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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09</title><author><name sortKey="Macintyre, Chandini Raina" sort="Macintyre, Chandini Raina" uniqKey="Macintyre C" first="Chandini Raina" last="Macintyre">Chandini Raina Macintyre</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>Biosecurity Program,</institution><institution>The Kirby Institute, UNSW Medicine, University of New South Wales,</institution></institution-wrap>Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Chughtai, Abrar Ahmad" sort="Chughtai, Abrar Ahmad" uniqKey="Chughtai A" first="Abrar Ahmad" last="Chughtai">Abrar Ahmad Chughtai</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Barnes, Michelle" sort="Barnes, Michelle" uniqKey="Barnes M" first="Michelle" last="Barnes">Michelle Barnes</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Ridda, Iman" sort="Ridda, Iman" uniqKey="Ridda I" first="Iman" last="Ridda">Iman Ridda</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Seale, Holly" sort="Seale, Holly" uniqKey="Seale H" first="Holly" last="Seale">Holly Seale</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Toms, Renin" sort="Toms, Renin" uniqKey="Toms R" first="Renin" last="Toms">Renin Toms</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Heywood, Anita" sort="Heywood, Anita" uniqKey="Heywood A" first="Anita" last="Heywood">Anita Heywood</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30526505</idno><idno type="pmc">6286525</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286525</idno><idno type="RBID">PMC:6286525</idno><idno type="doi">10.1186/s12879-018-3548-0</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000195</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000195</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09</title><author><name sortKey="Macintyre, Chandini Raina" sort="Macintyre, Chandini Raina" uniqKey="Macintyre C" first="Chandini Raina" last="Macintyre">Chandini Raina Macintyre</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>Biosecurity Program,</institution><institution>The Kirby Institute, UNSW Medicine, University of New South Wales,</institution></institution-wrap>Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Chughtai, Abrar Ahmad" sort="Chughtai, Abrar Ahmad" uniqKey="Chughtai A" first="Abrar Ahmad" last="Chughtai">Abrar Ahmad Chughtai</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Barnes, Michelle" sort="Barnes, Michelle" uniqKey="Barnes M" first="Michelle" last="Barnes">Michelle Barnes</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Ridda, Iman" sort="Ridda, Iman" uniqKey="Ridda I" first="Iman" last="Ridda">Iman Ridda</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Seale, Holly" sort="Seale, Holly" uniqKey="Seale H" first="Holly" last="Seale">Holly Seale</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Toms, Renin" sort="Toms, Renin" uniqKey="Toms R" first="Renin" last="Toms">Renin Toms</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author><author><name sortKey="Heywood, Anita" sort="Heywood, Anita" uniqKey="Heywood A" first="Anita" last="Heywood">Anita Heywood</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</nlm:aff></affiliation></author></analytic><series><title level="j">BMC Infectious Diseases</title><idno type="eISSN">1471-2334</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the pandemic of influenza A(H1N1)pdm09.</p></sec><sec><title>Methods</title><p id="Par2">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.</p></sec><sec><title>Results</title><p id="Par3">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 (<italic>Streptococcus pneumoniae 29%)</italic>. Eleven studies reported bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia, with a mean of 19% positive for bacteria (<italic>Streptococcus pneumoniae 54%)</italic>. Of 16 studies of intensive care unit (ICU) patients, bacterial co-infection identified in a mean of 19% of cases (<italic>Streptococcus pneumoniae 26%)</italic>. The mean prevalence of bacterial co-infection was 12% in studies of hospitalised patients not requiring ICU (<italic>Streptococcus pneumoniae 33%)</italic> and 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards (<italic>Streptococcus pneumoniae 16%)</italic>.</p></sec><sec><title>Conclusion</title><p id="Par4">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 <italic>Streptococcus pneumoniae</italic> 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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lee, Eh" uniqKey="Lee E">EH Lee</name></author><author><name sortKey="Wu, C" uniqKey="Wu C">C Wu</name></author><author><name sortKey="Lee, Eu" uniqKey="Lee E">EU Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gill, Jr" uniqKey="Gill J">JR Gill</name></author><author><name sortKey="Sheng, Zm" uniqKey="Sheng Z">ZM Sheng</name></author><author><name sortKey="Ely, Sf" uniqKey="Ely S">SF Ely</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chien, Ys" uniqKey="Chien Y">YS Chien</name></author><author><name sortKey="Su, Cp" uniqKey="Su C">CP Su</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">BMC Infect. Dis</journal-id><journal-title-group><journal-title>BMC Infectious Diseases</journal-title></journal-title-group><issn pub-type="epub">1471-2334</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30526505</article-id><article-id pub-id-type="pmc">6286525</article-id><article-id pub-id-type="publisher-id">3548</article-id><article-id pub-id-type="doi">10.1186/s12879-018-3548-0</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>MacIntyre</surname><given-names>Chandini Raina</given-names></name><address><email>hos-sphcm@unsw.edu.au</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Chughtai</surname><given-names>Abrar Ahmad</given-names></name><address><phone>+61 2 9385 009</phone><email>journal.health.au@gmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Barnes</surname><given-names>Michelle</given-names></name><address><email>michell@med.usyd.edu.au</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ridda</surname><given-names>Iman</given-names></name><address><email>imanridda@hotmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Seale</surname><given-names>Holly</given-names></name><address><email>h.seale@unsw.edu.au</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Toms</surname><given-names>Renin</given-names></name><address><email>rmbst288@uowmail.edu.au</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Heywood</surname><given-names>Anita</given-names></name><address><email>a.heywood@unsw.edu.au</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>Biosecurity Program,</institution><institution>The Kirby Institute, UNSW Medicine, University of New South Wales,</institution></institution-wrap>Sydney, NSW 2052 Australia</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4902 0432</institution-id><institution-id institution-id-type="GRID">grid.1005.4</institution-id><institution>School of Public Health and Community Medicine, Faculty of Medicine,</institution><institution>UNSW Medicine, the University of New South Wales,</institution></institution-wrap>Samuels Building, Room 209, Sydney, NSW 2052 Australia</aff></contrib-group><pub-date pub-type="epub"><day>7</day><month>12</month><year>2018</year></pub-date><pub-date pub-type="pmc-release"><day>7</day><month>12</month><year>2018</year></pub-date><pub-date pub-type="collection"><year>2018</year></pub-date><volume>18</volume><elocation-id>637</elocation-id><history><date date-type="received"><day>27</day><month>10</month><year>2017</year></date><date date-type="accepted"><day>23</day><month>11</month><year>2018</year></date></history><permissions><copyright-statement>© The Author(s). 2018</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the pandemic of influenza A(H1N1)pdm09.</p></sec><sec><title>Methods</title><p id="Par2">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.</p></sec><sec><title>Results</title><p id="Par3">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 (<italic>Streptococcus pneumoniae 29%)</italic>. Eleven studies reported bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia, with a mean of 19% positive for bacteria (<italic>Streptococcus pneumoniae 54%)</italic>. Of 16 studies of intensive care unit (ICU) patients, bacterial co-infection identified in a mean of 19% of cases (<italic>Streptococcus pneumoniae 26%)</italic>. The mean prevalence of bacterial co-infection was 12% in studies of hospitalised patients not requiring ICU (<italic>Streptococcus pneumoniae 33%)</italic> and 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards (<italic>Streptococcus pneumoniae 16%)</italic>.