoniae 29%). Eleven studies reported bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia, with a mean of 19% positive for bacteria (Streptococcus pneumoniae 54%). Of 16 studies of intensive care unit (ICU) patients, bacterial co-infection identified in a mean of 19% of cases (Streptococcus pneumoniae 26%). The mean prevalence of bacterial co-infection was 12% in studies of hospitalised patients not requiring ICU (Streptococcus pneumoniae 33%) and 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards (Streptococcus pneumoniae 16%).


We found that few studies of the 2009 influenza pandemic reported on bacterial complications and testing. Of studies which did report on this, secondary bacterial infection was identified in almost one in four patients, with Streptococcus pneumoniae the most common bacteria identified. Bacterial complications were associated with serious outcomes such as death and admission to intensive care. Prevention and treatment of bacterial secondary infection should be an integral part of pandemic planning, and improved uptake of routine pneumococcal vaccination in adults with an indication may reduce the impact of a pandemic.



Influenza pandemics cause morbidity and mortality from both direct viral effects, which tend to present early (within the first few days), and secondary bacterial complications, which tend to present later (after the first week). Evidence of influenza predisposing to bacterial co-infection is seen in seasonal influenza epidemics, past pandemics, pathology studies and animal models [[1][8]]. Infection with influenza disrupts the respiratory tract by direct pathogenic effects, which then predisposes to bacterial secondary infection. Conversely, bacterial pathogens in the respiratory tract may also predispose to influenza and other viral infection [[9]]. During the 1918 pandemic, bacterial pneumonia was a major cause of morbidity and mortality, as shown by studies at the time as well as retrospective study of pathology specimens [[10], [11]]. At that time, antibiotics were not widely available as they are now, and it is thought that the high observed mortality rate was partially due to the inability to treat secondary bacterial sepsis. The most important bacterial co-infections during an influenza pandemic S. pneumoniae, H. influenzae, S. aureus, and group A Streptococcus (1, 4). However, two early reviews of severe cases of 2009 pandemic influenza A (H1N1) showed no evidence of bacterial pneumonia among 30 hospitalized patients with laboratory-confirmed cases in California (5) and 10 intensive-care patients in Michigan (6). These reports might have led to a perception that bacterial co-infections played a limited role or no role in pandemic influenza deaths in 2009.

The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the 2009 pandemic of influenza A(H1N1)pdm09.


Search strategy

A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) [[12]].We sought primary studies that presented quantitative data of invasive bacterial co-infection in influenza A(H1N1)pdm09 patients, defined as isolation of a bacterial pathogen from a sterile site. Databases searched included Medline, Pre-Medline, EmBASE and LILACS. The search strategy included a combination of Medical Subject Headings (MeSH) and text words to improve the identification of relevant publications in which bacterial co-infection was not necessarily the primary outcome of interest. The World Health Organisation (WHO) advised on the use of the standardised nomenclature influenza A(H1N1)pdm09 in October 2011 [[13]]. Prior to this time, various names were used to describe the pandemic virus. As such, a broad search strategy was developed to identify relevant literature in which clinical outcomes of influenza A(H1N1)pdm09 infection were described.

The Medline search included a combination of two searches. The first included the MeSH term influenza A H1N1 subtype OR text words influenza or flu adjacent to H1N1/pandemic/swine AND the MeSH term bacterial infections OR text words bacteria*, streptococcus, pneumococcus or staphylococcus adjacent to pneumonia, secondary, infection or evidence. The second search strategy included the influenza search terms and a combination of severity terms including fatal, severe, death, mortality, morbidity, hospitalisation, critical and admitted. The same search terms were applied to the other databases, after ensuring the MeSH terms of the relevant search terms were consistent across databases. Searches were limited to human studies, published in the English language between 01/01/2009 and 05/07/2012 or accessible online, ahead of print within this timeframe. Hand-searching of the reference lists of included studies and relevant reviews were also undertaken to identify other relevant papers.

Inclusion and exclusion criteria

We included all studies of influenza A(H1N1)pdm09 which report bacterial infections (any sterile site) in influenza A(H1N1)pdm09 cases. Studies including only specific at-risk populations such as transplant or oncology patients or pregnant women were excluded. We included published English language papers of observational studies reporting on ≥10 influenza A(H1N1)pdm09 patients. Case reports and small case series of < 10 patients were also excluded.

Included cases were either fatal or hospitalised cases of confirmed or probable influenza A(H1N1)pdm09 confirmed by PCR or culture. Probable cases (13/75 studies) included those with positive influenza A serology during 2009–2010, but not testing of subtype.

However, studies which included a mixed cohort of influenza A(H1N1)pdm09 and other laboratory-confirmed influenza strains or influenza negative cases were only included if clinical outcomes could be distinguished between influenza A(H1N1)pdm09 and other confirmed strains. We excluded studies which described ambulatory influenza A(H1N1)pdm09 cases, including notifications, clinic visits or Emergency Department visits with no sub-group analysis in which hospital admission or death of patients was described.

For included studies, the definition of co-infection was broad and included any study reporting either pulmonary infection or site unspecified with or without data on bacterial type tested, or specimen tested, including those reporting negative findings. We excluded studies reporting suspected bacterial pneumonia on the basis of clinical findings alone and studies which tested specimens for presence of co-infection with respiratory viruses only. Studies reporting contamination of endotracheal tubes only and those in which patients were recruited on the basis of bacterial infection were excluded if no data on other results were reported. We present the number of cases of reported pneumonia and those requiring mechanical ventilation as per the investigators definition.

Data extraction and assessment

Five reviewers (AH, MB, RT, IR,, HS,) with experience in conducting systematic reviews independently reviewed the titles and abstracts to identify potentially relevant papers. All potentially relevant papers were read by two reviewers (AH, MB) to determine those which met the selection criteria. The results of the search strategy are shown in Fig. 1. An identical data extraction template was used by all reviewers to extract the clinical outcomes, diagnostic data and treatment. Clinical outcomes included the diagnosis of bacterial co-infection, pneumonia, and death. Treatment included mechanical ventilation and use of antibiotics. Diagnostic data included determination of pneumonia and bacterial testing. We also extracted methodological details of the relevant studies including study design, study location and methods of case ascertainment. To ensure consistency in data extraction, each study was independently data extracted by two reviewers. All findings, including discrepancies between reviewers were discussed with an independent senior reviewer (CRM).Fig. 1

Study diagram

We report bacterial findings separately from pulmonary specimens when available. When site of specimen is not specified or combined, this is reported as such. We report the percentage of tested cases positive for bacteria when available. The variability of the available data precluded the aggregation of results in a quantitative meta-analysis. Results of the studies are summarised and a critically evaluation and interpretation provided. We present results separately for fatal cases, hospitalised cases with confirmed pneumonia, cases admitted to intensive care units (ICU) and hospitalised cases admitted to general wards including criteria for admission if reported. Pneumonia, hospital admission and ICU admission were accepted according to classification in the reviewed papers.


Summary of included studies

A total of 7845 studies were identified on the 2009 pandemic, of which 1444 articles were initially identified from our search of studies potentially about both influenza A(H1N1)pdm09 and bacterial infection. After removal of duplicates, non-human, non-English language, and non-influenza A(H1N1)pdm09 studies, 863 articles remained and abstracts were reviewed. Of those, 350 full papers were reviewed for relevance and 75 studies met the inclusion criteria. The PRISMA diagram of the study selection is shown in Fig. 1.

Reporting of patient clinical outcomes, bacterial testing and bacterial findings varied widely in the included published studies. It was not clear in many studies if pneumonia was community or hospital acquired. The studies also varied in their methodologies and proportion of patients tested, as well as reporting of bacterial testing. Samples and time of sampling were not adequately described in most of the studies.

Eleven studies were on fatal cases, including eight reporting autopsy results and three studies reporting bacterial findings from medical record reviews of notified deaths of confirmed influenza A(H1N1)pdm09. The remaining studies reported bacterial findings from hospitalised cases. Figure 2 shows the average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients.Fig. 2

Average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients

Bacterial co-infection among fatal cases of A(H1N1)2009pdm

Eleven studies reported evidence of bacterial co-infection of fatal confirmed cases of influenza A(H1N1)pdm09 occurring between April 2009 and May 2010 [[1], [2], [14][22]]. Eight studies reported autopsy results, including 8 autopsy case series [[1], [2], [16][19], [21], [22]] and 3 reporting bacterial findings from medical records reviews only [[14], [15], [20]]. Five studies were based in the USA [[1], [2], [15], [16], [18]] while the others were from Mexico [[14]], Estonia [[22]], Brazil [[17]], the United Kingdom [[19]], Korea [[20]] and Japan [[21]].

Influenza A(H1N1)pdm09 infection was confirmed by reverse transcriptase polymerase chain reaction (rtPCR) in either ante-mortem nasopharyngeal swab or post-mortem lung tissue specimens for all cases in all studies. Case definitions for an included fatal case reflected national surveillance reporting and/or autopsy requirements during the pandemic period and enhanced surveillance for the identification of fatal cases included the review of the death certificate registries for influenza as a cause of death.

