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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged ≥5 Years in a High HIV-Prevalence Setting, 2009–2012</title><author><name sortKey="Cohen, Cheryl" sort="Cohen, Cheryl" uniqKey="Cohen C" first="Cheryl" last="Cohen">Cheryl Cohen</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Walaza, Sibongile" sort="Walaza, Sibongile" uniqKey="Walaza S" first="Sibongile" last="Walaza">Sibongile Walaza</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moyes, Jocelyn" sort="Moyes, Jocelyn" uniqKey="Moyes J" first="Jocelyn" last="Moyes">Jocelyn Moyes</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Groome, Michelle" sort="Groome, Michelle" uniqKey="Groome M" first="Michelle" last="Groome">Michelle Groome</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tempia, Stefano" sort="Tempia, Stefano" uniqKey="Tempia S" first="Stefano" last="Tempia">Stefano Tempia</name><affiliation><nlm:aff id="aff005"><addr-line>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pretorius, Marthi" sort="Pretorius, Marthi" uniqKey="Pretorius M" first="Marthi" last="Pretorius">Marthi Pretorius</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hellferscee, Orienka" sort="Hellferscee, Orienka" uniqKey="Hellferscee O" first="Orienka" last="Hellferscee">Orienka Hellferscee</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dawood, Halima" sort="Dawood, Halima" uniqKey="Dawood H" first="Halima" last="Dawood">Halima Dawood</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Medicine, Pietermaritzburg Metropolitan Hospital and University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haffejee, Summaya" sort="Haffejee, Summaya" uniqKey="Haffejee S" first="Summaya" last="Haffejee">Summaya Haffejee</name><affiliation><nlm:aff id="aff008"><addr-line>School of Pathology, University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Variava, Ebrahim" sort="Variava, Ebrahim" uniqKey="Variava E" first="Ebrahim" last="Variava">Ebrahim Variava</name><affiliation><nlm:aff id="aff009"><addr-line>Department of Medicine, Klerksdorp Tshepong Hospital, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kahn, Kathleen" sort="Kahn, Kathleen" uniqKey="Kahn K" first="Kathleen" last="Kahn">Kathleen Kahn</name><affiliation><nlm:aff id="aff011"><addr-line>MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff012"><addr-line>Centre for Global Health Research, Umeå University, Umeå, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>INDEPTH Network, Accra, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tshangela, Akhona" sort="Tshangela, Akhona" uniqKey="Tshangela A" first="Akhona" last="Tshangela">Akhona Tshangela</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Von Gottberg, Anne" sort="Von Gottberg, Anne" uniqKey="Von Gottberg A" first="Anne" last="Von Gottberg">Anne Von Gottberg</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wolter, Nicole" sort="Wolter, Nicole" uniqKey="Wolter N" first="Nicole" last="Wolter">Nicole Wolter</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cohen, Adam L" sort="Cohen, Adam L" uniqKey="Cohen A" first="Adam L." last="Cohen">Adam L. Cohen</name><affiliation><nlm:aff id="aff005"><addr-line>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kgokong, Babatyi" sort="Kgokong, Babatyi" uniqKey="Kgokong B" first="Babatyi" last="Kgokong">Babatyi Kgokong</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Venter, Marietjie" sort="Venter, Marietjie" uniqKey="Venter M" first="Marietjie" last="Venter">Marietjie Venter</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Zoonoses Research Unit, Department of Medical Virology, University of Pretoria, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Madhi, Shabir A" sort="Madhi, Shabir A" uniqKey="Madhi S" first="Shabir A." last="Madhi">Shabir A. Madhi</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25706880</idno><idno type="pmc">4337909</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337909</idno><idno type="RBID">PMC:4337909</idno><idno type="doi">10.1371/journal.pone.0117716</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000139</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000139</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged ≥5 Years in a High HIV-Prevalence Setting, 2009–2012</title><author><name sortKey="Cohen, Cheryl" sort="Cohen, Cheryl" uniqKey="Cohen C" first="Cheryl" last="Cohen">Cheryl Cohen</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Walaza, Sibongile" sort="Walaza, Sibongile" uniqKey="Walaza S" first="Sibongile" last="Walaza">Sibongile Walaza</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moyes, Jocelyn" sort="Moyes, Jocelyn" uniqKey="Moyes J" first="Jocelyn" last="Moyes">Jocelyn Moyes</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Groome, Michelle" sort="Groome, Michelle" uniqKey="Groome M" first="Michelle" last="Groome">Michelle Groome</name><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tempia, Stefano" sort="Tempia, Stefano" uniqKey="Tempia S" first="Stefano" last="Tempia">Stefano Tempia</name><affiliation><nlm:aff id="aff005"><addr-line>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pretorius, Marthi" sort="Pretorius, Marthi" uniqKey="Pretorius M" first="Marthi" last="Pretorius">Marthi Pretorius</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hellferscee, Orienka" sort="Hellferscee, Orienka" uniqKey="Hellferscee O" first="Orienka" last="Hellferscee">Orienka Hellferscee</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dawood, Halima" sort="Dawood, Halima" uniqKey="Dawood H" first="Halima" last="Dawood">Halima Dawood</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Medicine, Pietermaritzburg Metropolitan Hospital and University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haffejee, Summaya" sort="Haffejee, Summaya" uniqKey="Haffejee S" first="Summaya" last="Haffejee">Summaya Haffejee</name><affiliation><nlm:aff id="aff008"><addr-line>School of Pathology, University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Variava, Ebrahim" sort="Variava, Ebrahim" uniqKey="Variava E" first="Ebrahim" last="Variava">Ebrahim Variava</name><affiliation><nlm:aff id="aff009"><addr-line>Department of Medicine, Klerksdorp Tshepong Hospital, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kahn, Kathleen" sort="Kahn, Kathleen" uniqKey="Kahn K" first="Kathleen" last="Kahn">Kathleen