</p></sec><sec><title>Conclusion</title><p id="Par4">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 <italic>Streptococcus pneumoniae</italic> 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.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Influenza A(H1N1)pdm09</kwd><kwd>Bacterial infection</kwd><kwd>Pneumonia</kwd><kwd>Respiratory infections hospitalization</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2018</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p id="Par24">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 [<xref ref-type="bibr" rid="CR1">1</xref>–<xref ref-type="bibr" rid="CR8">8</xref>]. 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 [<xref ref-type="bibr" rid="CR9">9</xref>]. 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 [<xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR11">11</xref>]. 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 <italic>S. pneumoniae</italic>, <italic>H. influenzae, S. aureus,</italic> and group A <italic>Streptococcus</italic> (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.</p><p id="Par25">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.</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Search strategy</title><p id="Par26">A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) [<xref ref-type="bibr" rid="CR12">12</xref>].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 [<xref ref-type="bibr" rid="CR13">13</xref>]. 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.</p><p id="Par27">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.</p></sec><sec id="Sec4"><title>Inclusion and exclusion criteria</title><p id="Par28">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.</p><p id="Par29">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.</p><p id="Par30">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.</p><p id="Par31">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.</p></sec><sec id="Sec5"><title>Data extraction and assessment</title><p id="Par32">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. <xref rid="Fig1" ref-type="fig">1</xref>. 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 id="Fig1"><label>Fig. 1</label><caption><p>Study diagram</p></caption><graphic xlink:href="12879_2018_3548_Fig1_HTML" id="MO1"></graphic></fig></p><p id="Par33">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.</p></sec></sec><sec id="Sec6"><title>Results</title><sec id="Sec7"><title>Summary of included studies</title><p id="Par34">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. <xref rid="Fig1" ref-type="fig">1</xref>.</p><p id="Par35">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.</p><p id="Par36">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 <xref rid="Fig2" ref-type="fig">2</xref> shows the average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients.<fig id="Fig2"><label>Fig. 2</label><caption><p>Average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients</p></caption><graphic xlink:href="12879_2018_3548_Fig2_HTML" id="MO2"></graphic></fig></p></sec><sec id="Sec8"><title>Bacterial co-infection among fatal cases of A(H1N1)2009pdm</title><p id="Par37">Eleven studies reported evidence of bacterial co-infection of fatal confirmed cases of influenza A(H1N1)pdm09 occurring between April 2009 and May 2010 [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR14">14</xref>–<xref ref-type="bibr" rid="CR22">22</xref>]. Eight studies reported autopsy results, including 8 autopsy case series [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR16">16</xref>–<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR22">22</xref>] and 3 reporting bacterial findings from medical records reviews only [<xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR20">20</xref>]. Five studies were based in the USA [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR18">18</xref>] while the others were from Mexico [<xref ref-type="bibr" rid="CR14">14</xref>], Estonia [<xref ref-type="bibr" rid="CR22">22</xref>], Brazil [<xref ref-type="bibr" rid="CR17">17</xref>], the United Kingdom [<xref ref-type="bibr" rid="CR19">19</xref>], Korea [<xref ref-type="bibr" rid="CR20">20</xref>] and Japan [<xref ref-type="bibr" rid="CR21">21</xref>].</p><p id="Par38">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.</p><p id="Par39">The study details, bacterial testing and bacterial findings are summarised in Table <xref rid="Tab1" ref-type="table">1</xref>. 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%) [<xref ref-type="bibr" rid="CR9">9</xref>] 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 [<xref ref-type="bibr" rid="CR20">20</xref>].<table-wrap id="Tab1"><label>Table 1</label><caption><p>Bacterial co-infection among the fatal cases of A(H1N1)2009pdm (<italic>n</italic> = 11)</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Author (year)<break></break>Study location/ period</th><th rowspan="2">Study type</th><th rowspan="2">Study population</th><th rowspan="2">N (%) autopsied</th><th rowspan="2">N (%) hospitalised prior to death</th><th colspan="2">Requirement for</th><th rowspan="2">Antivirals<sup>a</sup><break></break>n/N (%) any n/N (%) 48 h</th><th rowspan="2">Antibiotics<sup>b</sup><break></break>n/N (%) pre n/N (%) on<break></break>n/N (%) during admission</th><th rowspan="2">Positive bacterial growth</th><th rowspan="2">N (%) bacterial pneumonia</th><th rowspan="2">N (%) with <italic>S.pneumoniae</italic><break></break>Site of isolation</th></tr><tr><th>ICU</th><th>Mechanical Ventilation</th></tr></thead><tbody><tr><td><p>Fajardo-Dolci (2009) [<xref ref-type="bibr" rid="CR14">14</xref>]</p><p>Mexico</p><p>16/3/09–16/5/09</p></td><td>Medical record review</td><td><p><italic>N</italic> = 100</p><p>Consecutive notified hospitalized fatal cases</p></td><td>0/100 (0)</td><td>100/100 (100)</td><td>NR</td><td>84/100 (84.0)</td><td><p>56/100 (56)</p><p>NR</p></td><td>94/100 (94)</td><td><p>2/100 (2%)</p><p>(Site not mentioned)</p></td><td><p>77/82 (94.0)</p><p>CXR suggestive of pneumonia.</p></td><td>NR</td></tr><tr><td><p>Lee (2010) [<xref ref-type="bibr" rid="CR1">1</xref>]</p><p>USA</p><p>4/09–7/09</p></td><td>Enhanced surveillance/confirmed cases in New York City.</td><td><italic>N</italic> = 47</td><td>31/47 (66)</td><td>47/47 (100.0)</td><td>All 28 cases who died after > 24 in hospital were admitted to ICU</td><td>25/47 (80.6)</td><td><p>32/47 (68.0)</p><p>NR</p></td><td>NR</td><td>NR</td><td><p>13/47 (27.6)</p><p>By immunohistochemical analysis or PCR</p><p>21/28 with abnormal CXR and multilobar infiltrates.</p></td><td><p>8/47 (17.0) Lung/airway tissue</p><p>By immunohistochemical analysis or PCR</p></td></tr><tr><td><p>Lucas (2010) [<xref ref-type="bibr" rid="CR19">19</xref>]</p><p>UK</p><p>4/09–1/10</p></td><td><p>Case series.</p><p>15% of reported H1N1 deaths</p></td><td><p><italic>N</italic> = 68</p><p>Autopsied fatal cases</p></td><td>68/68 (100)</td><td>68/68 (100)</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td><p>20/68 (29.4)</p><p>(Culture of lung/ blood)</p></td><td><p>28/68 (41.2)</p><p>- Autopsy findings</p><p>- Culture and histopathology</p></td><td><p>7/68 (10.3)</p><p>(6 confirmed and 1 possible through histology) isolation site Lung/ and or blood</p></td></tr><tr><td><p>Gill (2010) [<xref ref-type="bibr" rid="CR2">2</xref>]</p><p>USA</p><p>5/09–7/09</p></td><td><p>Case series.</p><p>Autopsy request New York City (NYC) Office of chief medical examiner (<italic>n</italic> = 32), family requests (n = 10), deaths outside of NYC (<italic>n</italic> = 2)</p></td><td><p><italic>N</italic> = 34</p><p>Autopsied fatal cases</p></td><td>34/34 (100)</td><td>21/34 (61.8)</td><td>NR</td><td>12/21 (57.1)</td><td>NR</td><td>NR</td><td>10/30 (33.3) Positive bacteria by culture, immunohistochemistry, and/or PCR</td><td>18/33 (54.4) have evidence of bacterial co-infection by tissue Gram stain.</td><td><p>6/30 (20) Positive for streptococcus by culture, immunohistochemistry, and/or PCR</p><p>16/33 (55) have evidence of bacterial co-infection by tissue Gram stain morphologically compatible with streptococcus.</p></td></tr><tr><td><p>CDC (2009) [<xref ref-type="bibr" rid="CR15">15</xref>]</p><p>USA</p><p>4/09–8/09</p></td><td><p>Multicenter case series.</p><p>100% of reported deaths</p></td><td><p><italic>N</italic> = 36</p><p>Pediatric (< 18 yrs).