The study details, bacterial testing and bacterial findings are summarised in Table 1. Where data were available, 44–100% of cases were hospitalised before death, including 55–100% in ICUs, with 35–100% requiring mechanical ventilation support during their hospitalisation and 25–94% of patients with clinical and/or autopsy evidence of pneumonia (viral or bacterial). From chart reviews, positive bacterial growth ranged from 2 to 38% (mean bacterial 23%) [[9]] of autopsied cases. Of the total coinfection cases, 29% were Streptococcus pneumoniae. The overall rate of bacterial infection was significantly higher in fatal cases compared to nonfatal cases (OR 1.71, 95% CI 1.33 to 2.20). The Korean study of standardised case reports of A(H1N1)pdm09-associated deaths identified during a period of active surveillance estimated ILI case-fatality rate to be 16 per 100,000 cases [[20]].Table 1

Bacterial co-infection among the fatal cases of A(H1N1)2009pdm (n = 11)

Author (year)Study location/ period Study type Study population N (%) autopsied N (%) hospitalised prior to death Requirement for Antiviralsan/N (%) any n/N (%) 48 h Antibioticsbn/N (%) pre n/N (%) onn/N (%) during admission Positive bacterial growth N (%) bacterial pneumonia N (%) with S.pneumoniaeSite of isolation
ICU Mechanical Ventilation
Fajardo-Dolci (2009) [[14]]Mexico16/3/09–16/5/09 Medical record review N = 100Consecutive notified hospitalized fatal cases 0/100 (0) 100/100 (100) NR 84/100 (84.0) 56/100 (56)NR 94/100 (94) 2/100 (2%)(Site not mentioned) 77/82 (94.0)CXR suggestive of pneumonia. NR
Lee (2010) [[1]]USA4/09–7/09 Enhanced surveillance/confirmed cases in New York City. N = 47 31/47 (66) 47/47 (100.0) All 28 cases who died after > 24 in hospital were admitted to ICU 25/47 (80.6) 32/47 (68.0)NR NR NR 13/47 (27.6)By immunohistochemical analysis or PCR21/28 with abnormal CXR and multilobar infiltrates. 8/47 (17.0) Lung/airway tissueBy immunohistochemical analysis or PCR
Lucas (2010) [[19]]UK4/09–1/10 Case series.15% of reported H1N1 deaths N = 68Autopsied fatal cases 68/68 (100) 68/68 (100) NR NR NR NR 20/68 (29.4)(Culture of lung/ blood) 28/68 (41.2)- Autopsy findings- Culture and histopathology 7/68 (10.3)(6 confirmed and 1 possible through histology) isolation site Lung/ and or blood
Gill (2010) [[2]]USA5/09–7/09 Case series.Autopsy request New York City (NYC) Office of chief medical examiner (n = 32), family requests (n = 10), deaths outside of NYC (n = 2) N = 34Autopsied fatal cases 34/34 (100) 21/34 (61.8) NR 12/21 (57.1) NR NR 10/30 (33.3) Positive bacteria by culture, immunohistochemistry, and/or PCR 18/33 (54.4) have evidence of bacterial co-infection by tissue Gram stain. 6/30 (20) Positive for streptococcus by culture, immunohistochemistry, and/or PCR16/33 (55) have evidence of bacterial co-infection by tissue Gram stain morphologically compatible with streptococcus.
CDC (2009) [[15]]USA4/09–8/09 Multicenter case series.100% of reported deaths N = 36Pediatric (< 18 yrs).Hospitalized fatal cases NR 28/33 (84.8) 24/36 (66.7) NR 19/30 (63.3)Status unknown for 6 cases4/30 (13%) NR NR 10/23 (43.5)Based on culture and pathology results 3/23 (13) from multiple sites in px (BC, lung tissue, pleural fluid, CSF)
Shieh (2010) [[18]]USA5/09–10/09 Notified fatal case series/US CDC N = 100Autopsied fatal cases 100/100 (100) 58/87 (66.7) NR 42/57 (73.7) 44/67 (65.7)NR NR NR 29/100 (29)Bacterial co-infection positive through PCR and histopathology on lung tissue38/64 (59) radiological diagnosis of pneumonia 10/100 (10)Lung tissue through PCR
CDC (2009) [[16]]USA5/09–8/09 Case series (US CDC), multiple (8) states N = 77Autopsied fatal cases 77/77 (100) 8/18 (44.0) NR 7/7 (100.0) NR 7/9 (77.8) NR 22/77 (28.6)Histopathology and positive PCR for bacteria 10/77 (positive through immunohistochemical assays) respiratory tissue
Mauad (2010) [[17]]Brazil7/09–8/09 Case series N = 21Autopsied fatal cases 21 (100) 21 (100.0) 16/21 (76.2) 21/21 (100.0) 16/21 (76.2)NR 13/21 (61.9) 3/9 (33.3) 8/21 (38.1) 6/21 (28.6) diagnosed by culture of bronchial aspirate and/or tissue PCR
Kim (2011) [[20]]Korea8/09–11/09 Active mortality inpatient surveillance N = 115Notified hospitalized fatal cases 0/115 (0) 115/115 (100%) 63/115 (54.8) NR 100/115 (87%)41/115 (35.6) NR 34/115 (29.6) positive on blood or sputum culture 34/115 (29.6) positive on blood or sputum culture97/113 (85.8)CXR suggestive of pneumonia 3/115 (2.6) bronchoalveolar lavage (BAL)Streptococcus was also isolated from blood of one case
Nakajima (2012) [[21]]Japan8/09–2/10 Multicenter (15), case series, Tokyo. N = 20Autopsied fatal cases 20/20 (100) 11/20 (55.0) NR 7/20 (35.0) 14/20 (70%)13/20 (65%) 10/20 (50%) 4/11 (36.4%) 5/20 (25%) Based on histopathological finding (bacteria isolated in 4 of 5) 2/10 (20%)sputum, blood cultures; lung tissue
Tamme (2012) [[22]]Estonia10/09–5/10 Case series N = 21Autopsied fatal cases 19/21 (90) 17/21 (81.0) 15/21(71.4) NR 3/21 (14.3)1/21 (4.8%) 16/21 (76.2) 8/21 (38.1)(Culture performed on 14 samples) 9/21 (42.8)Culture or Autopsy findings consistent with sepsis or bacterial infection 2/21 (9.5)Blood and/or lung tissue culture

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

aNumber (percentage) of cases on antivirals; N (%) started within 48 h of symptom onset

bNumber (percentage) of cases on antibiotics commencing pre-admission, on admission or during admission (if reported)

The lowest proportion of co-infection was reported in the first 100 confirmed deaths in Mexico [[14]] where 94% of patients had multiple foci of pneumonia (based on imaging) and 84% required mechanical ventilation, and only 2 cases had positive bacterial cultures (Staphylococcus epidermidis and Staphylococcus hominis). Of the eight autopsy case series, 3 studies tested lung tissue specimens for evidence of bacterial infection in all included subjects [[16][18]] and identified bacterial co-infection diagnosed either before or after death in between 29 and 43% of fatal cases [[16][18]]. The highest proportion of culture positive bacterial co-infection from autopsy samples (38%) was reported by Tamme [[22]].

The reported post-mortem bacteriologic samples included culture, immunohistochemistry and PCR. No studies gave a complete picture of pulmonary bacterial co-infection during the clinical course and corresponding post-mortem findings. Bacterial co-infection identified prior to death was identified from clinically driven testing and no studies had a standardised testing protocol for all included fatal cases. On this basis, bacterial infection complicating A(H1N1)pdm09 ranged from 5 to 14% of fatal cases in the four studies [[1], [17], [21], [22]] reporting data from clinical testing prior to death (Table 1). Specimens obtained included sputum, bronchial aspirates and bronchoalveolar lavage, but no studies reported details of testing conducted prior to death, including the proportion tested, or the types of bacteria tested for.

Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia

Eleven studies reported on influenza A(H1N1)pdm09 among hospitalised cases with evidence of pneumonia and are summarised in Table 2. Pneumonia was largely defined based on radiological findings in these studies. Any positive bacterial testing was reported in 9/11 studies and positive bacterial growth was ranged from 0 to 47% (mean 19%). Streptococcus pneumoniae was the most commonly isolated pathogen (54%). In these 9 studies, Acinobacter baumanii was the next most commonly identified bacteria (5–21%), followed by MRSA (3–6%), S. pneumoniae (2–4%) and K. Pneumonia in (1–8%). Of the 11 studies, 2 reported no evidence of bacterial co-infection in their cohort of patients [[4], [23]], however, neither reported the proportion of patients tested. The study conducted in Mexico early in the pandemic [[23]] isolated ventilator-associated bacteria in 4 (22%) cases, with Acinetobacter baumannii, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus, and Escherichia coli identified.Table 2

Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia (n = 11)

Author and year Study type Study population Case severity Antivirals*n/N (%) anyn/N (%) 48 h Antibiotics†n/N (%) pren/N (%) onn/N (%) during admission Any positive bacterial growth n/N (%) S.pneumoniae[Site of isolation] N (%)pneumoniaMethodDiff/no diff
ICU Mechanical Ventilation Deaths
Perez-Padilla (2009) [[23]]Mexico3/09–4/09 Single-centre case series (retrospective medical record review) of patients admitted to hospital with pneumonia and A(H1N1)pdm09 (N = 18) N = 18 12/18 (66.7) 12/18 (66.7) 7/18 (38.9) 14/18 (77.7) 12/18 pre (66.7)17/18 post (94.4) 0/6 (0) BC0/2 (0) BA0/1 (0) pleural fluid4/18 (22.2) Ventilator Associated pneumonia 0/18 [NR]NP swab and bronchial aspirates 18 (100)CXRNo diff
Chien (2010) [[3]]Taiwan07/09–8/09 Nation-wide notified cases (retrospective medical record review)New pulmonary infiltrates consistent with pneumonia, compatible clinical presentations.Identification of clinicalyl significant bacteria in respiratory secretion or specimens from sterile compartments was recorded as secondary bacterial infection. N = 96 35/96 (36.5) NR 10/96 (10.4) 96/96 (100.0)- NR NR 13/96 (13.2) pulmonary NFI (13.5) 2/99 (2) [Respiratory secretions] 13 (13.5)CXR positive
Champunot (2010) [[53]]Thailand7/09–10/09 Single-centre case series (prospective);Community acquired, new pulmonary infiltrate (CXR) within 24 h of admission, clinical symptoms N = 24 13/24 (54.2) 11/24 (45.8) 5/24 (8.3) 24/24 (100%)- NR 21/24 (87.5)- Pre = 6 Blood culture 0/24 (0)Sputum culture 2/24(8.3)1/24 (4.2) [urine pneumococcal AgTOTAL 3/24 (12.5) 1/24 (4.2) [urine pneumococcal Ag] 24 (100.0)CXRNo diff
Cui (2010) [[24]]China11/09–12/09 Single-centre case series (retrospective medical record review) of patients admitted to a tertiary hospital with pneumonia and H1N1(N = 68)Blood cultures (BC) - Any patient with high fever > 38.0 °C for ≥3 days or repeated fever.Sputum cultures (SC) - patients with symptoms of expectoration especially with yellowish/purulent sputum. N = 68 30/68 (44) 13/68 (19.1) 10/68 (14.7) 68/68 (100.0)50/68 (74%) All received antibiotics65/68 (95.6) received preadmission antibiotics 5/11 (45.5) [BC]9/29 (31.0) [SC]Total 11/29 (37.9) 0/11 (0.0) [BC]0/29 (0.0) [SC] 68/68 (100.0)CXRNo diff
Cuquemelle [[54]](2011)France11/09–4/10 Multicenter (24) case series (retrospective)/ not having received prior antibiotics (N = 103)Microbiological investigations and biomarker levels were obtained as part of the routine clinical management of patients, at the discretion of the treating physician N = 103 103/103 (100) 62/103 (60.2) 18/103 (17.5) NR 0/103 (0) 48/103 (46.6)Isolation of bacteria 26/103 (25.2) [NS] Infiltrates on all CXR
Choi [[55]] Definition: the presence of an infiltrate on plain chest radiograph. N = 17 17/17 (100)All in acute care unit 1/17 (5.9) 1/17 (5.9) 17/17 (100) 17/17 (100) 0/17 (0) BC0/17 (0) SC2/17 (11.8) urine Ag test (Legionella)1/17 (5.9) PCR (TB) 0/17 (100)Testing for S. pneumo 16/17 (94.1)CXRNo diff
Viasus [[56]] Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature 38.0-C) and/or respiratory symptoms N = 234 (210 tested for microbiologic studies) 53/234 (22.6) 42/234 (17.9) 12/234 (5.1) 229/234 (97.9)50/234 (22.4) 228/234 (97.9) 36/210 (17.1)Specimens included: culture of blood, normally sterile fluids, or sputum and/or a positive urinary antigen test 26/210 (12.4) All CXR positive
Piacentini [[57]] Compares H1N1 with pneumonia in ICU and community acquired N = 10 10/10 (100) 5/10 (50) 0/10 (0) 10/10 (100) 10/10 (100) 2/10 (20.0)Pre-treatment BC, SC, and urinary Ag for S. pneumoniae and Legionella sp. 2/10 (20)Specimen type NR CXR positive (multilobar infiltrates) all except 2 (single lobe infiltrates)
Mulrennan [[58]] New pulmonary infiltrates on imaging + clinical symptomsCompared with non-pneumonia H1N1 N = 35 11/35 (31.4) 10/35 (28.6) 2/35 (5.7) 35/35 (100) NR 5/35 (14.3)NP, lower resp. tarct NR 35/35 (100)CXRno diff
Ugarte (2010) [[25]]Chile5/09–9/09Adults Multicenter (11) case series (retrospective) / adult ICU admissionsDefinition: positive culture from a sterile site (e.g. blood) and/or lower respiratory tract specimens, or seroconversion to atypical bacterial pathogens. LRT specimens included expectorated sputum, ET aspirated sputum and BAL N = 75 75/75 (100.0)) 56/75 (74.7)- 19/75 (25.3) NR NR 7/75 (9.3)Specimens NR 4/75 (5.3) on admission. Site NR1/5 (20) empyema patients BC 74 (98.7)CXRNo diff
Busi [[4]] N = 40 NR NR 1/40 (2.5) NR NR 0/40 (0) Specimen NR 40/40 (100) 40 had findings consistent with pneumonia. These 28/40 (70 bilaterial) Non-Diff

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS;

No diff Did not differentiate between aetiology of abnormal chest imaging, NR not reported

Six studies reported use of antibiotics prior to specimen collection in subjects with bacterial co-infection in 21–22% of those tested [[23], [24]]. One study reported factors associated with acute respiratory distress syndrome (ARDS) or death, with the ARDS-death group more likely to have bacterial co-infections than patients who survived without ARDS or had mild disease [[25]]. Specimens included sputum, bronchial aspirate, pleural fluid, urine and blood with testing mainly being bacterial culture, but also multiplex PCR assay for respiratory bacterial panels (for detection of Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae) and Binax NOW, an in vitro immunochromatographic assay for Streptococcus pneumonia. However, the mPCR assay did not test for S. pneumoniae in one study and the authors could not report the presence of this organism [[23]].

Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted to ICUs

Sixteen studies reported on influenza A(H1N1)pdm09 cases admitted to ICU wards and are summarised in Table 3. Criteria for admission to ICU varied in the included studies, including acute respiratory distress (ARD) [[26], [27]], acute respiratory failure [[28], [29]], required mechanical ventilation (MV) [[5], [30], [31]] or MV or low O2/IV vasoconstrictive drugs [[32], [33]], MV or ECMO [[34]] or admitted with no criteria provided [[35][41]]. Eleven studies included only PCR confirmed A(H1N1)pdm09 cases, while three included probable cases [[31], [39], [40]] and another three included both probable and suspected cases [[5], [33], [34]]. Any positive bacterial testing was reported in 12 studies and bacterial co-infection was identified in 1–43% of cases (mean bacterial 19%, Streptococcus pneumoniae 26%). One study assessed differences in mortality outcomes based on secondary bacterial pneumonia. In a large study involving admissions to 35 ICUs for ILI and ARF requiring mechanical ventilation in Argentina (n = 337), 24% of included patients had bacterial pneumonia on admission, 8% with S. pneumoniae [[5]]. S.pneumoniae co-infection was associated with higher mortality (OR 2.72 95% CI 1.05–7.06), despite concurrent antibiotic treatment on admission [[5]]. A Canadian study (N = 168) attributed secondary bacterial infection as a leading cause of death in the 29 (17.3%) fatalities that occurred in this cohort [[33]].Table 3

Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted in ICUs (n = 16)