Kahn</name><affiliation><nlm:aff id="aff011"><addr-line>MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff012"><addr-line>Centre for Global Health Research, Umeå University, Umeå, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>INDEPTH Network, Accra, Ghana</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tshangela, Akhona" sort="Tshangela, Akhona" uniqKey="Tshangela A" first="Akhona" last="Tshangela">Akhona Tshangela</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Von Gottberg, Anne" sort="Von Gottberg, Anne" uniqKey="Von Gottberg A" first="Anne" last="Von Gottberg">Anne Von Gottberg</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wolter, Nicole" sort="Wolter, Nicole" uniqKey="Wolter N" first="Nicole" last="Wolter">Nicole Wolter</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cohen, Adam L" sort="Cohen, Adam L" uniqKey="Cohen A" first="Adam L." last="Cohen">Adam L. Cohen</name><affiliation><nlm:aff id="aff005"><addr-line>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kgokong, Babatyi" sort="Kgokong, Babatyi" uniqKey="Kgokong B" first="Babatyi" last="Kgokong">Babatyi Kgokong</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Venter, Marietjie" sort="Venter, Marietjie" uniqKey="Venter M" first="Marietjie" last="Venter">Marietjie Venter</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Zoonoses Research Unit, Department of Medical Virology, University of Pretoria, Pretoria, South Africa</addr-line></nlm:aff></affiliation></author><author><name sortKey="Madhi, Shabir A" sort="Madhi, Shabir A" uniqKey="Madhi S" first="Shabir A." last="Madhi">Shabir A. Madhi</name><affiliation><nlm:aff id="aff001"><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff004"><addr-line>Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Objective</title><p>There are few published studies describing severe acute respiratory illness (SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged ≥5 years in South Africa.</p></sec><sec id="sec002"><title>Methods</title><p>We conducted prospective surveillance for individuals with SARI from 2009–2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators.</p></sec><sec id="sec003"><title>Findings</title><p>We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9% (600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13–19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR):1.7; 95%CI:1.1–2.7), have pneumococcal infection (OR 2.4; 95%CI:1.7–3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95%CI:1.2–2.2) and had a higher case-fatality ratio (8% vs 5%;OR1.7; 95%CI:1.2–2.3), but were less likely to be infected with influenza (OR 0.6; 95%CI:0.5–0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8;95%CI:1.3–2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95%CI:1.3–32.0) and supplemental-oxygen therapy (OR 2.6; 95%CI:2.1–3.2).</p></sec><sec id="sec004"><title>Conclusion</title><p>The burden of hospitalized SARI amongst individuals aged ≥5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Feldman, C" uniqKey="Feldman C">C Feldman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feikin, Dr" uniqKey="Feikin D">DR Feikin</name></author><author><name sortKey="Njenga, Mk" uniqKey="Njenga M">MK Njenga</name></author><author><name sortKey="Bigogo, G" uniqKey="Bigogo G">G Bigogo</name></author><author><name sortKey="Aura, B" uniqKey="Aura B">B Aura</name></author><author><name sortKey="Aol, G" uniqKey="Aol G">G Aol</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Lf" uniqKey="Johnson L">LF Johnson</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Pretorius, Ma" uniqKey="Pretorius M">MA Pretorius</name></author><author><name sortKey="Madhi, Sa" uniqKey="Madhi S">SA Madhi</name></author><author><name sortKey="Cohen, C" uniqKey="Cohen C">C Cohen</name></author><author><name sortKey="Naidoo, D" uniqKey="Naidoo D">D Naidoo</name></author><author><name sortKey="Groome, M" uniqKey="Groome M">M Groome</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carvalho, Mg" uniqKey="Carvalho M">MG Carvalho</name></author><author><name sortKey="Tondella, Ml" uniqKey="Tondella M">ML Tondella</name></author><author><name sortKey="Mccaustland, K" uniqKey="Mccaustland K">K McCaustland</name></author><author><name sortKey="Weidlich, L" uniqKey="Weidlich L">L Weidlich</name></author><author><name sortKey="Mcgee, L" uniqKey="Mcgee L">L McGee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, E" uniqKey="Singh E">E Singh</name></author><author><name sortKey="Cohen, C" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25706880</article-id><article-id pub-id-type="pmc">4337909</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0117716</article-id><article-id pub-id-type="publisher-id">PONE-D-14-41116</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged ≥5 Years in a High HIV-Prevalence Setting, 2009–2012</article-title><alt-title alt-title-type="running-head">SARI Epidemiology South Africa</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>Cheryl</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref rid="cor001" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Walaza</surname><given-names>Sibongile</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Moyes</surname><given-names>Jocelyn</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Groome</surname><given-names>Michelle</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tempia</surname><given-names>Stefano</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pretorius</surname><given-names>Marthi</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hellferscee</surname><given-names>Orienka</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dawood</surname><given-names>Halima</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haffejee</surname><given-names>Summaya</given-names></name><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Variava</surname><given-names>Ebrahim</given-names></name><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="aff" rid="aff010"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kahn</surname><given-names>Kathleen</given-names></name><xref ref-type="aff" rid="aff011"><sup>11</sup></xref><xref ref-type="aff" rid="aff012"><sup>12</sup></xref><xref ref-type="aff" rid="aff013"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tshangela</surname><given-names>Akhona</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Gottberg</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wolter</surname><given-names>Nicole</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>Adam L.