</p><p>Hospitalized fatal cases</p></td><td>NR</td><td>28/33 (84.8)</td><td>24/36 (66.7)</td><td>NR</td><td><p>19/30 (63.3)</p><p>Status unknown for 6 cases</p><p>4/30 (13%)</p></td><td>NR</td><td>NR</td><td><p>10/23 (43.5)</p><p>Based on culture and pathology results</p></td><td>3/23 (13) from multiple sites in px (BC, lung tissue, pleural fluid, CSF)</td></tr><tr><td><p>Shieh (2010) [<xref ref-type="bibr" rid="CR18">18</xref>]</p><p>USA</p><p>5/09–10/09</p></td><td>Notified fatal case series/US CDC</td><td><p>N = 100</p><p>Autopsied fatal cases</p></td><td>100/100 (100)</td><td>58/87 (66.7)</td><td>NR</td><td>42/57 (73.7)</td><td><p>44/67 (65.7)</p><p>NR</p></td><td>NR</td><td>NR</td><td><p>29/100 (29)</p><p>Bacterial co-infection positive through PCR and histopathology on lung tissue</p><p>38/64 (59) radiological diagnosis of pneumonia</p></td><td><p>10/100 (10)</p><p>Lung tissue through PCR</p></td></tr><tr><td><p>CDC (2009) [<xref ref-type="bibr" rid="CR16">16</xref>]</p><p>USA</p><p>5/09–8/09</p></td><td>Case series (US CDC), multiple (8) states</td><td><p><italic>N</italic> = 77</p><p>Autopsied fatal cases</p></td><td>77/77 (100)</td><td>8/18 (44.0)</td><td>NR</td><td>7/7 (100.0)</td><td>NR</td><td>7/9 (77.8)</td><td>NR</td><td><p>22/77 (28.6)</p><p>Histopathology and positive PCR for bacteria</p></td><td>10/77 (positive through immunohistochemical assays) respiratory tissue</td></tr><tr><td><p>Mauad (2010) [<xref ref-type="bibr" rid="CR17">17</xref>]</p><p>Brazil</p><p>7/09–8/09</p></td><td>Case series</td><td><p><italic>N</italic> = 21</p><p>Autopsied fatal cases</p></td><td>21 (100)</td><td>21 (100.0)</td><td>16/21 (76.2)</td><td>21/21 (100.0)</td><td><p>16/21 (76.2)</p><p>NR</p></td><td>13/21 (61.9)</td><td>3/9 (33.3)</td><td>8/21 (38.1)</td><td>6/21 (28.6) diagnosed by culture of bronchial aspirate and/or tissue PCR</td></tr><tr><td><p>Kim (2011) [<xref ref-type="bibr" rid="CR20">20</xref>]</p><p>Korea</p><p>8/09–11/09</p></td><td>Active mortality inpatient surveillance</td><td><p><italic>N</italic> = 115</p><p>Notified hospitalized fatal cases</p></td><td>0/115 (0)</td><td>115/115 (100%)</td><td>63/115 (54.8)</td><td>NR</td><td><p>100/115 (87%)</p><p>41/115 (35.6)</p></td><td>NR</td><td>34/115 (29.6) positive on blood or sputum culture</td><td><p>34/115 (29.6) positive on blood or sputum culture</p><p>97/113 (85.8)</p><p>CXR suggestive of pneumonia</p></td><td><p>3/115 (2.6) bronchoalveolar lavage (BAL)</p><p>Streptococcus was also isolated from blood of one case</p></td></tr><tr><td><p>Nakajima (2012) [<xref ref-type="bibr" rid="CR21">21</xref>]</p><p>Japan</p><p>8/09–2/10</p></td><td>Multicenter (15), case series, Tokyo.</td><td><p><italic>N</italic> = 20</p><p>Autopsied fatal cases</p></td><td>20/20 (100)</td><td>11/20 (55.0)</td><td>NR</td><td>7/20 (35.0)</td><td><p>14/20 (70%)</p><p>13/20 (65%)</p></td><td>10/20 (50%)</td><td>4/11 (36.4%)</td><td>5/20 (25%) Based on histopathological finding (bacteria isolated in 4 of 5)</td><td><p>2/10 (20%)</p><p>sputum, blood cultures; lung tissue</p></td></tr><tr><td><p>Tamme (2012) [<xref ref-type="bibr" rid="CR22">22</xref>]</p><p>Estonia</p><p>10/09–5/10</p></td><td>Case series</td><td><p>N = 21</p><p>Autopsied fatal cases</p></td><td>19/21 (90)</td><td>17/21 (81.0)</td><td>15/21(71.4)</td><td>NR</td><td><p>3/21 (14.3)</p><p>1/21 (4.8%)</p></td><td>16/21 (76.2)</td><td><p>8/21 (38.1)</p><p>(Culture performed on 14 samples)</p></td><td><p>9/21 (42.8)</p><p>Culture or Autopsy findings consistent with sepsis or bacterial infection</p></td><td><p>2/21 (9.5)</p><p>Blood and/or lung tissue culture</p></td></tr></tbody></table><table-wrap-foot><p>Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission</p><p><italic>Diff</italic> Differentiated between bacterial pneumonia, viral pneumonia and ARDS</p><p><italic>No diff</italic> Did not differentiate between aetiology of abnormal chest imaging</p><p><sup>a</sup>Number (percentage) of cases on antivirals; N (%) started within 48 h of symptom onset</p><p><sup>b</sup>Number (percentage) of cases on antibiotics commencing pre-admission, on admission or during admission (if reported)</p></table-wrap-foot></table-wrap></p><p id="Par40">The lowest proportion of co-infection was reported in the first 100 confirmed deaths in Mexico [<xref ref-type="bibr" rid="CR14">14</xref>] 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 (<italic>Staphylococcus epidermidis</italic> and <italic>Staphylococcus hominis)</italic>. Of the eight autopsy case series, 3 studies tested lung tissue specimens for evidence of bacterial infection in all included subjects [<xref ref-type="bibr" rid="CR16">16</xref>–<xref ref-type="bibr" rid="CR18">18</xref>] and identified bacterial co-infection diagnosed either before or after death in between 29 and 43% of fatal cases [<xref ref-type="bibr" rid="CR16">16</xref>–<xref ref-type="bibr" rid="CR18">18</xref>]. The highest proportion of culture positive bacterial co-infection from autopsy samples (38%) was reported by Tamme [<xref ref-type="bibr" rid="CR22">22</xref>].</p><p id="Par41">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 [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR17">17</xref>, <xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR22">22</xref>] reporting data from clinical testing prior to death (Table <xref rid="Tab1" ref-type="table">1</xref>). 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.</p></sec><sec id="Sec9"><title>Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia</title><p id="Par42">Eleven studies reported on influenza A(H1N1)pdm09 among hospitalised cases with evidence of pneumonia and are summarised in Table <xref rid="Tab2" ref-type="table">2</xref>. 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, <italic>Acinobacter baumanii</italic> was the next most commonly identified bacteria (5–21%), followed by MRSA (3–6%), <italic>S. pneumoniae</italic> (2–4%) and <italic>K. Pneumonia in</italic> (1–8%). Of the 11 studies, 2 reported no evidence of bacterial co-infection in their cohort of patients [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR23">23</xref>], however, neither reported the proportion of patients tested. The study conducted in Mexico early in the pandemic [<xref ref-type="bibr" rid="CR23">23</xref>] isolated ventilator-associated bacteria in 4 (22%) cases, with <italic>Acinetobacter baumannii, Achromobacter xylosoxidans,</italic> methicillin-resistant <italic>Staphylococcus aureus,</italic> and <italic>Escherichia coli</italic> identified.<table-wrap id="Tab2"><label>Table 2</label><caption><p>Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia (<italic>n</italic> = 11)</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Author and year</th><th rowspan="2">Study type</th><th rowspan="2">Study population</th><th colspan="3">Case severity</th><th rowspan="2">Antivirals*<break></break>n/N (%) any<break></break>n/N (%) 48 h</th><th rowspan="2">Antibiotics†<break></break>n/N (%) pre<break></break>n/N (%) on<break></break>n/N (%) during admission</th><th rowspan="2">Any positive bacterial growth</th><th rowspan="2">n/N (%) <italic>S.pneumoniae</italic><break></break>[Site of isolation]</th><th rowspan="2">N (%)pneumonia<break></break>Method<break></break>Diff/no diff</th></tr><tr><th>ICU</th><th>Mechanical Ventilation</th><th>Deaths</th></tr></thead><tbody><tr><td><p>Perez-Padilla (2009) [<xref ref-type="bibr" rid="CR23">23</xref>]</p><p>Mexico</p><p>3/09–4/09</p></td><td>Single-centre case series (retrospective medical record review) of patients admitted to hospital with pneumonia and A(H1N1)pdm09 (<italic>N</italic> = 18)</td><td><italic>N</italic> = 18</td><td>12/18 (66.7)</td><td>12/18 (66.7)</td><td>7/18 (38.9)</td><td>14/18 (77.7)</td><td><p>12/18 pre (66.7)</p><p>17/18 post (94.4)</p></td><td><p>0/6 (0) BC</p><p>0/2 (0) BA</p><p>0/1 (0) pleural fluid</p><p>4/18 (22.2) Ventilator Associated pneumonia</p></td><td><p>0/18 [NR]</p><p>NP swab and bronchial aspirates</p></td><td><p>18 (100)</p><p>CXR</p><p>No diff</p></td></tr><tr><td><p>Chien (2010) [<xref ref-type="bibr" rid="CR3">3</xref>]</p><p>Taiwan</p><p>07/09–8/09</p></td><td><p>Nation-wide notified cases (retrospective medical record review)</p><p>New pulmonary infiltrates consistent with pneumonia, compatible clinical presentations.</p><p>Identification of clinicalyl significant bacteria in respiratory secretion or specimens from sterile compartments was recorded as secondary bacterial infection.</p></td><td><italic>N</italic> = 96</td><td>35/96 (36.5)</td><td>NR</td><td>10/96 (10.4)</td><td><p>96/96 (100.0)</p><p>- NR</p></td><td>NR</td><td>13/96 (13.2) pulmonary NFI (13.5)</td><td>2/99 (2) [Respiratory secretions]</td><td><p>13 (13.5)</p><p>CXR positive</p></td></tr><tr><td><p>Champunot (2010) [<xref ref-type="bibr" rid="CR53">53</xref>]</p><p>Thailand</p><p>7/09–10/09</p></td><td><p>Single-centre case series (prospective);</p><p>Community acquired, new pulmonary infiltrate (CXR) within 24 h of admission, clinical symptoms</p></td><td><italic>N</italic> = 24</td><td>13/24 (54.2)</td><td>11/24 (45.8)</td><td>5/24 (8.3)</td><td><p>24/24 (100%)</p><p>- NR</p></td><td><p>21/24 (87.5)</p><p>- Pre = 6</p></td><td><p>Blood culture 0/24 (0)</p><p>Sputum culture 2/24(8.3)</p><p>1/24 (4.2) [urine pneumococcal Ag</p><p>TOTAL 3/24 (12.5)</p></td><td>1/24 (4.2) [urine pneumococcal Ag]</td><td><p>24 (100.0)</p><p>CXR</p><p>No diff</p></td></tr><tr><td><p>Cui (2010) [<xref ref-type="bibr" rid="CR24">24</xref>]</p><p>China</p><p>11/09–12/09</p></td><td><p>Single-centre case series (retrospective medical record review) of patients admitted to a tertiary hospital with pneumonia and H1N1(N = 68)</p><p>Blood cultures (BC) - Any patient with high fever > 38.0 °C for ≥3 days or repeated fever.