Author and year Study type Study population Case severity Antiviralsan/N (%) anyn/N (%) 48 h Antibiotics†n/N (%) pren/N (%) onn/N (%) during admission Any positive bacterial growth Number (%) patients with S.pneumoniae and site of isolation Number (%) with bacterial pneumonia- Method- Diff/no diff
ICU - ECMO Mechanical Ventilation Deaths
Miller (2010) [[36]]Utah, USA5/09–6/09Adults(16+) Multicentre (4) case series (+ comparison with local resident population) / Adult (> 15 y) ICU admissions N = 47 47/47 (100)- 0 13/47 (27.7)IV = 11/47 (84.6) 8/47 (14) 47/47 (100.0)- 45/47 (95.7) 44/47 (93.6)- NS 6/47 (13) 0/47 (0) BC0/47 (0) ET aspirate0/47 (0) SC0/47 (0) BAL fluid 43/47(91.5)- CXR- No diff
Rello [[29]] (2009)Spain6/09–7/09Adults Multicentre (20) case series (retrospective) / ICU adult admissions with ARF N = 32 32/32 (100)- 0 24/32 (75.0)- IV = 22/32 (91.7)- NIV = 2/32 (8.3) 8/32 (25) 32/32 (100.0)-NS 32/32 (100.0) 1/32 (3.1)Secondary superinfection with Pseudomonasaeruginosa were also documented in three patients (9.3). 1/32 (3.1) aspirate0/32 (0) BC 1/32 (3.1)respiratory culture
ANZ ECMO [[34]] (2009)Australia and New Zealand6/09–8/09All ages Multicentre (15) cohort study (retrospective) / All ages ICU admission with ARDS treated with ECMOIncludes probable casesa N = 68 68/68 (100)- 68/68 (100) 68/68 (100) 14/68 (20.6) 64/68 (94.1)- NS NR 19/68 (28) 10/68 (14.7) [respiratory secretion/BC] 66/68 (97.1)CXR/CTNo diff
Estenssoro (2010) [[5]]Argentina6/09–9/09Adults(15+) Multicentre (35) inception cohort study (prospective & retrospective) / adult (≥ 15 years) ICU admissions with ILI & ARF requiring MVIncludes probable casesa N = 337 337/337 (100) 337/337 (100)NIV = 64/337 (19.0) 156/337 (46.3) 328/336 (98)- NS 337/337 (100)- NS 28/337 (8.3) 28 /337 [NS]8.3 80/337 (23.7)CXR/CTDiff
Nin [[31]] (2011)Chile, Uruguay6/09–9/09 Multicenter (10) case series (> 18 yrs) (retrospective and prospective) / Respiratory failure requiring ICU mechanical ventilation **(confirmed = 77/ 96)Includes probable casesa N = 96 96/96 (100)13/96 (13.5) 96/96 (100)NIV = 10/96 (10.4)IV = 86/96 (89.6)Prone ventilation = 44 /96 (45.8)HFOV = 10/96 (10.4) 48/96 (50) 84/96 (87.5)- NS 91/96 (94.8)- NS 8/96 (8) NR 32/96 (33.3, 8 within first week of admission)- Purulent sputum, significant growth of pathogen in ET aspirate- diff
Koegelenberg (2010) [[30]]South Africa8/09–9/09Adults(18+) Single-centre case series (prospective)/Adult (> = 18 y) ICU admissions with ARF requiring MV N = 19 19/19 (100)- NR 19/19 (100)- NIV = 2/19 (10.5) 13/19 (68.4) 19/19 (100)- 14 (73.7) NR 0/19 (19) 0/19 (0) BC0/19 (0) ET aspirates0/19 (0) other NS 0/19 (0)(10 cases of nosocomial infection (> = 48 h admission)- CXR
Martin-Loeches [[28]] (2010)Spain1st case - 12/09Adults (16+) Multicentre (148) case series (prospective) /Adult (> = 15 y) ICU admissions with ARF N = 645 645/645 (100) NR- IV = 389/645 (60.3) 112/645 (17.4) 620/645 (96.1)- NS 645/645 (100)- NS 113/645 (17.5) 62 /645 (9.6)site NSCultures routinely every day 113/645 (17.5)- CXR + pos culture- diff
Rice [[39]] (2012)US4/09–4/10 Multicenter (35) case series (retrospective and prospective) / Critically ill cases (> 13 years) admitted to adult ICU’s (Confirmed = 424/683, 62%)Includes probable casesa N = 683 683/683 (100) 231/683 (33.8)- IV = 175/683 (75.8)- NIV = 56/683 (24.2) 309/683 (45.2) 683/683 (100)-NS NR Total 154/683 (22.5)Sputum specimen84/683 (12.3)Bacteraemia 50 (7.3)Both 20 (2.9) 10/683 (1.5) BC 207/683 (30.3) clinical coinfection, non-diff
CDC [[27]] Patients at a tertiary care hospital in Michigan N = 10 10/10 (100) 10/10 (100) 3/10 (30%) 10/10 (100) 10/10 (100) NR NR NR
Kim [[32]] ICU in 28 Hospitals in SK 245 245/245 (100) 162/245 (100) 99/245 (40.4) 103/245 (42) 243/245 (99.2) 91/245 (37.1) 0/245 (0) 91/245 (37.1)
Malato [[35]] ICU in one hosiptal 24 24/24 (100) 6/24 (25) 4/24 (16.7) 20/20 (100) NR 6/24 (25) 0/24 (0) 6/24 (25)
Kumar [[33]] (2009)Canada4/09–8/09All ages Multicentre (38) cohort study (prospective & retrospective) /All age critically ill patients = ICU & requiring MV or IV medication or ≥ 60% inspired O2 fractionIncludes probable casesa N = 168 168/168 (100)- 7/168 (4.2) 136/168 (81.0)- IV = 128/168 (94.1)- HFOV = 20/168 (14.7) 29/168 (17.3) NR NR 5/168 (2.9) site NS 54/168 (32.1) possible at presentation; 41/168 (24.4) clinically dx cases following ICU admission- CXR + culture /clinical opinion
Roch [[26]] ARDS cases in ICU N = 18 18/18 (100) 10/18 (100) 10/10 (100) NR NR 0/18 (0) 0/18 (0) 0/18 (0)
Lucker [[37]] One hospital ICU, medical charts reviewed 14 14/14 (100) 10/14 (71.4) 2/14 (14.3) 14/14 (100) 13/14 (92.9) 6/14 (42.8)Of ICU cases 0/14 (0) 6/14 (42.9)
Leen [[38]] 22 bed ICU in one hospital N = 31 31/31 (100) 3/31 (10) NR NR NR NR 10/31 (32.2)Method not mentioned
Torres [[40]] Hospital in Chile. Includes probable casesa N = 11 11/11 (100) 11/11 (100) 0/11 (0) 11/11 (100) 7/11 (63.6) 1/11 (0.9)Group A StreptococcusSite NR 0/11 (0) 6/11 (54.5)Non Diff

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

aH1N1 testing = 53 (77.9) PCR/viral culture, 8 (11.8) serologically diagnosed but flu A not typed [[34]]; probable cases not defined [[31]]; Probable: Flu A, not otherwise subtyped [[39]]

Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU

Twenty two studies reported on hospitalised influenza A(H1N1)pdm09 cases (not requiring ICU) and are summarised in Table 4. Almost all studies include patients admitted to general wards, however some were transferred to ICU during the course of treatment. Most of the studies (19/22) reported bacteria testing and any positive bacterial growth was reported in 1.6–76% cases (mean bacterial 12%, Streptococcus pneumoniae 33%). The number of patients with S.pneumoniae co-infection varied from 1 to 31% depending on site of sample. Palacios et al. conducted a study in Argentina and bacteria was found in 76% of nasopharyngeal samples (152/199), of which Streptococcus pneumoniae was isolated in 31% (62/199) samples [[42]].Table 4

Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU (n = 22)