</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kgokong</surname><given-names>Babatyi</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Venter</surname><given-names>Marietjie</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff014"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Madhi</surname><given-names>Shabir A.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref rid="cor001" ref-type="corresp">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa</addr-line></aff><aff id="aff002"><label>2</label><addr-line>School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria, South Africa</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Medicine, Pietermaritzburg Metropolitan Hospital and University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></aff><aff id="aff008"><label>8</label><addr-line>School of Pathology, University of KwaZulu Natal, Pietermaritzburg, South Africa</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Department of Medicine, Klerksdorp Tshepong Hospital, South Africa</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></aff><aff id="aff011"><label>11</label><addr-line>MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Centre for Global Health Research, Umeå University, Umeå, Sweden</addr-line></aff><aff id="aff013"><label>13</label><addr-line>INDEPTH Network, Accra, Ghana</addr-line></aff><aff id="aff014"><label>14</label><addr-line>Zoonoses Research Unit, Department of Medical Virology, University of Pretoria, Pretoria, South Africa</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Hill</surname><given-names>Philip C.</given-names></name><role>Academic Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Otago, NEW ZEALAND</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>HD has received honoraria from Novartis and MSD and sponsored travel by Mylan. SAM has received honorarium from GSK, Pfizer, Novartis, Sanofi and MERCK. The other authors do not declare any conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: CC JM ST MG SAM. Performed the experiments: CC JM ST MG SW MP OH HD SH EV KK AT AvG NW ALC BK MV SAM. Analyzed the data: CC ST AT. Contributed reagents/materials/analysis tools: CC JM ST MG SW MP OH HD SH EV KK AT AvG NW ALC BK MV SAM. Wrote the paper: CC JM ST MG SW MP OH HD SH EV KK AT AvG NW ALC BK MV SAM.</p></fn><corresp id="cor001">* E-mail: <email>cherylc@nicd.ac.za</email> (CC); <email>shabirm@nicd.ac.za</email> (SAM)</corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>2</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>10</volume><issue>2</issue><elocation-id>e0117716</elocation-id><history><date date-type="received"><day>15</day><month>9</month><year>2014</year></date><date date-type="accepted"><day>30</day><month>12</month><year>2014</year></date></history><permissions><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">Creative Commons CC0</ext-link> public domain dedication</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0117716.pdf"></self-uri><abstract><sec id="sec001"><title>Objective</title><p>There are few published studies describing severe acute respiratory illness (SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged ≥5 years in South Africa.</p></sec><sec id="sec002"><title>Methods</title><p>We conducted prospective surveillance for individuals with SARI from 2009–2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators.</p></sec><sec id="sec003"><title>Findings</title><p>We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9% (600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13–19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR):1.7; 95%CI:1.1–2.7), have pneumococcal infection (OR 2.4; 95%CI:1.7–3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95%CI:1.2–2.2) and had a higher case-fatality ratio (8% vs 5%;OR1.7; 95%CI:1.2–2.3), but were less likely to be infected with influenza (OR 0.6; 95%CI:0.5–0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8;95%CI:1.3–2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95%CI:1.3–32.0) and supplemental-oxygen therapy (OR 2.6; 95%CI:2.1–3.2).</p></sec><sec id="sec004"><title>Conclusion</title><p>The burden of hospitalized SARI amongst individuals aged ≥5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.</p></sec></abstract><funding-group><funding-statement>This study received funding from the NICD/NHLS and was supported in part by funds from the United States Centers for Disease Control and Prevention (CDC), Atlanta, Georgia Preparedness and Response to Avian and Pandemic Influenza in South Africa (Cooperative Agreement Number: U51/IP000155-04). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC. The funders had no role in study design, implementation, manuscript writing or the decision to submit for publication.</funding-statement></funding-group><counts><fig-count count="2"></fig-count><table-count count="4"></table-count><page-count count="16"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper.</p></notes></front><body><sec sec-type="intro" id="sec005"><title>Introduction</title><p>Pneumonia was the second leading underlying natural cause of death amongst persons aged ≥15 years in South Africa from 2009–2010 and pneumonia is an important cause of morbidity and mortality in HIV-infected adults.[<xref rid="pone.0117716.ref001" ref-type="bibr">1</xref>, <xref rid="pone.0117716.ref002" ref-type="bibr">2</xref>] There are few published studies estimating the incidence and viral aetiology of severe acute respiratory illness (SARI) amongst older children and adults from high HIV-prevalence settings in Sub-Saharan Africa.[<xref rid="pone.0117716.ref003" ref-type="bibr">3</xref>]</p><p>Data on the burden, severity and aetiology of SARI amongst HIV-infected and -uninfected older children and adults are necessary to guide the relative prioritisation of prevention and control efforts. In South Africa, the HIV prevalence amongst individuals aged 15–49 years, the age group with the highest prevalence of HIV, was estimated to be 17% in 2012.[<xref rid="pone.0117716.ref004" ref-type="bibr">4</xref>] South Africa embarked on a national programme of provision of antiretroviral therapy (ART) in 2004.