</p><p>Sputum cultures (SC) - patients with symptoms of expectoration especially with yellowish/purulent sputum.</p></td><td><italic>N</italic> = 68</td><td>30/68 (44)</td><td>13/68 (19.1)</td><td>10/68 (14.7)</td><td><p>68/68 (100.0)</p><p>50/68 (74%)</p></td><td><p>All received antibiotics</p><p>65/68 (95.6) received preadmission antibiotics</p></td><td><p>5/11 (45.5) [BC]</p><p>9/29 (31.0) [SC]</p><p>Total 11/29 (37.9)</p></td><td><p>0/11 (0.0) [BC]</p><p>0/29 (0.0) [SC]</p></td><td><p>68/68 (100.0)</p><p>CXR</p><p>No diff</p></td></tr><tr><td><p>Cuquemelle [<xref ref-type="bibr" rid="CR54">54</xref>]</p><p>(2011)</p><p>France</p><p>11/09–4/10</p></td><td><p>Multicenter (24) case series (retrospective)/ not having received prior antibiotics (<italic>N</italic> = 103)</p><p>Microbiological investigations and biomarker levels were obtained as part of the routine clinical management of patients, at the discretion of the treating physician</p></td><td><italic>N</italic> = 103</td><td>103/103 (100)</td><td>62/103 (60.2)</td><td>18/103 (17.5)</td><td>NR</td><td>0/103 (0)</td><td><p>48/103 (46.6)</p><p>Isolation of bacteria</p></td><td>26/103 (25.2) [NS]</td><td>Infiltrates on all CXR</td></tr><tr><td>Choi [<xref ref-type="bibr" rid="CR55">55</xref>]</td><td>Definition: the presence of an infiltrate on plain chest radiograph.</td><td><italic>N</italic> = 17</td><td><p>17/17 (100)</p><p>All in acute care unit</p></td><td>1/17 (5.9)</td><td>1/17 (5.9)</td><td>17/17 (100)</td><td>17/17 (100)</td><td><p>0/17 (0) BC</p><p>0/17 (0) SC</p><p>2/17 (11.8) urine Ag test (Legionella)</p><p>1/17 (5.9) PCR (TB)</p></td><td><p>0/17 (100)</p><p>Testing for <italic>S. pneumo</italic></p></td><td><p>16/17 (94.1)</p><p>CXR</p><p>No diff</p></td></tr><tr><td>Viasus [<xref ref-type="bibr" rid="CR56">56</xref>]</td><td>Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature 38.0-C) and/or respiratory symptoms</td><td><italic>N</italic> = 234 (210 tested for microbiologic studies)</td><td>53/234 (22.6)</td><td>42/234 (17.9)</td><td>12/234 (5.1)</td><td><p>229/234 (97.9)</p><p>50/234 (22.4)</p></td><td>228/234 (97.9)</td><td><p>36/210 (17.1)</p><p>Specimens included: culture of blood, normally sterile fluids, or sputum and/or a positive urinary antigen test</p></td><td>26/210 (12.4)</td><td>All CXR positive</td></tr><tr><td>Piacentini [<xref ref-type="bibr" rid="CR57">57</xref>]</td><td>Compares H1N1 with pneumonia in ICU and community acquired</td><td><italic>N</italic> = 10</td><td>10/10 (100)</td><td>5/10 (50)</td><td>0/10 (0)</td><td>10/10 (100)</td><td>10/10 (100)</td><td><p>2/10 (20.0)</p><p>Pre-treatment BC, SC, and urinary Ag for <italic>S. pneumoniae</italic> and <italic>Legionella</italic> sp.</p></td><td><p>2/10 (20)</p><p>Specimen type NR</p></td><td>CXR positive (multilobar infiltrates) all except 2 (single lobe infiltrates)</td></tr><tr><td>Mulrennan [<xref ref-type="bibr" rid="CR58">58</xref>]</td><td><p>New pulmonary infiltrates on imaging + clinical symptoms</p><p>Compared with non-pneumonia H1N1</p></td><td><italic>N</italic> = 35</td><td>11/35 (31.4)</td><td>10/35 (28.6)</td><td>2/35 (5.7)</td><td>35/35 (100)</td><td>NR</td><td><p>5/35 (14.3)</p><p>NP, lower resp. tarct</p></td><td>NR</td><td><p>35/35 (100)</p><p>CXR</p><p>no diff</p></td></tr><tr><td><p>Ugarte (2010) [<xref ref-type="bibr" rid="CR25">25</xref>]</p><p>Chile</p><p>5/09–9/09</p><p>Adults</p></td><td><p>Multicenter (11) case series (retrospective) / adult ICU admissions</p><p>Definition: 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</p></td><td><italic>N</italic> = 75</td><td>75/75 (100.0))</td><td><p>56/75 (74.7)</p><p>-</p></td><td>19/75 (25.3)</td><td>NR</td><td>NR</td><td><p>7/75 (9.3)</p><p>Specimens NR</p></td><td><p>4/75 (5.3) on admission. Site NR</p><p>1/5 (20) empyema patients BC</p></td><td><p>74 (98.7)</p><p>CXR</p><p>No diff</p></td></tr><tr><td>Busi [<xref ref-type="bibr" rid="CR4">4</xref>]</td><td></td><td><italic>N</italic> = 40</td><td>NR</td><td>NR</td><td>1/40 (2.5)</td><td>NR</td><td>NR</td><td>0/40 (0) Specimen NR</td><td></td><td>40/40 (100) 40 had findings consistent with pneumonia. These 28/40 (70 bilaterial) Non-Diff</td></tr></tbody></table><table-wrap-foot><p>Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission</p><p><italic>Diff</italic> Differentiated between bacterial pneumonia, viral pneumonia and ARDS;</p><p><italic>No diff</italic> Did not differentiate between aetiology of abnormal chest imaging, <italic>NR</italic> not reported</p></table-wrap-foot></table-wrap></p><p id="Par43">Six studies reported use of antibiotics prior to specimen collection in subjects with bacterial co-infection in 21–22% of those tested [<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. 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 [<xref ref-type="bibr" rid="CR25">25</xref>]. 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 <italic>Legionella pneumophila, Chlamydophila pneumoniae,</italic> and <italic>Mycoplasma pneumoniae)</italic> and Binax NOW, an in vitro immunochromatographic assay for <italic>Streptococcus pneumonia.</italic> However, the mPCR assay did not test for <italic>S. pneumoniae</italic> in one study and the authors could not report the presence of this organism [<xref ref-type="bibr" rid="CR23">23</xref>].</p></sec><sec id="Sec10"><title>Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted to ICUs</title><p id="Par44">Sixteen studies reported on influenza A(H1N1)pdm09 cases admitted to ICU wards and are summarised in Table <xref rid="Tab3" ref-type="table">3</xref>. Criteria for admission to ICU varied in the included studies, including acute respiratory distress (ARD) [<xref ref-type="bibr" rid="CR26">26</xref>, <xref ref-type="bibr" rid="CR27">27</xref>], acute respiratory failure [<xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR29">29</xref>], required mechanical ventilation (MV) [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR30">30</xref>, <xref ref-type="bibr" rid="CR31">31</xref>] or MV or low O2/IV vasoconstrictive drugs [<xref ref-type="bibr" rid="CR32">32</xref>, <xref ref-type="bibr" rid="CR33">33</xref>], MV or ECMO [<xref ref-type="bibr" rid="CR34">34</xref>] or admitted with no criteria provided [<xref ref-type="bibr" rid="CR35">35</xref>–<xref ref-type="bibr" rid="CR41">41</xref>]. Eleven studies included only PCR confirmed A(H1N1)pdm09 cases, while three included probable cases [<xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR39">39</xref>, <xref ref-type="bibr" rid="CR40">40</xref>] and another three included both probable and suspected cases [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR33">33</xref>, <xref ref-type="bibr" rid="CR34">34</xref>]. 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 (<italic>n</italic> = 337), 24% of included patients had bacterial pneumonia on admission, 8% with <italic>S. pneumoniae</italic> [<xref ref-type="bibr" rid="CR5">5</xref>]. <italic>S.pneumoniae</italic> co-infection was associated with higher mortality (OR 2.72 95% CI 1.05–7.06), despite concurrent antibiotic treatment on admission [<xref ref-type="bibr" rid="CR5">5</xref>]. A Canadian study (<italic>N</italic> = 168) attributed secondary bacterial infection as a leading cause of death in the 29 (17.3%) fatalities that occurred in this cohort [<xref ref-type="bibr" rid="CR33">33</xref>].