Author and year Study type Study population Case severity n (%) Antiviral agents- Number (%) started ≤48 h of symptoms Antibiotics†n/N (%) pren/N (%) onn/N (%) during admission Any positive bacterial growth Number (%) patients with S.pneumoniae and site of isolation Number (%) with bacterial pneumonia- Method- Diff/no diff
ICUN MV- type Deaths
CDC (2009) [[59]]California, USA4/09–5/09 State-wide passive surveillance of notified cases / Hospitalized cases for > 24 h N = 30 6/30 (20) 4/30 (13.3) 0/23 (0)7 were still hospitalised 15/30 (50)5/30 (16.7) 0 0/100 (0) 0/100 (0) 15/25 (60)CXR Non diff
Jain [[60]] (2009)USA4/09–6/09 Notified cases from 24 state health departments to CDC / Hospitalized ≥24 h N = 272 67/272 (24.6) 42/272 (15.4) 19/272 (7.0) 200/268 (74.6)78 (29.1) 206/260 (79.2)- Pre: 30/198- on: 117/198 3/182 (1.6) 2/182 (1.1) 1 had positive lung tissue culture)1/n urinary antigen test1/n BAL fluid0/n ET aspirate - CXR 100/249 (40)(66 patients with bilateral infiltrates)26 limited to 1 lobe, 6 limited to multiple lobes- not diff
Louie [[61]] (2009)California, USA4/09–8/09 State-wide enhanced surveillance /Hospitalized or fatal all ages cases N = 1088 340/1088 (31.3) 193/297 (64.9) 118/1088 (10.8) 701/884 (79.3)- 357 (40.4) NR 46/1088 (4.2) NR 547/833 (65.7)- CXR/CT + pos bacterial culture(s) 46- No diff
Dhanoa [[62]] (2011)Malaysia9/09–5/10 Single-centre case series (retrospective)/ Hospitalised patients all ages N = 50 9/50 (18.0) 6/50 (12.0) 2/50 (4.0) 50/50 (100) 49 (98.0)- Pre = 8- On =41 14/45 (31.1)total 45 culture samples sent 2/45 (4.4) site NR 25/50 (50)-CXR + clinical opinion- No diff
To [[63]] (2010)China6/09–10/09 Single-centre case series (retrospective)/ Hospitalized adult patients N = 69 28/69 (40.6) 26/69 (37.7)- NS 13/69 (18.8) 69/69 (100) 37/69 (53.6)- On = 37 0/69 (0) 0/69 (0) 25/69 (36.2)CXR Non-diff
Viasus [[64]] (2011)Spain6/09–11/09 Multicentre (13) case series (prospective)/ Hospitalized ≥24 h and had a chest radiograph done N = 585 71/585 (12.1) 52/585 (8.9) 13/585 (2.2) 545/585 (93.3) 416/585 (71.7) 45/585 (7.7) 28/585 (4.8) 234/585 (40)CXR non diff
Palacios (2009) [[42]]Argentina6/09–7/09 Random sample specimens N = 199 19/199 (9.5) NR 20/199 (10) 96/120 (80) 14/120 (11.7) 152/199 (76.3) 62/199 (31.1) 152//199 (76)Culture pos
Chitnis [[6]] Wisconsin, hospital acute carePCR + cases N = 252 59/252 (23.4) 34/59 (58)Of tho9se cases admitted to ICU 11/252 (4.3) 215/250 (86) 204/249 (81.9) 19/241 (7.9) NR 123/229 (53.7)CXR non diff
Riera [[65]] 13 Hospitals in Spain N = 585 71/585 (12.1) 52/585 (8.9) 13/585 (2.2) 545/585 (93.1)202/585 (34.5) 316/585 (54) 45/585 (7.7) (Sputum) 2/585 (0.3)(1 sputum and 1 antigenuria positive CXR infil 234/585 (40)Multilobarl infilt 135/585 (23.1)
Semionov [[66]] 147 cases with CXR results available in Montreal N = 147 8/147 (5.4) 6/147 (4.1) 4/147 (2.7) NR NR 21/42 (50)(of 42 radiological positive cases) 5/21 (23.8)(of 21 positive bacterial cases) 42/147 (28.6)cases positive CXRNon diff
To [[67]] 74 cases in Hong Kong N = 74 28/74 (37.8) 26/74 (35.1) 2/74 (2.7) 69/74 (93.2) 52/74 (70.3) 9/74 (12.2) bacterial positive8 sputum1 blood 0/74 (0) 9/74 (12.2) bacterial positive8 sputum1 bloodDiff
Masia [[68]] Complicated hospital admitted cases in Spain > 18 years, out patients N = 100 4/100 (4) NR 0/100 (0) NR NR 14/100 (14) 14/100 (14)Diff8 urinary antigen pos, 2 isolated from blood and 4 from sputum 14/100 (14)Diff
Pecavar [[69]] Hospitalized cases N = 66 7/66 (10.6) NR NR 62/64 (96.9) 35/61 (57.4) 5/63 (7.9) 2/63 (3.2) 29/57 (50.9)CXR Non diff
Liu [[70]] One hospital in China N = 46 NR NR NR 46/46 (100) 9/46 (19.6) 9/15 (60) NR 44/46 (95.6)CXR or CT scan abnormalNon diff
Nguyen (2010) [[71]]UK4/09–9/09 Multicentre (55) case series (retrospective)/ Hospitalized cases N = 631 53/631 (8.4) NR- IV = 21/631 (3.3) 29/631 (4.6) 474/631 (75.1)- NS 366/631 (58) 4/102 (3.9%) of cases with radiological pneumonia 1/102 (0.9) sputum culture0/102 (0) BC 102/349 (29.2)- CXR- No diff
Santa-Olalla Peralta [[72]] (2010)Spain4/09–12/09 National surveillance of severe cases (retrospective) / Hospitalized patients all ages (, in Spain N = 3025 852/3025 (28.2) 438/3.25 (14.5) 200/3025 (6.6) 2521/2779 (90.7)- 711/2020 (35.2) NR 292/957 (30.5, bacteria isolated not reported) NR NR
Venkata [[73]] (2010)USA5/09–12/09 Single-centre case series (retrospective)/ Electronic medical records of hospitalized adult patients N = 66 29/66 (43.9) 23/66 (34.8)- IV = 17 (73.9)- NIV = 6 (26.1) 5/66 (7.6)4 more died after discharge from hospital 60/66 (90.9)- NR 14/ 29 (48.2)Bac culture pos 3/29 (10.3), site NS 14/29 (48.2) confirmed and 10/29 (34.5) probable bacterial pneumonia- NR- Diff
Jartti [[74]] Cases with severe cases and CXR finding available, I hospital in Finland N = 135 18/135 (13%) 18/135 (13.3) 3/135 (2.2) NR NR 5/135 (3.7)Site not mentioned 1 /135 (0.7)Isolated from Plural Fluid 84/135 (62.2)
Rizzo [[75]] Sentinel sites, Italy N = 1278 NR NR NR NR NR 33/1278 (2.6) 0/1278 (0) 271/1278 (21.2)Non-diff
Kopel [[76]] Til Aviv, cases in ICU and PICU N = 17 17/17 (100) NR 7/17 (41.2) NR NR 9/17 cases (52.9)(but likely nosocomial infection, so not included) 0/17 (0) NR
D’Ortenzio [[41]] ReUnion Island, all sites, included 785 reported cases, 282 hospitalized cases included here N = 282 24/282 (8.5) 15/282 (5.3) 7/282 (2.5) 92/171 (53.8)39/163 (23.9)(within 48 h) NR NR NR 24/83 (28.9)(Confirmed and suspected)Sample not reported
Dominguez-Cherit [[77]] Critically ill, hospitalized in 6 hospital in Maxico N = 58 58/58 (100) 54/58 (93.1) 24/ 58 (41.4) 57/58 (98.3) 52/58 (89.6) 4/58 (6.9) 0/58 (0) NR

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09

Fifteen studies reported on admitted paediatric influenza A(H1N1)pdm09 cases, including 11 to any hospital ward and 6 restricted to PICU and are summarised in Table 5. The mean prevalence of bacterial co-infection was 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards. Rates of bacterial co-infections vary in these studies, ranging from 0 to 87% (mean 5%) in any hospital ward admission to 13–34% (mean 32%) in admission to PICU. The highest rate was reported by Okada [[43]] who conducted a study in Japan on 46 hospitalised children from July 2009 to January 2010. Bacteria were isolated from nasopharyngeal swabs of 87% admitted cases (40/46)- S. pneumoniae 37.0%; S. pneumoniae and H. influenzae 23.9%, H. influenza, 26.1% and S. aureus 23.9%.Table 5

Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09 (n = 15)