[<xref rid="pone.0117716.ref005" ref-type="bibr">5</xref>] ART coverage amongst eligible HIV-infected adults (CD4+ T cell count<350/mm<sup>3</sup>) in South Africa was estimated to be 29% in 2009 and 52% in 2011.[<xref rid="pone.0117716.ref006" ref-type="bibr">6</xref>]</p><p>We aimed to describe the incidence, viral aetiology and factors associated with death amongst HIV-infected and -uninfected individuals aged ≥5 years hospitalised with SARI in South Africa from 2009 through 2012.</p></sec><sec sec-type="materials|methods" id="sec006"><title>Methods</title><sec id="sec007"><title>Description of the surveillance programme</title><p>From February 2009, active, prospective, hospital-based surveillance (the Severe Acute Respiratory Illness (SARI) programme) was implemented in three of the nine provinces of South Africa (Chris Hani-Baragwanath Academic Hospital (CHBAH) in an urban area of Gauteng Province, Edendale Hospital in a peri-urban area of KwaZulu-Natal Province and Matikwana and Mapulaneng Hospitals in a rural area of Mpumalanga Province). In June 2010, an additional surveillance site was introduced at Klerksdorp and Tshepong Hospitals in a peri-urban area of the Northwest Province.</p></sec><sec id="sec008"><title>Case definition</title><p>A case of SARI was defined as a hospitalised individual with symptom onset less than seven days prior to admission meeting an adapted World Health Organisation (WHO) case definition for SARI: (1) sudden onset of fever (>38°C) or reported fever, (2) cough or sore throat, and (3) shortness of breath, or difficulty breathing.[<xref rid="pone.0117716.ref007" ref-type="bibr">7</xref>]</p></sec><sec id="sec009"><title>Study procedures</title><p>All patients admitted during Monday through Friday were eligible, except for adult patients at CHBAH where enrolment occurred for two of every five working days (enrolment days varied systematically according to the intake days of the two participating wards) per week due to large patient numbers and limited resources. Daily numbers of patients admitted, numbers screened, numbers meeting study case definitions and numbers enrolled were collected in study logs. Study staff completed case report forms until discharge and collected nasopharyngeal (NP) and throat swabs as well as blood specimens for pneumococcal testing from consenting patients. Hospital and ICU admission and collection of specimens for CD4+ T-cell counts was performed at the discretion of the attending-physician. Underlying medical conditions were defined as documented presence of asthma, other chronic lung disease, chronic heart disease, liver disease, renal disease, diabetes mellitus, immunocompromising conditions (excluding HIV infection) or neurological disease.</p></sec><sec id="sec010"><title>Laboratory methods</title><p>NP and throat swabs were transported in a single viral transport medium tube at 4–8°C to the National Institute for Communicable Diseases (NICD) within 72 hours of collection. Respiratory specimens were tested by a multiplex real-time reverse-transcription polymerase chain reaction (PCR) assay for influenza A and B viruses, parainfluenza virus 1–3, respiratory syncytial virus (RSV), enterovirus, human metapneumovirus (hMPV), adenovirus and human rhinovirus.[<xref rid="pone.0117716.ref008" ref-type="bibr">8</xref>] Influenza positive specimens were subtyped using the US Centers for Disease Control and Prevention (CDC) real-time reverse-transcription PCR protocol for characterisation of influenza virus. <italic>Streptococcus pneumoniae</italic> was identified by quantitative real-time PCR detecting the <italic>lytA</italic> gene from whole blood specimens.[<xref rid="pone.0117716.ref009" ref-type="bibr">9</xref>] The focus of the surveillance programme was viral pathogens and pneumococcus, therefore patients were not systematically tested for tuberculosis or other respiratory pathogens.</p></sec><sec id="sec011"><title>Evaluation of HIV sero-status</title><p>HIV-infection status data was obtained based on testing undertaken as part of standard-of-care,[<xref rid="pone.0117716.ref010" ref-type="bibr">10</xref>] or through anonymised linked dried blood spot specimen testing by enzyme-linked immunosorbent assay (ELISA) in patients providing written informed consent. Results from anonymised testing were used preferentially if both standard-of-care and anonymised results were available. CD4+ T-cell counts were determined by flow cytometry.[<xref rid="pone.0117716.ref011" ref-type="bibr">11</xref>] Patients were categorised into two immunosuppression categories: (1) moderate immunosupression (CD4+ T-lymphocytes ≥200/mm<sup>3</sup>), or (2) severe immunosuppression (CD4+ T-lymphocytes <200/mm<sup>3</sup>).[<xref rid="pone.0117716.ref012" ref-type="bibr">12</xref>] Patients diagnosed by clinicians as HIV-infected on the current admission were referred for HIV management as part of routine care.</p></sec><sec id="sec012"><title>Calculation of incidence</title><p>Calculation of incidence was conducted at one surveillance site (CHBAH) where population denominator data were available. This hospital is the only public hospital serving a community of about 1.8 million persons aged ≥5 years in 2012 amongst whom ~10% have private medical insurance.[<xref rid="pone.0117716.ref013" ref-type="bibr">13</xref>] The vast majority (>80%) of uninsured individuals and approximately 10% of medically-insured individuals seek care at public hospitals, consequently the majority of individuals requiring hospitalisation from this community are admitted to CHBAH. We estimated the total number of SARI hospitalisations from the number of enrolled individuals adjusting for non-enrollment in three of five adult wards and during weekends and refusal to participate using information from study logs. The total number of SARI hospitalizations at CHBAH was obtained using the following formula:</p><disp-formula id="pone.0117716.e001"><alternatives><graphic xlink:href="pone.0117716.e001.jpg" id="pone.0117716.e001g" position="anchor" mimetype="image" orientation="portrait"></graphic><mml:math