<table-wrap id="Tab3"><label>Table 3</label><caption><p>Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted in ICUs (<italic>n</italic> = 16)</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Author and year</th><th rowspan="2">Study type</th><th rowspan="2">Study population</th><th colspan="3">Case severity</th><th rowspan="2">Antivirals<sup>a</sup><break></break>n/N (%) any<break></break>n/N (%) 48 h</th><th rowspan="2">Antibiotics†<break></break>n/N (%) pre<break></break>n/N (%) on<break></break>n/N (%) during admission</th><th rowspan="2">Any positive bacterial growth</th><th rowspan="2">Number (%) patients with <italic>S.pneumoniae</italic> and site of isolation</th><th rowspan="2">Number (%) with bacterial pneumonia<break></break>- Method<break></break>- Diff/no diff</th></tr><tr><th>ICU - ECMO</th><th>Mechanical Ventilation</th><th>Deaths</th></tr></thead><tbody><tr><td><p>Miller (2010) [<xref ref-type="bibr" rid="CR36">36</xref>]</p><p>Utah, USA</p><p>5/09–6/09</p><p>Adults(16+)</p></td><td>Multicentre (4) case series (+ comparison with local resident population) / Adult (> 15 y) ICU admissions</td><td><italic>N</italic> = 47</td><td><p>47/47 (100)</p><p>- 0</p></td><td><p>13/47 (27.7)</p><p>IV = 11/47 (84.6)</p></td><td>8/47 (14)</td><td><p>47/47 (100.0)</p><p>- 45/47 (95.7)</p></td><td><p>44/47 (93.6)</p><p>- NS</p></td><td>6/47 (13)</td><td><p>0/47 (0) BC</p><p>0/47 (0) ET aspirate</p><p>0/47 (0) SC</p><p>0/47 (0) BAL fluid</p></td><td><p>43/47(91.5)</p><p>- CXR</p><p>- No diff</p></td></tr><tr><td><p>Rello [<xref ref-type="bibr" rid="CR29">29</xref>] (2009)</p><p>Spain</p><p>6/09–7/09</p><p>Adults</p></td><td>Multicentre (20) case series (retrospective) / ICU adult admissions with ARF</td><td><italic>N</italic> = 32</td><td><p>32/32 (100)</p><p>- 0</p></td><td><p>24/32 (75.0)</p><p>- IV = 22/32 (91.7)</p><p>- NIV = 2/32 (8.3)</p></td><td>8/32 (25)</td><td><p>32/32 (100.0)</p><p>-NS</p></td><td>32/32 (100.0)</td><td><p>1/32 (3.1)</p><p>Secondary superinfection with Pseudomonas</p><p>aeruginosa were also documented in three patients (9.3).</p></td><td><p>1/32 (3.1) aspirate</p><p>0/32 (0) BC</p></td><td><p>1/32 (3.1)</p><p>respiratory culture</p></td></tr><tr><td><p>ANZ ECMO [<xref ref-type="bibr" rid="CR34">34</xref>] (2009)</p><p>Australia and New Zealand</p><p>6/09–8/09</p><p>All ages</p></td><td><p>Multicentre (15) cohort study (retrospective) / All ages ICU admission with ARDS treated with ECMO</p><p>Includes probable cases<sup>a</sup></p></td><td><italic>N</italic> = 68</td><td><p>68/68 (100)</p><p>- 68/68 (100)</p></td><td>68/68 (100)</td><td>14/68 (20.6)</td><td><p>64/68 (94.1)</p><p>- NS</p></td><td>NR</td><td>19/68 (28)</td><td>10/68 (14.7) [respiratory secretion/BC]</td><td><p>66/68 (97.1)</p><p>CXR/CT</p><p>No diff</p></td></tr><tr><td><p>Estenssoro (2010) [<xref ref-type="bibr" rid="CR5">5</xref>]</p><p>Argentina</p><p>6/09–9/09</p><p>Adults(15+)</p></td><td><p>Multicentre (35) inception cohort study (prospective & retrospective) / adult (≥ 15 years) ICU admissions with ILI & ARF requiring MV</p><p>Includes probable cases<sup>a</sup></p></td><td><italic>N</italic> = 337</td><td>337/337 (100)</td><td><p>337/337 (100)</p><p>NIV = 64/337 (19.0)</p></td><td>156/337 (46.3)</td><td><p>328/336 (98)</p><p>- NS</p></td><td><p>337/337 (100)</p><p>- NS</p></td><td>28/337 (8.3)</td><td><p>28 /337 [NS]</p><p>8.3</p></td><td><p>80/337 (23.7)</p><p>CXR/CT</p><p>Diff</p></td></tr><tr><td><p>Nin [<xref ref-type="bibr" rid="CR31">31</xref>] (2011)</p><p>Chile, Uruguay</p><p>6/09–9/09</p></td><td><p>Multicenter (10) case series (> 18 yrs) (retrospective and prospective) / Respiratory failure requiring ICU mechanical ventilation **</p><p>(confirmed = 77/ 96)</p><p>Includes probable cases<sup>a</sup></p></td><td><italic>N</italic> = 96</td><td><p>96/96 (100)</p><p>13/96 (13.5)</p></td><td><p>96/96 (100)</p><p>NIV = 10/96 (10.4)</p><p>IV = 86/96 (89.6)</p><p>Prone ventilation = 44 /96 (45.8)HFOV = 10/96 (10.4)</p></td><td>48/96 (50)</td><td><p>84/96 (87.5)</p><p>- NS</p></td><td><p>91/96 (94.8)</p><p>- NS</p></td><td>8/96 (8)</td><td>NR</td><td><p>32/96 (33.3, 8 within first week of admission)</p><p>- Purulent sputum, significant growth of pathogen in ET aspirate</p><p>- diff</p></td></tr><tr><td><p>Koegelenberg (2010) [<xref ref-type="bibr" rid="CR30">30</xref>]</p><p>South Africa</p><p>8/09–9/09</p><p>Adults(18+)</p></td><td>Single-centre case series (prospective)/Adult (> = 18 y) ICU admissions with ARF requiring MV</td><td><italic>N</italic> = 19</td><td><p>19/19 (100)</p><p>- NR</p></td><td><p>19/19 (100)</p><p>- NIV = 2/19 (10.5)</p></td><td>13/19 (68.4)</td><td><p>19/19 (100)</p><p>- 14 (73.7)</p></td><td>NR</td><td>0/19 (19)</td><td><p>0/19 (0) BC</p><p>0/19 (0) ET aspirates</p><p>0/19 (0) other NS</p></td><td><p>0/19 (0)</p><p>(10 cases of nosocomial infection (> = 48 h admission)</p><p>- CXR</p></td></tr><tr><td><p>Martin-Loeches [<xref ref-type="bibr" rid="CR28">28</xref>] (2010)</p><p>Spain</p><p>1st case - 12/09</p><p>Adults (16+)</p></td><td>Multicentre (148) case series (prospective) /Adult (> = 15 y) ICU admissions with ARF</td><td><italic>N</italic> = 645</td><td>645/645 (100)</td><td><p>NR</p><p>- IV = 389/645 (60.3)</p></td><td>112/645 (17.4)</td><td><p>620/645 (96.1)</p><p>- NS</p></td><td><p>645/645 (100)</p><p>- NS</p></td><td>113/645 (17.5)</td><td><p>62 /645 (9.6)</p><p>site NS</p><p>Cultures routinely every day</p></td><td><p>113/645 (17.5)</p><p>- CXR + pos culture</p><p>- diff</p></td></tr><tr><td><p>Rice [<xref ref-type="bibr" rid="CR39">39</xref>] (2012)</p><p>US</p><p>4/09–4/10</p></td><td><p>Multicenter (35) case series (retrospective and prospective) / Critically ill cases (> 13 years) admitted to adult ICU’s (Confirmed = 424/683, 62%)</p><p>Includes probable cases<sup>a</sup></p></td><td><italic>N</italic> = 683</td><td>683/683 (100)</td><td><p>231/683 (33.8)</p><p>- IV = 175/683 (75.8)</p><p>- NIV = 56/683 (24.2)</p></td><td>309/683 (45.2)</td><td><p>683/683 (100)</p><p>-NS</p></td><td>NR</td><td><p>Total 154/683 (22.5)</p><p>Sputum specimen</p><p>84/683 (12.3)</p><p>Bacteraemia 50 (7.3)</p><p>Both 20 (2.9)</p></td><td>10/683 (1.5) BC</td><td>207/683 (30.3) clinical coinfection, non-diff</td></tr><tr><td>CDC [<xref ref-type="bibr" rid="CR27">27</xref>]</td><td>Patients at a tertiary care hospital in Michigan</td><td><italic>N</italic> = 10</td><td>10/10 (100)</td><td>10/10 (100)</td><td>3/10 (30%)</td><td>10/10 (100)</td><td>10/10 (100)</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Kim [<xref ref-type="bibr" rid="CR32">32</xref>]</td><td>ICU in 28 Hospitals in SK</td><td>245</td><td>245/245 (100)</td><td>162/245 (100)</td><td>99/245 (40.4)</td><td>103/245 (42)</td><td>243/245 (99.2)</td><td>91/245 (37.1)</td><td>0/245 (0)</td><td>91/245 (37.1)</td></tr><tr><td>Malato [<xref ref-type="bibr" rid="CR35">35</xref>]</td><td>ICU in one hosiptal</td><td>24</td><td>24/24 (100)</td><td>6/24 (25)</td><td>4/24 (16.7)</td><td>20/20 (100)</td><td>NR</td><td>6/24 (25)</td><td>0/24 (0)</td><td>6/24 (25)</td></tr><tr><td><p>Kumar [<xref ref-type="bibr" rid="CR33">33</xref>] (2009)</p><p>Canada</p><p>4/09–8/09</p><p>All ages</p></td><td><p>Multicentre (38) cohort study (prospective & retrospective) /All age critically ill patients = ICU & requiring MV or IV medication or ≥ 60% inspired O2 fraction</p><p>Includes probable cases<sup>a</sup></p></td><td>N = 168</td><td><p>168/168 (100)</p><p>- 7/168 (4.2)</p></td><td><p>136/168 (81.0)</p><p>- IV = 128/168 (94.1)</p><p>- HFOV = 20/168 (14.7)</p></td><td>29/168 (17.3)</td><td>NR</td><td>NR</td><td></td><td>5/168 (2.9) site NS</td><td><p>54/168 (32.1) possible at presentation; 41/168 (24.4) clinically dx cases following ICU admission</p><p>- CXR + culture /clinical opinion</p></td></tr><tr><td>Roch [<xref ref-type="bibr" rid="CR26">26</xref>]</td><td>ARDS cases in ICU</td><td><italic>N</italic> = 18</td><td>18/18 (100)</td><td>10/18 (100)</td><td>10/10 (100)</td><td>NR</td><td>NR</td><td>0/18 (0)</td><td>0/18 (0)</td><td>0/18 (0)</td></tr><tr><td>Lucker [<xref ref-type="bibr" rid="CR37">37</xref>]</td><td>One hospital ICU, medical charts reviewed</td><td>14</td><td>14/14 (100)</td><td>10/14 (71.4)</td><td>2/14 (14.3)</td><td>14/14 (100)</td><td>13/14 (92.9)</td><td><p>6/14 (42.8)</p><p>Of ICU cases</p></td><td>0/14 (0)</td><td>6/14 (42.9)</td></tr><tr><td>Leen [<xref ref-type="bibr" rid="CR38">38</xref>]</td><td>22 bed ICU in one hospital</td><td><italic>N</italic> = 31</td><td>31/31 (100)</td><td></td><td>3/31 (10)</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td><p>10/31 (32.2)</p><p>Method not mentioned</p></td></tr><tr><td>Torres [<xref ref-type="bibr" rid="CR40">40</xref>]</td><td>Hospital in Chile. Includes probable cases<sup>a</sup></td><td><italic>N</italic> = 11</td><td>11/11 (100)</td><td>11/11 (100)</td><td>0/11 (0)</td><td>11/11 (100)</td><td>7/11 (63.6)</td><td><p>1/11 (0.9)</p><p>Group A Streptococcus</p><p>Site NR</p></td><td>0/11 (0)</td><td><p>6/11 (54.5)</p><p>Non Diff</p></td></tr></tbody></table><table-wrap-foot><p>Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission</p><p><italic>Diff</italic> Differentiated between bacterial pneumonia, viral pneumonia and ARDS</p><p><italic>No diff</italic> Did not differentiate between aetiology of abnormal chest imaging</p><p><sup>a</sup>H1N1 testing = 53 (77.9) PCR/viral culture, 8 (11.8) serologically diagnosed but flu A not typed [<xref ref-type="bibr" rid="CR34">34</xref>]; probable cases not defined [<xref ref-type="bibr" rid="CR31">31</xref>]; Probable: Flu A, not otherwise subtyped [<xref ref-type="bibr" rid="CR39">39</xref>]</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec11"><title>Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU</title><p id="Par45">Twenty two studies reported on hospitalised influenza A(H1N1)pdm09 cases (not requiring ICU) and are summarised in Table <xref rid="Tab4" ref-type="table">4</xref>. 