Author and year Study type Diagnosis of influenza/ cases Antiviral agents- Number (%) started ≤48 h of symptoms Number (%) patients with S.pneumoniae and site of isolation Any bacteria positive Number (%) with bacterial pneumonia- Method- Diff/no diff Antibiotics used (Pre, on, during) Required
ICU - ECMO MV Deaths
Louie (2010) [[7]]California USA4/09–8/09 State-wide surveillance (California) / Hospitalized or died cases (< 18 years) PCR/345 221/345 (64.1)88/ 345 (25.5) with in 48 h 3/345 (0.9)isolation site NR 15/345 (4.3) 138/229 (60.3)(F: 4/5; H: 134/224)163/278 (CT + CXR pos)- No diff NR 94/345 (27.4) 35/94 (37) in text 9/345 (2.6)
Libster [[78]] (2010)Argentina5/09–7/09 Multicentre (6) case series (retrospective)/ Hospitalized cases (< 18 years) PCR/ 251 - 22/ 171(12.9) with in 48 h(4/34 PICU Px, 18/137 ward px) 2/121 (1.7) BC1/4 (25.0) empyema 10 /121 (8)Blood culture 25/251 (10.0) bacterial confirm- Among 92 CXR, 78% diagnosis was pneumonia-NonDiff 186/251 (74.1)- On = 82 47/251 (18.7) 42/251 (16.7) 13/251 (5.2)
Okada [[43]] 2011Japan7/09–1/10 Single-centre case series (retrospective) / Pneumonia, pharyngitis or bronchitis cases (< 15 years) (n = unclear). PCR/46 44/46 (95.6)- NR 28/46 (60.9)NP 40/46 (86.9)NP positive swab 40/46 (86.9%)NP swabBac pneumonia21/46 (45.6%) unilateral infiltrates- CXR- No diff 32/46 (69.6)- NS NR NR 0/46 (0)
Kumar [[79]] (2010)Wisconsin, USA4/09–8/09 Single-centre case series (retrospective record review)/ Hospitalized (> = 24 h) cases (< 19 years) PCR/75 74/75 (98.7)- NR 0 /75 (0) 0/75 (0) 23/75 (34.3)- CXR- Diff 60/75 (80.0)- Pre = 12- On/during = 48 14/75 (18.7) 4/75 (5.3) 2/75 (2.7)
Miroballi [[80]] (2010)New York, USA05/09–07/09 Multicentre (2) case series (retrospective) / Hospitalized cases (< 18) PCR (54), EIA, DFA, viral culture/ 115 97/115 (84.3)- NR 2/115 (1.7) BC1/115 (0.9) respiratory secretions 4/115 (3.5) Total NR (11/35 in PICU)- NR- Diff NS 89/115 (77.4)- NS 35/115 (30.4) 11/115 (9.6) in PICU 1/115 (0.9)
O’Riordan [[81]] Retrospective case review/hospitalised cases (< 18 yrs) PCR/ 58 12/58 (20.7)- NR 1/58 (1.7)BC 1/58 (1.7)bacterial culture positive 17/58 (29.3)- CXR- No diff 56/58 (96.6)- NS 12/58 (20.7) 7/58 (12.1) 0/58 (0)
Bettinger [[82]] (2010)Canada5/09–8/09 National active surveillance / hospitalized cases (< 17 years) PCR/235 107/235 (45.5)- NR 3/235 (1.3) isolation site NR 8/235 (3.4) culture positive 8/235 (3.4) culture positive 203/235 (86.4)- NS 39/235 (16.6) 15/235 (6.4) 2/235 (0.9)
Lockman [[83]] 2010 Retrospective case review (notes)/cases admitted to ICU PCR/ 13 11/13 (84.6)- 5 (45.5) 0/13 (0) 0/13 (0) 3/13 (23%)Nondiff CXR 3/13 (23.1)- NS 13/13 (100) 6/13 (46.2)- IV =4 (66.7)- NIV = 2 (33.3) 0/13 (0)
 Stein [[84]] < 18 year, ARI cases, hospitalized in 7 medical centers in Israel PCR/ 478 413/478 (87.1) 2/478 (0.4) 4/478 (0.8) 172/478 (35.9) CXR non-diff 215/478 (45) 42/478 (8.8) 15/478 (3.1) 3/478 (0.6%)
 Tamma [[85]] 1 hospital, lab confirm US, <  18 years, retrospective cohot in US PCR/ 133 106/133 (79.7)51/133 < 48 h 0/133 (0) 0/133 (0) 28/122 (22.9)CXR nondiff 61/85 (72%) 27 (20.3) 11/133 (8%) 0
 Parakh [[86]] 1 hospital, retrospective record review, India PICU and ICU, cases with age < 18 with ILI PCR/ 25 25/25 (100) 0/25 (0) 0/25 (0) 8/25 (32)CXR nondiff NR 7/25 (28) 4/25 (16) 3/25 (12)
 Farias [[87]] Prospective multicentred study/includes nosocomial cases in Argentina(n = 147) PCR/ 147 135/147 (91.8)- 116/147 (85.9) 6/147 (4) isolation site NR 50/147 (34) NR 143/147 (97.3) 147/147 (100) 139/147 (94.6)- IV = 117 (84.2)- NIV = 22 (15.8) 57/147 (38.8)
 Randolph (2011) [[88]]USA4/09–4/10 Multicentre (35) case series (retrospective & prospective). Probable 293/838 (35%) casesPICU cases (< 21 years) Confirmed- PCR, viral cultureProbable- direct fluorescent antibody, rapid influenza diagnostic test (n = 838) 751/838 (89.6)- NR (before ICU admission =49) 0/38 (0) BC15/274 (5.5) respiratory secretionsBC: 0 274/838 (32.7) had pneumonia/other bacterial co-infectionFrom resp. secretions 274/838 (32.7) had pneumonia/other bacterial co-infectionFrom resp. secretions NR 838/838 (100)- 33 (3.9) 546/838 (67.3) 75/838 (8.9)
 Shin [[89]] South Korea, critically ill cases PCR/30 29/30 (96.7) 0/30 (0) 4/30 (13.3)Blood c/s positive 22/29 (75.9)CXR non diff NR 30/30 (0) 16/30 (53.3) 14//30 (46.7)
 Jouvet [[8]] Canada PICUs, PCR or culture positive /57 44/57 (77.2) 5/27 (18.5)Lower resp. samples 12/57 (21.1)Lower resp. samples 12/57 (21.1)Lower resp. samples 54/57 (94.7) 2/57 (3.5) 39/57 (68.4) 4/57 (7)

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging


Secondary bacterial infection was an important complication of the 2009 influenza pandemic, with almost 1 in 4 severe or fatal cases having bacterial secondary infections, albeit with varying rates. Bacterial infection appeared to be associated with morbidity and mortality, with higher rates in adults, ICU patients and those with a fatal outcome. Streptococcus pneumoniae was the most common bacteria identified, and in ICU patients, ventilator associated pneumonia with organisms such as Acinetobacter baumannii, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus, and Escherichia coli was common. The prevalence of bacterial co-infection was lower in studies of hospitalized patients not requiring ICU and in studies of paediatric hospitalized patients, although the latter was quite varied.

The overall morbidity and mortality of the 2009 pandemic varied by country, but was cited as being similar to a severe seasonal influenza epidemic [[44]]. However, two important differences in the epidemiologic pattern of the 2009 pandemic were firstly, a low average age of death in fatal cases (53 years compared to 83 years during seasonal influenza) and high intensive care unit (ICU) occupancy rates [[45]]. These two features hint at a severe population impact, and a UK study showed a “w” shaped morbidity curve with a peak in young adults [[46]].

The 1918 pandemic has served as a reference point in pandemic planning, but availability of antibiotics, critical care and extra-corporeal membrane oxygenation (ECMO) have vastly improved survival during a contemporary pandemic, so it would be unlikely that case fatality rates of 1918 would recur in the modern era [[45]]. The use of ECMO rose sharply in 2009 and is associated with high rates of survival [[47]].

Further, in understanding the morbidity and mortality impact of a modern pandemic, it is important to quantify the relative contribution of direct viral effects compared to bacterial secondary infections, as treatment and prevention options are also available for bacterial infections.

Testing for bacterial complications during an influenza pandemic is important, but was neglected in most studies which we screened for this review. For optimal response and mitigation of preventable morbidity and mortality, active surveillance during both seasonal and pandemic influenza is necessary, and systems should be in place for rapid assessment of secondary bacterial morbidity and mortality. Diagnosis and treatment of secondary bacterial infections should always be considered during a pandemic [[10]].

Currently there are limited data on bacterial coinfection during influenza pandemic in 1918. Morens et al. reviewed autopsy data from 58 lung tissue samples collected during the 1918 influenza pandemic and histologic evidence of severe bacterial pneumonia was found in almost all samples [[10]]. The authors also did a literature search around autopsy case series and examined data of 3074 subjects in 68 high quality autopsy case series. This showed that more than 92% of autopsy lung cultures were positive for at least one bacterium [[10]]. Another study by Chien et al. reviewed the studies that reported more than 10 sterile-site antemortem cultures from adults with pneumonia during 1918 pandemic [[48]]. Culture positivity rates among influenza cases without pneumonia was very low (mean < 1%), compare to those with pneumonia (mean, 16%; range, 2 to 50) [[48]]. Bacterial co-infection rates among hospitalised cases with confirmed pneumonia in this study was 19%, which is comparable to Chien et al.

The rate of bacterial co-infection may be underestimated as many cases are not tested for bacterial infections, and bacterial pneumonia cannot always be differentiated from viral pneumonia on the basis of clinical presentation, radiology and routine blood tests. There is also a need to develop diagnostic algorithms for early identification of bacterial infections in these cases to ensure early detection and treatment of bacterial complications.

The WHO guidelines on vaccines and antivirals for a pandemic, along with many country-specific pandemic plans, do not consider pneumococcal vaccines [[49]]. The CAPITA trial shows efficacy of conjugate pneumococcal vaccine against pneumonia [[50]], and the polysaccharide vaccine also has efficacy against invasive pneumococcal disease [[51]]. We have found evidence that severe and fatal cases of influenza during the 2009 pandemic did comprise secondary bacterial causes, including streptococcus pneumoniae as a contributing factor. Vaccination against streptococcus pneumonia is often neglected in pandemic planning [[52]], but could have a positive impact on morbidity and mortality. The evidence confirms that prevention of bacterial secondary infection should be an integral part of pandemic planning. Improving uptake of routine pneumococcal vaccination in adults with an indication will cover most patients at risk, and may reduce the impact of a pandemic.

To our knowledge, this is the first systematic review to estimate the prevalence of pneumonia and secondary bacterial infections during pandemic influenza A(H1N1)pdm09. We calculated bacterial co-infection rates separately for fatal cases, hospitalised cases with confirmed pneumonia, hospitalised cases admitted to ICU, hospitalised cases admitted to general wards and paediatric hospitalised cases, showing the highest risk of bacterial infection for fatal and ICU admitted cases.