id="M1"><mml:mrow><mml:mi>S</mml:mi><mml:mi>A</mml:mi><mml:mi>R</mml:mi><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>T</mml:mi><mml:mi>o</mml:mi><mml:mi>t</mml:mi><mml:mi>a</mml:mi><mml:mi>l</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo></mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mtext></mml:mtext><mml:mi>S</mml:mi><mml:mi>A</mml:mi><mml:mi>R</mml:mi><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>E</mml:mi><mml:mi>n</mml:mi><mml:mi>r</mml:mi><mml:mi>o</mml:mi><mml:mi>l</mml:mi><mml:mi>l</mml:mi><mml:mi>e</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo></mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>*</mml:mo><mml:mtext></mml:mtext><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>5</mml:mn><mml:mo>/</mml:mo><mml:mn>2</mml:mn></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>*</mml:mo><mml:mo stretchy="false">(</mml:mo><mml:mn>7</mml:mn><mml:mo>/</mml:mo><mml:mn>5</mml:mn><mml:mo stretchy="false">)</mml:mo><mml:mo>*</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>1</mml:mn><mml:mo>/</mml:mo><mml:msub><mml:mi>X</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo></mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives><label>1</label></disp-formula><p>Where <italic>SARI</italic><sub><italic>Total</italic><sub><italic>ij</italic></sub></sub> is the estimated total number of SARI hospitalization in year <italic>i</italic> (2009–2012) and age group <italic>j</italic> (5–14, 15–24, 25–44, 45–64 and ≥65 years of age); <italic>SARI</italic><sub><italic>Enrolled</italic><sub><italic>ij</italic></sub></sub> is the number of SARI cases enrolled in year <italic>i</italic> and age group <italic>j</italic>; 5/2 is the coefficient used to adjust for enrolment of patients in 2/5 adult wards; 7/5 is the coefficient used to adjust for non-enrolment over weekends; and <italic>X</italic><sub><italic>ij</italic></sub> is the proportion of all eligible cases that were enrolled in year <italic>i</italic> and age group <italic>j</italic>. The adjustment factor varied from 2.2 to 7.9 depending on the age-group and year of enrolment. We estimated incidence of SARI hospitalisations per 100,000 individuals by age groups and HIV status using the adjusted number of SARI hospitalisations divided by the mid-year total population estimates for each year, multiplied by 100,000.[<xref rid="pone.0117716.ref014" ref-type="bibr">14</xref>] HIV prevalence in the study population was estimated from the projections of the Actuarial Society of South Africa AIDS and Demographic model.[<xref rid="pone.0117716.ref004" ref-type="bibr">4</xref>] For estimation of incidence, we assumed that the HIV prevalence by age group amongst patients not tested for HIV was the same as that amongst those tested.</p><p>Confidence intervals for incidence estimates were calculated using the Poisson distribution. Age-specific and overall age-adjusted relative risk of SARI hospitalisation in HIV-infected compared to -uninfected persons was determined using log-binomial regression. To explore the possible effect of missing data on estimates of hospitalisation incidence by HIV status, we conducted a sensitivity analysis in which all cases not tested for HIV were assumed to be HIV uninfected.</p></sec><sec id="sec013"><title>Analysis of factors associated with HIV sero-status and death</title><p>Univariable and multivariable analyses were performed with Stata version 12 (StataCorp Limited, College Station, United States). To identify factors associated with HIV-infection status and death among SARI patients we implemented multivariable logistic regression models, starting with all variables that were significant at p<0.1 on univariable analysis and dropping non-significant factors with stepwise backward selection. All pairwise interactions of factors significant at the final multivariable additive model were evaluated. Two-sided p-values <0.05 were considered significant. For each univariable analysis, we used all available case information. In the multivariable model, patients with missing data for included variables were dropped from the model. Age group, duration of hospitalisation and year of admission were defined as categorical variables in multiple levels. All other variables were defined as the presence or absence of the attribute excluding missing data. To explore possible bias, individuals tested for HIV were compared to those not tested.</p></sec><sec id="sec014"><title>Ethical considerations</title><p>The protocol was approved by the Research Ethics Committees of the Universities of the Witwatersrand and KwaZulu-Natal. This surveillance was deemed non-research by the U.S. CDC and did not need human subjects review by that institution. Written informed consent was obtained from all participants.</p></sec></sec><sec sec-type="results" id="sec015"><title>Results</title><sec id="sec016"><title>Demographic, clinical characteristics and aetiology</title><p>From February 2009 through December 2012, 7977 individuals ≥5 years of age who fulfilled the SARI case definition were screened for study enrolment, of whom 7193 (90%) were enrolled (<xref rid="pone.0117716.g001" ref-type="fig">Fig. 1</xref>). The most common reasons for non-enrolment were being confused or too ill to consent (55%) and study refusal (11%). Of the 7193 enrollees, 8% were 5–14 years of age, 8% 15–24 years, 53% 25–44 years, 25% 45–64 years and 6% ≥65 years (<xref rid="pone.0117716.t001" ref-type="table">Table 1</xref>). The majority of subjects were enrolled at CHBAH (76%), and 61% were female. Among patients with available information, the overall case-fatality ratio was 7%.</p><fig id="pone.0117716.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.g001</object-id><label>Fig 1</label><caption><title>Flow chart of patients aged ≥5 years included in the study.</title><p>SARI—severe acute respiratory illness, HIV—human immunodeficiency virus.</p></caption><graphic xlink:href="pone.0117716.g001"></graphic></fig><table-wrap id="pone.0117716.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.t001</object-id><label>Table 1</label><caption><title>Comparison of the clinical and epidemiologic characteristics of HIV-infected and -uninfected individuals aged ≥5 years hospitalised with severe acute respiratory illness (SARI) at four sentinel surveillance sites, South Africa, 2009–2012.</title></caption><alternatives><graphic id="pone.0117716.t001g" xlink:href="pone.0117716.