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 [<xref ref-type="bibr" rid="CR42">42</xref>].<table-wrap id="Tab4"><label>Table 4</label><caption><p>Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU (<italic>n</italic> = 22)</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Author and year</th><th rowspan="2">Study type</th><th rowspan="2">Study population</th><th colspan="3">Case severity n (%)</th><th rowspan="2">Antiviral agents<break></break>- Number (%) started ≤48 h of symptoms</th><th rowspan="2">Antibiotics†<break></break>n/N (%) pre<break></break>n/N (%) on<break></break>n/N (%) during admission</th><th rowspan="2">Any positive bacterial growth</th><th rowspan="2">Number (%) patients with <italic>S.pneumoniae</italic> and site of isolation</th><th rowspan="2">Number (%) with bacterial pneumonia<break></break>- Method<break></break>- Diff/no diff</th></tr><tr><th>ICU<break></break><italic>N</italic></th><th>MV<break></break>- type</th><th>Deaths</th></tr></thead><tbody><tr><td><p>CDC (2009) [<xref ref-type="bibr" rid="CR59">59</xref>]</p><p>California, USA</p><p>4/09–5/09</p></td><td>State-wide passive surveillance of notified cases / Hospitalized cases for <underline>></underline> 24 h</td><td><italic>N</italic> = 30</td><td>6/30 (20)</td><td>4/30 (13.3)</td><td><p>0/23 (0)</p><p>7 were still hospitalised</p></td><td><p>15/30 (50)</p><p>5/30 (16.7)</p></td><td>0</td><td>0/100 (0)</td><td>0/100 (0)</td><td><p>15/25 (60)</p><p>CXR Non diff</p></td></tr><tr><td><p>Jain [<xref ref-type="bibr" rid="CR60">60</xref>] (2009)</p><p>USA</p><p>4/09–6/09</p></td><td>Notified cases from 24 state health departments to CDC / Hospitalized ≥24 h</td><td><italic>N</italic> = 272</td><td>67/272 (24.6)</td><td>42/272 (15.4)</td><td>19/272 (7.0)</td><td><p>200/268 (74.6)</p><p>78 (29.1)</p></td><td><p>206/260 (79.2)</p><p>- Pre: 30/198</p><p>- on: 117/198</p></td><td>3/182 (1.6)</td><td><p>2/182 (1.1) 1 had positive lung tissue culture)</p><p>1/n urinary antigen test</p><p>1/n BAL fluid</p><p>0/n ET aspirate</p></td><td><p>- CXR 100/249 (40)</p><p>(66 patients with bilateral infiltrates)</p><p>26 limited to 1 lobe, 6 limited to multiple lobes</p><p>- not diff</p></td></tr><tr><td><p>Louie [<xref ref-type="bibr" rid="CR61">61</xref>] (2009)</p><p>California, USA</p><p>4/09–8/09</p></td><td>State-wide enhanced surveillance /Hospitalized or fatal all ages cases</td><td><italic>N</italic> = 1088</td><td>340/1088 (31.3)</td><td>193/297 (64.9)</td><td>118/1088 (10.8)</td><td><p>701/884 (79.3)</p><p>- 357 (40.4)</p></td><td>NR</td><td>46/1088 (4.2)</td><td>NR</td><td><p>547/833 (65.7)</p><p>- CXR/CT + pos bacterial culture(s) 46</p><p>- No diff</p></td></tr><tr><td><p>Dhanoa [<xref ref-type="bibr" rid="CR62">62</xref>] (2011)</p><p>Malaysia</p><p>9/09–5/10</p></td><td>Single-centre case series (retrospective)/ Hospitalised patients all ages</td><td><italic>N</italic> = 50</td><td>9/50 (18.0)</td><td>6/50 (12.0)</td><td>2/50 (4.0)</td><td>50/50 (100)</td><td><p>49 (98.0)</p><p>- Pre = 8</p><p>- On =41</p></td><td><p>14/45 (31.1)</p><p>total 45 culture samples sent</p></td><td>2/45 (4.4) site NR</td><td><p>25/50 (50)</p><p>-CXR + clinical opinion</p><p>- No diff</p></td></tr><tr><td><p>To [<xref ref-type="bibr" rid="CR63">63</xref>] (2010)</p><p>China</p><p>6/09–10/09</p></td><td>Single-centre case series (retrospective)/ Hospitalized adult patients</td><td><italic>N</italic> = 69</td><td>28/69 (40.6)</td><td><p>26/69 (37.7)</p><p>- NS</p></td><td>13/69 (18.8)</td><td>69/69 (100)</td><td><p>37/69 (53.6)</p><p>- On = 37</p></td><td>0/69 (0)</td><td>0/69 (0)</td><td><p>25/69 (36.2)</p><p>CXR Non-diff</p></td></tr><tr><td><p>Viasus [<xref ref-type="bibr" rid="CR64">64</xref>] (2011)</p><p>Spain</p><p>6/09–11/09</p></td><td>Multicentre (13) case series (prospective)/ Hospitalized ≥24 h and had a chest radiograph done</td><td><italic>N</italic> = 585</td><td>71/585 (12.1)</td><td>52/585 (8.9)</td><td>13/585 (2.2)</td><td>545/585 (93.3)</td><td>416/585 (71.7)</td><td>45/585 (7.7)</td><td>28/585 (4.8)</td><td><p>234/585 (40)</p><p>CXR non diff</p></td></tr><tr><td><p>Palacios (2009) [<xref ref-type="bibr" rid="CR42">42</xref>]</p><p>Argentina</p><p>6/09–7/09</p></td><td>Random sample specimens</td><td><italic>N</italic> = 199</td><td>19/199 (9.5)</td><td>NR</td><td>20/199 (10)</td><td>96/120 (80)</td><td>14/120 (11.7)</td><td>152/199 (76.3)</td><td>62/199 (31.1)</td><td><p>152//199 (76)</p><p>Culture pos</p></td></tr><tr><td>Chitnis [<xref ref-type="bibr" rid="CR6">6</xref>]</td><td><p>Wisconsin, hospital acute care</p><p>PCR + cases</p></td><td><italic>N</italic> = 252</td><td>59/252 (23.4)</td><td><p>34/59 (58)</p><p>Of tho9se cases admitted to ICU</p></td><td>11/252 (4.3)</td><td>215/250 (86)</td><td>204/249 (81.9)</td><td>19/241 (7.9)</td><td>NR</td><td><p>123/229 (53.7)</p><p>CXR non diff</p></td></tr><tr><td>Riera [<xref ref-type="bibr" rid="CR65">65</xref>]</td><td>13 Hospitals in Spain</td><td><italic>N</italic> = 585</td><td>71/585 (12.1)</td><td>52/585 (8.9)</td><td>13/585 (2.2)</td><td><p>545/585 (93.1)</p><p>202/585 (34.5)</p></td><td>316/585 (54)</td><td>45/585 (7.7) (Sputum)</td><td><p>2/585 (0.3)</p><p>(1 sputum and 1 antigenuria positive</p></td><td><p>CXR infil 234/585 (40)</p><p>Multilobarl infilt 135/585 (23.1)</p></td></tr><tr><td>Semionov [<xref ref-type="bibr" rid="CR66">66</xref>]</td><td>147 cases with CXR results available in Montreal</td><td><italic>N</italic> = 147</td><td>8/147 (5.4)</td><td>6/147 (4.1)</td><td>4/147 (2.7)</td><td>NR</td><td>NR</td><td><p>21/42 (50)</p><p>(of 42 radiological positive cases)</p></td><td><p>5/21 (23.8)</p><p>(of 21 positive bacterial cases)</p></td><td><p>42/147 (28.6)</p><p>cases positive CXR</p><p>Non diff</p></td></tr><tr><td>To [<xref ref-type="bibr" rid="CR67">67</xref>]</td><td>74 cases in Hong Kong</td><td><italic>N</italic> = 74</td><td>28/74 (37.8)</td><td>26/74 (35.1)</td><td>2/74 (2.7)</td><td>69/74 (93.2)</td><td>52/74 (70.3)</td><td><p>9/74 (12.2) bacterial positive</p><p>8 sputum</p><p>1 blood</p></td><td>0/74 (0)</td><td><p>9/74 (12.2) bacterial positive</p><p>8 sputum</p><p>1 blood</p><p>Diff</p></td></tr><tr><td>Masia [<xref ref-type="bibr" rid="CR68">68</xref>]</td><td>Complicated hospital admitted cases in Spain > 18 years, out patients</td><td><italic>N</italic> = 100</td><td>4/100 (4)</td><td>NR</td><td>0/100 (0)</td><td>NR</td><td>NR</td><td>14/100 (14)</td><td><p>14/100 (14)</p><p>Diff</p><p>8 urinary antigen pos, 2 isolated from blood and 4 from sputum</p></td><td><p>14/100 (14)</p><p>Diff</p></td></tr><tr><td>Pecavar [<xref ref-type="bibr" rid="CR69">69</xref>]</td><td>Hospitalized cases</td><td><italic>N</italic> = 66</td><td>7/66 (10.6)</td><td>NR</td><td>NR</td><td>62/64 (96.9)</td><td>35/61 (57.4)</td><td>5/63 (7.9)</td><td>2/63 (3.2)</td><td><p>29/57 (50.9)</p><p>CXR Non diff</p></td></tr><tr><td>Liu [<xref ref-type="bibr" rid="CR70">70</xref>]</td><td>One hospital in China</td><td><italic>N</italic> = 46</td><td>NR</td><td>NR</td><td>NR</td><td>46/46 (100)</td><td>9/46 (19.6)</td><td>9/15 (60)</td><td>NR</td><td><p>44/46 (95.6)</p><p>CXR or CT scan abnormal</p><p>Non diff</p></td></tr><tr><td><p>Nguyen (2010) [<xref ref-type="bibr" rid="CR71">71</xref>]</p><p>UK</p><p>4/09–9/09</p></td><td>Multicentre (55) case series (retrospective)/ Hospitalized cases</td><td><italic>N</italic> = 631</td><td>53/631 (8.4)</td><td><p>NR</p><p>- IV = 21/631 (3.3)</p></td><td>29/631 (4.6)</td><td><p>474/631 (75.1)</p><p>- NS</p></td><td>366/631 (58)</td><td>4/102 (3.9%) of cases with radiological pneumonia</td><td><p>1/102 (0.9) sputum culture</p><p>0/102 (0) BC</p></td><td><p>102/349 (29.2)</p><p>- CXR</p><p>- No diff</p></td></tr><tr><td><p>Santa-Olalla Peralta [<xref ref-type="bibr" rid="CR72">72</xref>] (2010)</p><p>Spain</p><p>4/09–12/09</p></td><td>National surveillance of severe cases (retrospective) / Hospitalized patients all ages (, in Spain</td><td><italic>N</italic> = 3025</td><td>852/3025 (28.2)</td><td>438/3.25 (14.5)</td><td>200/3025 (6.6)</td><td><p>2521/2779 (90.7)</p><p>- 711/2020 (35.2)</p></td><td>NR</td><td>292/957 (30.5, bacteria isolated not reported)</td><td>NR</td><td>NR</td></tr><tr><td><p>Venkata [<xref ref-type="bibr" rid="CR73">73</xref>] (2010)</p><p>USA</p><p>5/09–12/09</p></td><td>Single-centre case series (retrospective)/ Electronic medical records of hospitalized adult patients</td><td>N = 66</td><td>29/66 (43.9)</td><td><p>23/66 (34.8)</p><p>- IV = 17 (73.9)</p><p>- NIV = 6 (26.1)</p></td><td><p>5/66 (7.6)</p><p>4 more died after discharge from hospital</p></td><td><p>60/66 (90.9)</p><p>- NR</p></td><td></td><td><p>14/ 29 (48.2)</p><p>Bac culture pos</p></td><td>3/29 (10.3), site NS</td><td><p>14/29 (48.2) confirmed and 10/29 (34.5) probable bacterial pneumonia</p><p>- NR</p><p>- Diff</p></td></tr><tr><td>Jartti [<xref ref-type="bibr" rid="CR74">74</xref>]</td><td>Cases with severe cases and CXR finding available, I hospital in Finland</td><td><italic>N</italic> = 135</td><td>18/135 (13%)</td><td>18/135 (13.3)</td><td>3/135 (2.2)</td><td>NR</td><td>NR</td><td><p>5/135 (3.7)</p><p>Site not mentioned</p></td><td><p>1 /135 (0.7)</p><p>Isolated from Plural Fluid</p></td><td>84/135 (62.2)</td></tr><tr><td>Rizzo [<xref ref-type="bibr" rid="CR75">75</xref>]</td><td>Sentinel sites, Italy</td><td><italic>N</italic> = 1278</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>33/1278 (2.6)</td><td>0/1278 (0)</td><td><p>271/1278 (21.2)</p><p>Non-diff</p></td></tr><tr><td>Kopel [<xref ref-type="bibr" rid="CR76">76</xref>]</td><td>Til Aviv, cases in ICU and PICU</td><td>N = 17</td><td>17/17 (100)</td><td>NR</td><td>7/17 (41.2)</td><td>NR</td><td>NR</td><td><p>9/17 cases (52.9)</p><p>(but likely nosocomial infection, so not included)</p></td><td>0/17 (0)</td><td>NR</td></tr><tr><td>D’Ortenzio [<xref ref-type="bibr" rid="CR41">41</xref>]</td><td>ReUnion Island, all sites, included 785 reported cases, 282 hospitalized cases included here</td><td><italic>N</italic> = 282</td><td>24/282 (8.5)</td><td>15/282 (5.3)</td><td>7/282 (2.5)</td><td><p>92/171 (53.8)</p><p>39/163 (23.9)</p><p>(within 48 h)</p></td><td>NR</td><td>NR</td><td>NR</td><td><p>24/83 (28.9)</p><p>(Confirmed and suspected)</p><p>Sample not reported</p></td></tr><tr><td>Dominguez-Cherit [<xref ref-type="bibr" rid="CR77">77</xref>]</td><td>Critically ill, hospitalized in 6 hospital in Maxico</td><td>N = 58</td><td>58/58 (100)</td><td>54/58 (93.1)</td><td>24/ 58 (41.4)</td><td>57/58 (98.3)</td><td>52/58 (89.6)</td><td>4/58 (6.9)</td><td>0/58 (0)</td><td>NR</td></tr></tbody></table><table-wrap-foot><p>Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission</p><p><italic>Diff</italic> Differentiated between bacterial pneumonia, viral pneumonia and ARDS</p><p><italic>No diff</italic> Did not differentiate between aetiology of abnormal chest imaging</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec12"><title>Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09</title><p id="Par46">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 <xref rid="Tab5" ref-type="table">5</xref>. 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 [<xref ref-type="bibr" rid="CR43">43</xref>] 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 <italic>S. aureus</italic> 23.9%.<table-wrap id="Tab5"><label>Table 5</label><caption><p>Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09 (<italic>n</italic> = 15)</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Author and year</th><th rowspan="2">Study type</th><th rowspan="2">Diagnosis of influenza/ cases</th><th rowspan="2">Antiviral agents<break></break>- Number (%) started ≤48 h of symptoms</th><th rowspan="2">Number (%) patients with <italic>S.pneumoniae</italic> and site of isolation</th><th rowspan="2">Any bacteria positive</th><th rowspan="2">Number (%) with bacterial pneumonia<break></break>- Method<break></break>- Diff/no diff</th><th rowspan="2">Antibiotics used (Pre, on, during)</th><th colspan="3">Required</th></tr><tr><th>ICU - ECMO</th><th>MV</th><th>Deaths</th></tr></thead><tbody><tr><td colspan="11">Hospitalised</td></tr><tr><td><p>Louie (2010) [<xref ref-type="bibr" rid="CR7">7</xref>]</p><p>California USA</p><p>4/09–8/09</p></td><td>State-wide surveillance (California) / Hospitalized or died cases (< 18 years)</td><td>PCR/345</td><td><p>221/345 (64.1)</p><p>88/ 345 (25.5) with in 48 h</p></td><td><p>3/345 (0.9)</p><p>isolation site NR</p></td><td>15/345 (4.3)</td><td><p>138/229 (60.3)</p><p>(F: 4/5; H: 134/224)</p><p>163/278 (CT + CXR pos)</p><p>- No diff</p></td><td>NR</td><td>94/345 (27.4)</td><td>35/94 (37) in text</td><td>9/345 (2.6)</td></tr><tr><td><p>Libster [<xref ref-type="bibr" rid="CR78">78</xref>] (2010)</p><p>Argentina</p><p>5/09–7/09</p></td><td>Multicentre (6) case series (retrospective)/ Hospitalized cases (< 18 years)</td><td>PCR/ 251</td><td><p>- 22/ 171(12.9) with in 48 h</p><p>(4/34 PICU Px, 18/137 ward px)</p></td><td><p>2/121 (1.7) BC</p><p>1/4 (25.0) empyema</p></td><td><p>10 /121 (8)</p><p>Blood culture</p></td><td><p>25/251 (10.0) bacterial confirm</p><p>- Among 92 CXR, 78% diagnosis was pneumonia</p><p>-NonDiff</p></td><td><p>186/251 (74.1)</p><p>- On = 82</p></td><td>47/251 (18.7)</td><td>42/251 (16.7)</td><td>13/251 (5.2)</td></tr><tr><td><p>Okada [<xref ref-type="bibr" rid="CR43">43</xref>] 2011</p><p>Japan</p><p>7/09–1/10</p></td><td>Single-centre case series (retrospective) / Pneumonia, pharyngitis or bronchitis cases (< 15 years) (n = unclear).</td><td>PCR/46</td><td><p>44/46 (95.6)</p><p>- NR</p></td><td><p>28/46 (60.9)</p><p>NP</p></td><td><p>40/46 (86.9)</p><p>NP positive swab</p></td><td><p>40/46 (86.9%)</p><p>NP swab</p><p>Bac pneumonia</p><p>21/46 (45.6%) unilateral infiltrates</p><p>- CXR</p><p>- No diff</p></td><td><p>32/46 (69.6)</p><p>- NS</p></td><td>NR</td><td>NR</td><td>0/46 (0)</td></tr><tr><td><p>Kumar [<xref ref-type="bibr" rid="CR79">79</xref>] (2010)</p><p>Wisconsin, USA</p><p>4/09–8/09</p></td><td>Single-centre case series (retrospective record review)/ Hospitalized (> = 24 h) cases (< 19 years)</td><td>PCR/75</td><td><p>74/75 (98.7)</p><p>- NR</p></td><td>0 /75 (0)</td><td>0/75 (0)</td><td><p>23/75 (34.3)</p><p>- CXR</p><p>- Diff</p></td><td><p>60/75 (80.0)</p><p>- Pre = 12</p><p>- On/during = 48</p></td><td>14/75 (18.7)</td><td>4/75 (5.3)</td><td>2/75 (2.7)</td></tr><tr><td><p>Miroballi [<xref ref-type="bibr" rid="CR80">80</xref>] (2010)</p><p>New York, USA</p><p>05/09–07/09</p></td><td>Multicentre (2) case series (retrospective) / Hospitalized cases (< 18)</td><td>PCR (54), EIA, DFA, viral culture/ 115</td><td><p>97/115 (84.3)</p><p>- NR</p></td><td><p>2/115 (1.7) BC</p><p>1/115 (0.9) respiratory secretions</p></td><td>4/115 (3.5)</td><td><p>Total NR (11/35 in PICU)</p><p>- NR</p><p>- Diff NS</p></td><td><p>89/115 (77.4)</p><p>- NS</p></td><td>35/115 (30.4)</td><td>11/115 (9.6) in PICU</td><td>1/115 (0.9)</td></tr><tr><td>O’Riordan [<xref ref-type="bibr" rid="CR81">81</xref>]</td><td>Retrospective case review/hospitalised cases (< 18 yrs)</td><td>PCR/ 58</td><td><p>12/58 (20.7)</p><p>- NR</p></td><td><p>1/58 (1.7)</p><p>BC</p></td><td><p>1/58 (1.7)</p><p>bacterial culture positive</p></td><td><p>17/58 (29.3)</p><p>- CXR</p><p>- No diff</p></td><td><p>56/58 (96.6)</p><p>- NS</p></td><td>12/58 (20.7)</td><td>7/58 (12.1)</td><td>0/58 (0)</td></tr><tr><td><p>Bettinger [<xref ref-type="bibr" rid="CR82">82</xref>] (2010)</p><p>Canada</p><p>5/09–8/09</p></td><td>National active surveillance / hospitalized cases (< 17 years)</td><td>PCR/235</td><td><p>107/235 (45.5)</p><p>- NR</p></td><td>3/235 (1.3) isolation site NR</td><td>8/235 (3.4) culture positive</td><td>8/235 (3.4) culture positive</td><td><p>203/235 (86.4)</p><p>- NS</p></td><td>39/235 (16.6)</td><td>15/235 (6.4)</td><td>2/235 (0.9)</td></tr><tr><td>Lockman [<xref ref-type="bibr" rid="CR83">83</xref>] 2010</td><td>Retrospective case review (notes)/cases admitted to ICU</td><td>PCR/ 13</td><td><p>11/13 (84.6)</p><p>- 5 (45.5)</p></td><td>0/13 (0)</td><td>0/13 (0)</td><td><p>3/13 (23%)</p><p>Nondiff CXR</p></td><td><p>3/13 (23.1)</p><p>- NS</p></td><td>13/13 (100)</td><td><p>6/13 (46.2)</p><p>- IV =4 (66.7)</p><p>- NIV = 2 (33.3)</p></td><td>0/13 (0)</td></tr><tr><td> Stein [<xref ref-type="bibr" rid="CR84">84</xref>]</td><td>< 18 year, ARI cases, hospitalized in 7 medical centers in Israel</td><td>PCR/ 478</td><td>413/478 (87.1)</td><td>2/478 (0.4)</td><td>4/478 (0.8)</td><td>172/478 (35.9) CXR non-diff</td><td>215/478 (45)</td><td>42/478 (8.8)</td><td>15/478 (3.1)</td><td>3/478 (0.6%)</td></tr><tr><td> Tamma [<xref ref-type="bibr" rid="CR85">85</xref>]</td><td>1 hospital, lab confirm US, < 18 years, retrospective cohot in US</td><td>PCR/ 133</td><td><p>106/133 (79.7)</p><p>51/133 < 48 h</p></td><td>0/133 (0)</td><td>0/133 (0)</td><td><p>28/122 (22.9)</p><p>CXR nondiff</p></td><td>61/85 (72%)</td><td>27 (20.3)</td><td>11/133 (8%)</td><td>0</td></tr><tr><td> Parakh [<xref ref-type="bibr" rid="CR86">86</xref>]</td><td>1 hospital, retrospective record review, India PICU and ICU, cases with age < 18 with ILI</td><td>PCR/ 25</td><td>25/25 (100)</td><td>0/25 (0)</td><td>0/25 (0)</td><td><p>8/25 (32)</p><p>CXR nondiff</p></td><td>NR</td><td>7/25 (28)</td><td>4/25 (16)</td><td>3/25 (12)</td></tr><tr><td colspan="11">PICU</td></tr><tr><td> Farias [<xref ref-type="bibr" rid="CR87">87</xref>]</td><td>Prospective multicentred study/includes