We found that secondary bacterial infection was an important complication of the 2009 influenza pandemic, with Streptococcus pneumoniae the most common bacteria identified. Bacterial infection appeared to be associated with morbidity and mortality, with higher rates in adults, ICU patients and those with a fatal outcome. Prevention and treatment of bacterial secondary infection should be an integral part of pandemic planning, and improved uptake of routine pneumococcal vaccination in adults with an indication may reduce the impact of a pandemic.


We acknowledge the support of Anthea Katelaris, Anthony Newall and James Wood for some preliminary work on this project.


No funding was involved in this study.

Availability of data and materials

All data freely available.


  1. EH LeeC WuEU LeeFatalities associated with the 2009 H1N1 influenza A virus in New York cityClin Infect Dis2010501498150410.1086/65244620420514
  2. JR GillZM ShengSF ElyPulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infectionsArch Pathol Lab Med201013423524320121613
  3. YS ChienCP SuHT TsaiPredictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in TaiwanJ Inf Secur201060168174
  4. RE BusiV SchininaF FerraroRadiological findings of pneumonia in patients with swine-origin influenza A virus (H1N1)Radiol Med201011550751510.1007/s11547-010-0553-920526820
  5. E EstenssoroFG RiosC ApezteguiaPandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilationAm J Respir Crit Care Med2010182414810.1164/201001-0037OC20203241
  6. AS ChitnisSA TrueloveJK DruckenmillerRT HeffernanJP DavisEpidemiologic and clinical features among patients hospitalized in Wisconsin with 2009 H1N1 influenza A virus infections, April to August 2009WMJ201010920120820945721
  7. JK LouieS GavaliM AcostaChildren hospitalized with 2009 novel influenza A(H1N1) in CaliforniaArch Pediatr Adolesc Med20101641023103110.1001/archpediatrics.2010.20321041595
  8. P JouvetJ HutchisonR PintoCritical illness in children with influenza A/pH1N1 2009 infection in CanadaPediatr Crit Care Med20101160360910.1097/PCC.0b013e3181d9c80b20308929
  9. SA MadhiKP KlugmanA role for Streptococcus pneumoniae in virus-associated pneumoniaNat Med20041081181310.1038/nm107715247911
  10. DM MorensJK TaubenbergerAS FauciPredominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparednessJ Infect Dis200819896297010.1086/59170818710327
  11. JF BrundageGD ShanksDeaths from bacterial pneumonia during 1918-19 influenza pandemicEmerg Infect Dis2008141193119910.3201/eid1408.07131318680641
  12. D MoherA LiberatiJ TetzlaffDG AltmanGroup PPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statementInt J Surg2010833634110.1016/j.ijsu.2010.02.00720171303
  13. World Health Organisation (WHO)Standardization of terminology of the pandemic A(H1N1)2009 virus2011
  14. G Fajardo-DolciR Gutierrez-VegaH Arboleya-CasanovaClinical characteristics of fatalities due to influenza A (H1N1) virus in MexicoThorax20106550550910.1136/thx.2009.12695320522847
  15. Centers for Disease Control and PreventionSurveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection - United States, April–August 2009MMWR Morb Mortal Wkly Rep20095894194719730406
  16. Centers for Disease Control and PreventionBacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May–August 2009MMWR Morb Mortal Wkly Rep2009581071107419798021
  17. T MauadLA HajjarGD CallegariLung pathology in fatal novel human influenza A (H1N1) infectionAm J Respir Crit Care Med2010181727910.1164/rccm.200909-1420OC19875682
  18. W-J ShiehDM BlauAM Denison2009 pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United StatesAm J Pathol201017716617510.2353/ajpath.2010.10011520508031
  19. S LucasPredictive clinicopathological features derived from systematic autopsy examination of patients who died with A/H1N1 influenza infection in the UK 2009-10 pandemicHealth Technol Assess2010148311410.3310/hta14550-0221208548
  20. HS KimJH KimSY ShinFatal cases of 2009 pandemic influenza A (H1N1) in KoreaJ Korean Med Sci201126222710.3346/jkms.2011.26.1.2221218025
  21. N NakajimaY SatoH KatanoHistopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infectionMod Pathol20122511310.1038/modpathol.2011.12521874012
  22. K TammeA MinajevaV AdamsonClinical and pathological findings of fatal 2009-2010 pandemic influenza A (H1N1) infection in EstoniaMedicina (Kaunas)201248485610.3390/medicina4806004822370505
  23. R Perez-PadillaD De La Rosa-ZamboniS Ponce De LeonPneumonia and respiratory failure from swine-origin influenza A (H1N1) in MexicoN Engl J Med200936168068910.1056/NEJMoa090425219564631
  24. W CuiH ZhaoX LuFactors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, ChinaBMC Infect Dis20101014510.1186/1471-2334-10-14520513239
  25. S UgarteF ArancibiaR SotoInfluenza A pandemics: clinical and organizational aspects: the experience in ChileCrit Care Med2010384 Supple133e13710.1097/CCM.0b013e3181c8771619935412
  26. A RochR Lepaul-ErcoleD GrisoliExtracorporeal membrane oxygenation for severe influenza A (H1N1) acute respiratory distress syndrome: a prospective observational comparative studyIntensive Care Med2010361899190510.1007/s00134-010-2021-320721530
  27. Centers for Disease Control and PreventionIntensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009MMWR Morb Mortal Wkly Rep20095874975219609249
  28. I Martin-LoechesA Sanchez-CorralE DiazCommunity-acquired respiratory coinfection in critically ill patients with pandemic 2009 influenza A(H1N1) virusChest201113955556210.1378/chest.10-139620930007
  29. J RelloA RodriguezP IbanezIntensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in SpainCrit Care200913R14810.1186/cc804419747383
  30. CF KoegelenbergEM IrusenR CooperHigh mortality from respiratory failure secondary to swine-origin influenza A (H1N1) in South AfricaQjm201010331932510.1093/qjmed/hcq02220219780
  31. N NinL SotoJ HurtadoClinical characteristics and outcomes of patients with 2009 influenza A(H1N1) virus infection with respiratory failure requiring mechanical ventilationJ Crit Care20112618619210.1016/j.jcrc.2010.05.03120688465
  32. S-H KimS-B HongS-C YunCorticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scoresAm J Respir Crit Care Med20111831207121410.1164/rccm.201101-0110OC21471084
  33. A KumarR ZarychanskiR PintoCritically ill patients with 2009 influenza A(H1N1) infection in CanadaJAMA20093021872187910.1001/jama.2009.149619822627
  34. Australia, New Zealand Extracorporeal Membrane Oxygenation Influenza IA DaviesExtracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) acute respiratory distress syndromeJAMA20093021888189510.1001/jama.2009.153519822628
  35. Malato L, Llavador V, Marmier E, Youssef J, Balick Weber C, Rozé H, Bessede E, Fleury HJ. Pandemic influenza A(H1N1)2009: molecular characterisation and duration of viral shedding in intensive care patients in Bordeaux, south-west France, May 2009 to January 2010. Euro Surveill. 2011;16(4). Available online:
  36. IRR MillerBA MarkewitzRT RolfsClinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza a(H1N1) infectionChest201013775275810.1378/chest.09-251719933372
  37. LM LuckerO KheradA ItenClinical features and outcome of hospitalised adults and children with the 2009 influenza A H1N1 infection at Geneva’s University HospitalSwiss Med Wkly2011141w1317721416409
  38. T LeenTA WilliamsL CampbellEarly experience with influenza A H1N109 in an Australian intensive care unitIntensive Crit Care Nurs20102620721410.1016/j.iccn.2010.05.00520599382
  39. TW RiceL RubinsonTM UyekiCritical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United StatesCrit Care Med2012401487149810.1097/CCM.0b013e3182416f2322511131
  40. JP TorresM O'RyanB HerveImpact of the novel influenza A (H1N1) during the 2009 autumn-winter season in a large hospital setting in Santiago, ChileClin Infect Dis20105086086810.1086/65075020166819
  41. E D'OrtenzioP RenaultMC Jaffar-BandjeeA review of the dynamics and severity of the pandemic A(H1N1) influenza virus on Reunion island, 2009Clin Microbiol Infect20101630931610.1111/j.1469-0691.2010.03171.x20121825
  42. G PalaciosM HornigD CisternaStreptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenzaPLoS One200941510.1371/journal.pone.0005361
  43. T OkadaM MorozumiK MatsubaraCharacteristic findings of pediatric inpatients with pandemic (H1N1) 2009 virus infection among severe and nonsevere illnessesJ Infect Chemother20111723824510.1007/s10156-010-0115-z20827563