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Characteristics</th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">All patients n/N (%)</th><th align="left" rowspan="1" colspan="1">HIV-infected n/N (%)</th><th align="left" rowspan="1" colspan="1">HIV-uninfected n/N (%)</th><th align="left" rowspan="1" colspan="1">Univariable analysis<xref rid="t001fn002" ref-type="table-fn">†</xref></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Multivariable analysis<xref rid="t001fn003" ref-type="table-fn">††</xref></th><th align="left" rowspan="1" colspan="1"></th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">OR(95% CI)</th><th align="left" rowspan="1" colspan="1">p</th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">p</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Demographic characteristics</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Age group (years)</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">579/7193 (8)</td><td align="left" rowspan="1" colspan="1">191/4663 (4)</td><td align="left" rowspan="1" colspan="1">185/1671 (11)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">599/7193 (8)</td><td align="left" rowspan="1" colspan="1">336/4663 (7)</td><td align="left" rowspan="1" colspan="1">192/1671 (11)</td><td align="left" rowspan="1" colspan="1">1.7 (1.3–2.2)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.1 (0.8–1.6)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">3784/7193 (53)</td><td align="left" rowspan="1" colspan="1">3016/4663 (65)</td><td align="left" rowspan="1" colspan="1">405/1671 (24)</td><td align="left" rowspan="1" colspan="1">7.2 (5.7–9.1)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">5.4 (4.1–7.2)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">1778/7193 (25)</td><td align="left" rowspan="1" colspan="1">1047/4663 (22)</td><td align="left" rowspan="1" colspan="1">564/1671 (34)</td><td align="left" rowspan="1" colspan="1">1.8 (0.4–2.3)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.6 (1.2–2.1)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">453/7193 (6)</td><td align="left" rowspan="1" colspan="1">73/4663 (2)</td><td align="left" rowspan="1" colspan="1">325/1671 (19)</td><td align="left" rowspan="1" colspan="1">0.2 (0.2–0.3)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.2 (0.1–0.3)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Female</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">4413/7193 (61)</td><td align="left" rowspan="1" colspan="1">3037/4663 (65)</td><td align="left" rowspan="1" colspan="1">891/1671 (53)</td><td align="left" rowspan="1" colspan="1">1.6 (0.5–1.87)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">1.7 (1.5–2.0)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Black African race</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">6998/7185 (97)</td><td align="left" rowspan="1" colspan="1">4597/4659 (99)</td><td align="left" rowspan="1" colspan="1">1573/1670 (94)</td><td align="left" rowspan="1" colspan="1">4.5 (3.3–6.3)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">3.8 (2.6–5.6)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Underlying medical conditions</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Underlying medical condition excluding tuberculosis and HIV<xref rid="t001fn004" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">879/7191 (12)</td><td align="left" rowspan="1" colspan="1">345/4663 (7)</td><td align="left" rowspan="1" colspan="1">433/1671 (26)</td><td align="left" rowspan="1" colspan="1">0.2 (0.2–0.3)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">0.3 (0.2–0.4)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Underlying tuberculosis (receiving tuberculosis treatment on admission)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">276/7167 (4)</td><td align="left" rowspan="1" colspan="1">217/4646 (5)</td><td align="left" rowspan="1" colspan="1">28/1668 (2)</td><td align="left" rowspan="1" colspan="1">2.9 (1.9–4.3)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">2.1 (1.3–3.2)</td><td align="left" rowspan="1" colspan="1">0.002</td></tr><tr><td align="left" rowspan="1" colspan="1">Alcohol use</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1175/7174 (16)</td><td align="left" rowspan="1" colspan="1">729/4650 (16)</td><td align="left" rowspan="1" colspan="1">344/1667 (21)</td><td align="left" rowspan="1" colspan="1">0.7 (0.6–0.8)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">0.6 (0.5–0.7)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Smoking</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1029/7175 (14)</td><td align="left" rowspan="1" colspan="1">625/4651 (13)</td><td align="left" rowspan="1" colspan="1">310/1667 (19)</td><td align="left" rowspan="1" colspan="1">0.7 (0.6–0.8)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Infectious agents identified</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Pneumococcus<xref rid="t001fn005" ref-type="table-fn">**</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">600/6519 (9)</td><td align="left" rowspan="1" colspan="1">499/4506 (11)</td><td align="left" rowspan="1" colspan="1">70/1601(5)</td><td align="left" rowspan="1" colspan="1">2.7 (2.1–3.5)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">2.2 (1.6–2.9)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza (any type)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">621/7067 (9)</td><td align="left" rowspan="1" colspan="1">350/4609 (8)</td><td align="left" rowspan="1" colspan="1">185/1650 (11)</td><td align="left" rowspan="1" colspan="1">0.7 (0.5–0.8)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">0.6 (0.5–0.8)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza A</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">366/7067 (5)</td><td align="left" rowspan="1" colspan="1">190/4609 (4)</td><td align="left" rowspan="1" colspan="1">113/1650 (7)</td><td align="left" rowspan="1" colspan="1">0.6 (0.5–0.7)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza B</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">246/7067 (3)</td><td align="left" rowspan="1" colspan="1">153/4609 (3)</td><td align="left" rowspan="1" colspan="1">70/1650 (4)</td><td align="left" rowspan="1" colspan="1">0.8 (0.6–1.0)</td><td align="left" rowspan="1" colspan="1">0.083</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Parainfluenzavirus 2</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">43/7052 (1)</td><td align="left" rowspan="1" colspan="1">31/4610 (1)</td><td align="left" rowspan="1" colspan="1">3/1636 (<1)</td><td align="left" rowspan="1" colspan="1">3.7 (1.1–12.1)</td><td align="left" rowspan="1" colspan="1">0.031</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Any