nosocomial cases in Argentina(<italic>n</italic> = 147)</td><td>PCR/ 147</td><td><p>135/147 (91.8)</p><p>- 116/147 (85.9)</p></td><td>6/147 (4) isolation site NR</td><td>50/147 (34)</td><td>NR</td><td>143/147 (97.3)</td><td>147/147 (100)</td><td><p>139/147 (94.6)</p><p>- IV = 117 (84.2)</p><p>- NIV = 22 (15.8)</p></td><td>57/147 (38.8)</td></tr><tr><td><p> Randolph (2011) [<xref ref-type="bibr" rid="CR88">88</xref>]</p><p>USA</p><p>4/09–4/10</p></td><td><p>Multicentre (35) case series (retrospective & prospective). Probable 293/838 (35%) cases</p><p>PICU cases (< 21 years)</p></td><td><p>Confirmed- PCR, viral culture</p><p>Probable- direct fluorescent antibody, rapid influenza diagnostic test (<italic>n</italic> = 838)</p></td><td><p>751/838 (89.6)</p><p>- NR (before ICU admission =49)</p></td><td><p>0/38 (0) BC</p><p>15/274 (5.5) respiratory secretions</p><p>BC: 0</p></td><td><p>274/838 (32.7) had pneumonia/other bacterial co-infection</p><p>From resp. secretions</p></td><td><p>274/838 (32.7) had pneumonia/other bacterial co-infection</p><p>From resp. secretions</p></td><td>NR</td><td><p>838/838 (100)</p><p>- 33 (3.9)</p></td><td>546/838 (67.3)</td><td>75/838 (8.9)</td></tr><tr><td> Shin [<xref ref-type="bibr" rid="CR89">89</xref>]</td><td>South Korea, critically ill cases</td><td>PCR/30</td><td>29/30 (96.7)</td><td>0/30 (0)</td><td><p>4/30 (13.3)</p><p>Blood c/s positive</p></td><td><p>22/29 (75.9)</p><p>CXR non diff</p></td><td>NR</td><td>30/30 (0)</td><td>16/30 (53.3)</td><td>14//30 (46.7)</td></tr><tr><td> Jouvet [<xref ref-type="bibr" rid="CR8">8</xref>]</td><td>Canada PICUs,</td><td>PCR or culture positive /57</td><td>44/57 (77.2)</td><td><p>5/27 (18.5)</p><p>Lower resp. samples</p></td><td><p>12/57 (21.1)</p><p>Lower resp. samples</p></td><td><p>12/57 (21.1)</p><p>Lower resp. samples</p></td><td>54/57 (94.7)</td><td>2/57 (3.5)</td><td>39/57 (68.4)</td><td>4/57 (7)</td></tr></tbody></table><table-wrap-foot><p>Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission</p><p><italic>Diff</italic> Differentiated between bacterial pneumonia, viral pneumonia and ARDS</p><p><italic>No diff</italic> Did not differentiate between aetiology of abnormal chest imaging</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec13"><title>Discussion</title><p id="Par47">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. <italic>Streptococcus pneumoniae</italic> was the most common bacteria identified, and in ICU patients, ventilator associated pneumonia with organisms such as <italic>Acinetobacter baumannii, Achromobacter xylosoxidans,</italic> methicillin-resistant <italic>Staphylococcus aureus,</italic> and <italic>Escherichia coli</italic> 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.</p><p id="Par48">The overall morbidity and mortality of the 2009 pandemic varied by country, but was cited as being similar to a severe seasonal influenza epidemic [<xref ref-type="bibr" rid="CR44">44</xref>]. 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 [<xref ref-type="bibr" rid="CR45">45</xref>]. 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 [<xref ref-type="bibr" rid="CR46">46</xref>].</p><p id="Par49">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 [<xref ref-type="bibr" rid="CR45">45</xref>]. The use of ECMO rose sharply in 2009 and is associated with high rates of survival [<xref ref-type="bibr" rid="CR47">47</xref>].</p><p id="Par50">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.</p><p id="Par51">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 [<xref ref-type="bibr" rid="CR10">10</xref>].</p><p id="Par52">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 [<xref ref-type="bibr" rid="CR10">10</xref>]. 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 [<xref ref-type="bibr" rid="CR10">10</xref>]. 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 [<xref ref-type="bibr" rid="CR48">48</xref>]. Culture positivity rates among influenza cases without pneumonia was very low (mean < 1%), compare to those with pneumonia (mean, 16%; range, 2 to 50) [<xref ref-type="bibr" rid="CR48">48</xref>]. Bacterial co-infection rates among hospitalised cases with confirmed pneumonia in this study was 19%, which is comparable to Chien et al.</p><p id="Par53">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.</p><p id="Par54">The WHO guidelines on vaccines and antivirals for a pandemic, along with many country-specific pandemic plans, do not consider pneumococcal vaccines [<xref ref-type="bibr" rid="CR49">49</xref>]. The CAPITA trial shows efficacy of conjugate pneumococcal vaccine against pneumonia [<xref ref-type="bibr" rid="CR50">50</xref>], and the polysaccharide vaccine also has efficacy against invasive pneumococcal disease [<xref ref-type="bibr" rid="CR51">51</xref>]. We have found evidence that severe and fatal cases of influenza during the 2009 pandemic did comprise secondary bacterial causes, including <italic>streptococcus pneumoniae</italic> as a contributing factor. Vaccination against streptococcus pneumonia is often neglected in pandemic planning [<xref ref-type="bibr" rid="CR52">52</xref>], 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.</p><p id="Par55">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.</p></sec><sec id="Sec14"><title>Conclusion</title><p id="Par56">We found that secondary bacterial infection was an important complication of the 2009 influenza pandemic, with <italic>Streptococcus pneumoniae</italic> 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.</p></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>ARDS</term><def><p id="Par5">Acute respiratory distress syndrome</p></def></def-item><def-item><term>ARTI</term><def><p id="Par6">Acute respiratory tract infection</p></def></def-item><def-item><term>BAL</term><def><p id="Par7">Bronchoalveolar lavage</p></def></def-item><def-item><term>BAL</term><def><p id="Par8">Broncho-alveolar lavage</p></def></def-item><def-item><term>BC</term><def><p id="Par9">Blood culture</p></def></def-item><def-item><term>CT</term><def><p id="Par10">Computerised tomography</p></def></def-item><def-item><term>CXR</term><def><p id="Par11">Chest x-ray</p></def></def-item><def-item><term>ET</term><def><p id="Par12">Endotreacheal tube</p></def></def-item><def-item><term>ICU</term><def><p id="Par13">Intensive care unit</p></def></def-item><def-item><term>ILI</term><def><p id="Par14">Influenza like illness</p></def></def-item><def-item><term>IV</term><def><p id="Par15">Invasive ventilation</p></def></def-item><def-item><term>MeSH</term><def><p id="Par16">Medical Subject Headings</p></def></def-item><def-item><term>MV</term><def><p id="Par17">Mechanical ventilation</p></def></def-item><def-item><term>NIV</term><def><p id="Par18">Noninvasive ventilation</p></def></def-item><def-item><term>NR</term><def><p id="Par19">Not reported</p></def></def-item><def-item><term>NS</term><def><p id="Par20">Not specified</p></def></def-item><def-item><term>PICU</term><def><p id="Par21">Pediatric intensive care unit</p></def></def-item><def-item><term>PRISMA</term><def><p id="Par22">Preferred Reporting Items for Systematic Reviews</p></def></def-item><def-item><term>SC</term><def><p id="Par23">Sputum culture</p></def></def-item></def-list></glossary><ack><p>We acknowledge the support of Anthea Katelaris, Anthony Newall and James Wood for some preliminary work on this project.</p><sec id="FPar1"><title>Funding</title><p id="Par57">No funding was involved in this study.</p></sec><sec id="FPar2" sec-type="data-availability"><title>Availability of data and materials</title><p id="Par58">All data freely available.</p></sec></ack><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>CRM: lead investigator, conception and design of the study, drafting and manuscript revision; AH, MB, RT, IR, HS: reviewed the titles and abstracts to identify potentially relevant papers; AH, MB: reviewed all potentially relevant papers to determine those which met the selection criteria and conducted literature review, AAC; reviewed and extracted data from selected paper, prepared first draft of manuscript. All authors approved the final version to be submitted.</p></notes><notes><title>Ethics approval and consent to participate</title><p id="Par59">Not applicable.</p></notes><notes><title>Consent for publication</title><p id="Par60">Not applicable.</p></notes><notes notes-type="COI-statement"><title>Competing interests</title><p id="Par61">C. Raina MacIntyre has received in-kind support and funding for investigator-driven research from GlaxoSmithKline, Pfizer, Merck, and Seqirus, and has sat on advisory boards for Merck, GlaxoSmithKline and Pfizer. IR: IR has received grant funds for investigator-driven research from GSK, Pfizer and for consultation from Merck. 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