  44. DJ MuscatelloMA CretikosCR MacintyreAll-cause mortality during first wave of pandemic (H1N1) 2009, New South Wales, Australia, 2009Emerg Infect Dis2010161396140210.3201/eid1609.09172320735923
  45. JF BishopMP MurnaneR OwenAustralia’s winter with the 2009 pandemic influenza A (H1N1) virusN Engl J Med20093612591259410.1056/NEJMp091044519940287
  46. PR MylesMG SempleWS LimPredictors of clinical outcome in a national hospitalised cohort across both waves of the influenza A/H1N1 pandemic 2009–2010 in the UKThorax20126770971710.1136/thoraxjnl-2011-20026622407890
  47. B BridgesP RycusC FonnesbeckG FlemingN HalasaGlobal trends in Extracorporeal membranous Oxygenation use and survival of patients with Influenza-associated illnessPediatr Crit Care Med20161787688310.1097/PCC.000000000000084327427879
  48. Y-W ChienKP KlugmanDM MorensBacterial pathogens and death during the 1918 influenza pandemicN Engl J Med20093612582258310.1056/NEJMc090821620032332
  49. World Health Organisation (WHO)WHO guidelines on the use of vaccines and antivirals during influenza pandemics2004
  50. M BontenM BolkenbaasS HuijtsCommunity acquired pneumonia immunisation trial in adults (CAPITA)Pneumonia2014395
  51. LA JacksonKM NeuzilO YuEffectiveness of pneumococcal polysaccharide vaccine in older adultsN Engl J Med20033481747175510.1056/NEJMoa02267812724480
  52. R ItzwerthPandemic influenza and critical infrastructure2013SydneyUniversity of New South Wales (UNSW)
  53. R ChampunotS TanjathamA KerdsinImpact of pandemic influenza (H1N1) virus-associated community-acquired pneumonia among adults in a tertiary hospital in ThailandJpn J Infect Dis20106325125620657064
  54. E CuquemelleF SoulisD VillersCan procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre studyIntensive Care Med20113779680010.1007/s00134-011-2189-121369807
  55. WJ ChoiWY KimSH KimClinical characteristics of pneumonia in hospitalized patients with novel influenza A (H1N1) in KoreaScand J Infect Dis20104231131410.3109/0036554090349002620222847
  56. D ViasusJR Pano-PardoJ PachonPneumonia complicating pandemic (H1N1) 2009: risk factors, clinical features, and outcomesMedicine (Baltimore)20119032833610.1097/MD.0b013e31822e67a721862936
  57. E PiacentiniB SanchezV ArauzoProcalcitonin levels are lower in intensive care unit patients with H1N1 influenza A virus pneumonia than in those with community-acquired bacterial pneumonia. A pilot studyJ Crit Care20112620120510.1016/j.jcrc.2010.07.00920813489
  58. S MulrennanSS TemponeITW LingPandemic influenza (H1N1) 2009 pneumonia: CURB-65 score for predicting severity and nasopharyngeal sampling for diagnosis are unreliablePLoS One20105e1284910.1371/journal.pone.001284920877727
  59. Centers for Disease ControlHospitalized patients with novel influenza A (H1N1) virus infection - California, April–May, 2009MMWR Morb Mortal Wkly Rep20095853654119478723
  60. S JainL KamimotoAM BramleyHospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009N Engl J Med20093611935194410.1056/NEJMoa090669519815859
  61. JK LouieM AcostaK WinterFactors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in CaliforniaJAMA20093021896190210.1001/jama.2009.158319887665
  62. A DhanoaNC FangSS HassanP KaniappanG RajasekaramEpidemiology and clinical characteristics of hospitalized patients with pandemic influenza A (H1N1) 2009 infections: the effects of bacterial coinfectionVirol J2011850110.1186/1743-422X-8-50122050645
  63. KKW ToSSY WongIWS LiConcurrent comparison of epidemiology, clinical presentation and outcome between adult patients suffering from the pandemic influenza A (H1N1) 2009 virus and the seasonal influenza A virus infectionPostgrad Med J20108651552110.1136/pgmj.2009.09620620693151
  64. D ViasusJR Pano-PardoJ PachonFactors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in SpainClin Microbiol Infect20111773874610.1111/j.1469-0691.2010.03362.x20825436
  65. M RieraA PayerasMA MarcosClinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter studyAids2010242461246710.1097/QAD.0b013e32833e508f20827165
  66. A SemionovC TremblayL SamsonPandemic influenza A (H1N1) 2009: chest radiographic findings from 147 proven cases in the Montreal areaCan Assoc Radiol J20106123324010.1016/j.carj.2010.03.00820510575
  67. KKW ToIFN HungIWS LiDelayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infectionClin Infect Dis20105085085910.1086/65058120136415
  68. M MasiaS PadillaP AntequeraPredictors of pneumococcal co-infection for patients with pandemic (H1N1) 2009Emerg Infect Dis2011171475147821801627
  69. B PecavarK NadrahL PapstClinical characteristics of adult patients with influenza-like illness hospitalized in general ward during Influenza A H1N1 pandemic 2009/2010Wien Klin Wochenschr201112366266710.1007/s00508-011-0054-421935645
  70. Y LiuH ChenY SunF ChenAntiviral role of toll-like receptors and cytokines against the new 2009 H1N1 virus infectionMol Biol Rep2012391163117210.1007/s11033-011-0846-721603856
  71. JS Nguyen-Van-TamPJM OpenshawA HashimRisk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009)Thorax20106564565110.1136/thx.2010.13521020627925
  72. P Santa-Olalla PeraltaM Cortes-GarciaM Vicente-HerreroRisk factors for disease severity among hospitalised patients with 2009 pandemic influenza A (H1N1) in Spain, April - December 2009Euro Surveill20101523
  73. C VenkataP SampathkumarB AfessaHospitalized patients with 2009 H1N1 Influenza infection: the Mayo Clinic experienceMayo Clin Proc20108579880510.4065/mcp.2010.016620664021
  74. A JarttiE RauvalaH KaumaChest imaging findings in hospitalized patients with H1N1 influenzaActa Radiol20115229730410.1258/ar.2010.10037921498366
  75. C RizzoMG CaporaliMC RotaPandemic influenza and pneumonia due to legionella pneumophila: a frequently underestimated coinfectionClin Infect Dis20105111510.1086/653444
  76. E KopelZ AmitaiI GrottoE KalinerI VolovikPatients with pandemic (H1N1) 2009 in intensive care units, IsraelEmerg Infect Dis20101672072110.3201/eid1604.09169620350400
  77. G Dominguez-CheritSE LapinskyAE MaciasCritically ill patients with 2009 influenza A(H1N1) in MexicoJAMA20093021880188710.1001/jama.2009.153619822626
  78. R LibsterJ BugnaS CovielloPediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in ArgentinaN Engl J Med2010362455510.1056/NEJMoa090767320032320
  79. S KumarPL HavensMJ ChusidClinical and epidemiologic characteristics of children hospitalized with 2009 pandemic H1N1 influenza a infectionPediatr Infect Dis J20102959159410.1097/INF.0b013e3181d73e3220589976
  80. Y MiroballiJS BairdS ZackaiNovel influenza A(H1N1) in a pediatric health care facility in New York City during the first wave of the 2009 pandemicArch Pediatr Adolesc Med2010164243010.1001/archpediatrics.2009.25920048238
  81. S O'RiordanM BartonY YauRisk factors and outcomes among children admitted to hospital with pandemic H1N1 influenzaCMAJ2010182394410.1503/cmaj.09172419926677
  82. JA BettingerLJ SauveDW ScheifelePandemic influenza in Canadian children: a summary of hospitalized pediatric casesVaccine2010283180318410.1016/j.vaccine.2010.02.04420189488
  83. JL LockmanWA FischerTM PerlA ValsamakisDG NicholsThe critically ill child with novel H1N1 influenza A: a case seriesPediatr Crit Care Med20101117317810.1097/PCC.0b013e3181ccedae20048690
  84. M SteinD TasherD GlikmanHospitalization of children with influenza A(H1N1) virus in Israel during the 2009 outbreak in Israel: a multicenter surveyArch Pediatr Adolesc Med20101641015102210.1001/archpediatrics.2010.19521041594
  85. PD TammaAE TurnbullAM MilstoneClinical outcomes of seasonal influenza and pandemic influenza A (H1N1) in pediatric inpatientsBMC Pediatr2010107210.1186/1471-2431-10-7220925926
  86. A ParakhA KumarV KumarAK DuttaS KharePediatric hospitalizations associated with 2009 pandemic influenza A (H1N1): an experience from a tertiary care center in North IndiaIndian J Pediatr20107798198510.1007/s12098-010-0168-020799074
  87. JA FariasA FernandezE MonteverdeCritically ill infants and children with influenza A (H1N1) in pediatric intensive care units in ArgentinaIntensive Care Med2010361015102210.1007/s00134-010-1853-120237757
  88. AG RandolphF VaughnR SullivanCritically ill children during the 2009-2010 influenza pandemic in the United StatesPediatrics2011128e1450e145810.1542/peds.2011-077422065262
  89. SY ShinJH KimHS KimClinical characteristics of Korean pediatric patients critically ill with influenza A (H1N1) virusPediatr Pulmonol2010451014102010.1002/ppul.2128820648671
The underlying source XML for this text is taken from The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as influenza.