virus identified***</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2279/7056 (32)</td><td align="left" rowspan="1" colspan="1">1507/4608 (33)</td><td align="left" rowspan="1" colspan="1">473/1640 (29)</td><td align="left" rowspan="1" colspan="1">1.2 (1.1–1.4)</td><td align="left" rowspan="1" colspan="1">0.004</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Clinical presentation and course</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Symptoms ≥2 days prior to admission</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">5934/7059 (84)</td><td align="left" rowspan="1" colspan="1">3998/4576 (87)</td><td align="left" rowspan="1" colspan="1">1296/1636 (79)</td><td align="left" rowspan="1" colspan="1">1.8 (1.6–2.1)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">1.6 (1.3–1.9)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Admission to intensive care</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">11/7165 (<1)</td><td align="left" rowspan="1" colspan="1">7/4650 (<1)</td><td align="left" rowspan="1" colspan="1">2/1665 (<1)</td><td align="left" rowspan="1" colspan="1">1.3 (0.3–6.0)</td><td align="left" rowspan="1" colspan="1">0.778</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Mechanical ventilation</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">11/7167 (<1)</td><td align="left" rowspan="1" colspan="1">5/4651 (<1)</td><td align="left" rowspan="1" colspan="1">3/1666 (<1)</td><td align="left" rowspan="1" colspan="1">0.6 (0.1–2.5)</td><td align="left" rowspan="1" colspan="1">0.480</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Oxygen required</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2682/7164 (37)</td><td align="left" rowspan="1" colspan="1">1788/4649 (38)</td><td align="left" rowspan="1" colspan="1">641/1666 (38)</td><td align="left" rowspan="1" colspan="1">1.0 (0.9–1.1)</td><td align="left" rowspan="1" colspan="1">0.991</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Antibiotics prescribed on admission</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">6787/7002 (97)</td><td align="left" rowspan="1" colspan="1">4468/4569 (98)</td><td align="left" rowspan="1" colspan="1">1549/1630 (95)</td><td align="left" rowspan="1" colspan="1">2.3 (1.7–3.1)</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">2.5 (1.7–3.6)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of hospitalisation (days)</td><td align="left" rowspan="1" colspan="1"><2</td><td align="left" rowspan="1" colspan="1">525/7092 (7)</td><td align="left" rowspan="1" colspan="1">208/4605 (5)</td><td align="left" rowspan="1" colspan="1">158/1647 (10)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2–7</td><td align="left" rowspan="1" colspan="1">4014/7092 (57)</td><td align="left" rowspan="1" colspan="1">2580/4605 (56)</td><td align="left" rowspan="1" colspan="1">1016/1647 (62)</td><td align="left" rowspan="1" colspan="1">1.9 (1.5–2.4)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.6 (1.2–2.1)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">>7</td><td align="left" rowspan="1" colspan="1">2553/7092 (36)</td><td align="left" rowspan="1" colspan="1">1817/4605 (39)</td><td align="left" rowspan="1" colspan="1">473/1647 (29)</td><td align="left" rowspan="1" colspan="1">2.9 (2.3–3.7)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2.4 (1.8–3.2)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Case-fatality ratio</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">514/7154 (7)</td><td align="left" rowspan="1" colspan="1">352/4642 (8)</td><td align="left" rowspan="1" colspan="1">87/1660 (5)</td><td align="left" rowspan="1" colspan="1">1.5 (1.2–1.9)</td><td align="left" rowspan="1" colspan="1">0.001</td><td align="left" rowspan="1" colspan="1">1.6 (1.2–2.2)</td><td align="left" rowspan="1" colspan="1">0.002</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>OR—Odds ratio, CI—confidence interval, HIV—human immunodeficiency virus, CHBAH—Chris Hani Baragwanath Academic Hospital</p></fn><fn id="t001fn002"><p>† HIV-infected vs uninfected</p></fn><fn id="t001fn003"><p>†† HIV-infected vs uninfected. Odds ratios and p values shown for all variables included in the multivariable model</p></fn><fn id="t001fn004"><p>* Asthma, other chronic lung disease, chronic heart disease (valvular heart disease, coronary artery disease, or heart failure excluding hypertension), liver disease (cirrhosis or liver failure), renal disease (nephrotic syndrome, chronic renal failure), diabetes mellitis, immunocompromising conditions excluding HIV infection (organ transplant, immunosuppressive therapy, immunoglobulin deficiency, malignancy), neurological disease (cerebrovascular accident, spinal cord injury, seizures, neuromuscular conditions) or pregnancy. Comorbidities were considered absent in cases for which the medical records stated that the patient had no underlying medical condition or when there was no direct reference to that condition.</p></fn><fn id="t001fn005"><p>**Positive on <italic>lytA</italic> PCR</p></fn><fn id="t001fn006"><p>***Infection with at least one of influenza, parainfluenza virus 1, 2 and 3; respiratory syncytial virus; enterovirus; human metapneumovirus; adenovirus; rhinovirus in addition to influenza</p></fn></table-wrap-foot></table-wrap><p>HIV-infection status was available for 6334 (88%) of enrolled individuals. Age-specific HIV prevalence findings were not significantly different when only patients tested through anonymised linked testing were included (data not shown). When comparing patients tested for HIV to those not tested for HIV, controlling for year of test, surveillance site and age group there were no differences in patient epidemiologic characteristics or case-fatality ratios (data not shown). The overall HIV prevalence among persons ≥5 years with available data was 74% (4663/6334) and was highest in the 25–44 year age group (88%, 3016/3421) (<xref rid="pone.0117716.t001" ref-type="table">Table 1</xref>). Twelve percent of individuals had an underlying medical condition, excluding HIV. 53 women were pregnant. Only 14 individuals reported having been vaccinated against influenza in the current year and no subject had received pneumococcal vaccines.</p><p>Enrolment occurred throughout the year and peaked in the winter months (May-August) (<xref rid="pone.0117716.g002" ref-type="fig">Fig. 2</xref>). Overall, among those tested for respiratory viruses, 18% were positive for rhinovirus, 10% for adenovirus and 9% for influenza (<xref rid="pone.0117716.t002" ref-type="table">Table 2</xref>). Other respiratory viruses tested positive in less than 5% of individuals. Adenovirus, rhinovirus and enterovirus were more commonly identified in individuals 5–14 years old than other age groups. Also, 9% of subjects tested positive for pneumococcus on PCR of whole blood specimens. The detection of influenza virus-associated SARI peaked during the winter months (<xref rid="pone.0117716.g002" ref-type="fig">Fig. 2</xref>). Although pneumococcus (on <italic>lytA</italic> PCR or culture) was detected perennially, detection increased during winter-months of at least two years (2009 and 2010).</p><fig id="pone.0117716.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.g002</object-id><label>Fig 2</label><caption><title>Number of patients enrolled with SARI and influenza, pneumococcal and respiratory syncytial virus (RSV) detection rates by epidemiologic week and year at four sentinel surveillance sites, South Africa, 2009–2011.</title></caption><graphic xlink:href="pone.0117716.g002"></graphic></fig><table-wrap id="pone.0117716.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.t002</object-id><label>Table 2</label><caption><title>Percentage of patients testing positive for viral and bacterial pathogens by age group amongst individuals aged ≥5 years hospitalised with severe acute respiratory illness (SARI) at four sentinel surveillance sites, South Africa, 2009–2012.</title></caption><alternatives><graphic id="pone.0117716.t002g" xlink:href="pone.0117716.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Age group (years)</th><th align="left" rowspan="1" colspan="1">5–14 n/N (%)</th><th align="left" rowspan="1" colspan="1">15–24 n/N (%)</th><th align="left" rowspan="1" colspan="1">25–44 n/N (%)</th><th align="left" rowspan="1" colspan="1">45–64 n/N (%)</th><th align="left" rowspan="1" colspan="1">≥65 n/N (%)</th><th align="left" rowspan="1" colspan="1">All ages</th><th align="left" rowspan="1" colspan="1">p<xref rid="t002fn001" ref-type="table-fn">*</xref></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Influenza</td><td align="left" rowspan="1" colspan="1">64/560 (11)</td><td align="left" rowspan="1" colspan="1">64/590 (11)</td><td align="left" rowspan="1" colspan="1">306/3715 (8)</td><td align="left" rowspan="1" colspan="1">139/1756 (8)</td><td align="left" rowspan="1" colspan="1">48/446 (11)</td><td align="left" rowspan="1" colspan="1">621/7067 (9)</td><td align="left" rowspan="1" colspan="1">0.010</td></tr><tr><td align="left" rowspan="1" colspan="1">Adenovirus</td><td align="left" rowspan="1" colspan="1">115/489 (24)</td><td align="left" rowspan="1" colspan="1">49/520 (9)</td><td align="left" rowspan="1" colspan="1">286/3403 (8)</td><td align="left" rowspan="1" colspan="1">139/1628 (8)</td><td align="left" rowspan="1" colspan="1">25/413 (6)</td><td align="left" rowspan="1" colspan="1">613/6453 (10)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Enterovirus</td><td align="left" rowspan="1" colspan="1">43/550 (8)</td><td align="left" rowspan="1" colspan="1">12/585 (2)</td><td align="left" rowspan="1" colspan="1">40/3715 (1)</td><td align="left" rowspan="1" colspan="1">17/1756 (1)</td><td align="left" rowspan="1" colspan="1">7/446 (2)</td><td align="left" rowspan="1" colspan="1">119/6933 (2)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Rhinovirus</td><td align="left" rowspan="1" colspan="1">189/550 (34)</td><td align="left" rowspan="1" colspan="1">128/585 (22)</td><td align="left" rowspan="1" colspan="1">652/3715 (18)</td><td align="left" rowspan="1" colspan="1">249/1756 (14)</td><td align="left" rowspan="1" colspan="1">49/446 (11)</td><td align="left" rowspan="1" colspan="1">1267/7049 (18)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Human metapneumovirus</td><td align="left" rowspan="1" colspan="1">13/550 (2)</td><td align="left" rowspan="1" colspan="1">9/585 (2)</td><td align="left" rowspan="1" colspan="1">68/3715 (2)</td><td align="left" rowspan="1" colspan="1">26/1756 (1)</td><td align="left" rowspan="1" colspan="1">8/446 (2)</td><td align="left" rowspan="1" colspan="1">124/7052 (2)</td><td align="left" rowspan="1" colspan="1">0.694</td></tr><tr><td align="left" rowspan="1" colspan="1">Parainfluenzavirus 1</td><td align="left" rowspan="1" colspan="1">3/550 (1)</td><td align="left" rowspan="1" colspan="1">2/585 (<1)</td><td align="left" rowspan="1" colspan="1">11/3715 (<1)</td><td align="left" rowspan="1" colspan="1">9/1756 (1)</td><td align="left" rowspan="1" colspan="1">3/446 (1)</td><td align="left" rowspan="1" colspan="1">28/7052 (<1)</td><td align="left" rowspan="1" colspan="1">0.599</td></tr><tr><td align="left" rowspan="1" colspan="1">Parainfluenzavirus 2</td><td align="left" rowspan="1" colspan="1">8/550 (1)</td><td align="left" rowspan="1" colspan="1">4/585 (1)</td><td align="left" rowspan="1" colspan="1">25/3715 (1)</td><td align="left" rowspan="1" colspan="1">6/1756 (<1)</td><td align="left" rowspan="1" colspan="1">0/446 (0)</td><td align="left" rowspan="1" colspan="1">43/7052 (1)</td><td align="left" rowspan="1" colspan="1">0.021</td></tr><tr><td align="left" rowspan="1" colspan="1">Parainfluenzavirus 3</td><td align="left" rowspan="1" colspan="1">7/550 (1)</td><td align="left" rowspan="1" colspan="1">17/585 (3)</td><td align="left" rowspan="1" colspan="1">67/3715 (2)</td><td align="left" rowspan="1" colspan="1">27/1756 (2)</td><td align="left" rowspan="1" colspan="1">9/446 (2)</td><td align="left" rowspan="1" colspan="1">127/7050 (2)</td><td align="left" rowspan="1" colspan="1">0.220</td></tr><tr><td align="left" rowspan="1" colspan="1">Respiratory syncytial virus</td><td align="left" rowspan="1" colspan="1">36/550 (7)</td><td align="left" rowspan="1" colspan="1">21/585 (4)</td><td align="left" rowspan="1" colspan="1">171/3715 (5)</td><td align="left" rowspan="1" colspan="1">77/1756 (4)</td><td align="left" rowspan="1" colspan="1">16/446 (4)</td><td align="left" rowspan="1" colspan="1">321/7052 (5)</td><td align="left" rowspan="1" colspan="1">0.118</td></tr><tr><td align="left" rowspan="1" colspan="1">Any respiratory viral infection</td><td align="left" rowspan="1" colspan="1">315/550 (57)</td><td align="left" rowspan="1" colspan="1">209/585 (36)</td><td align="left" rowspan="1" colspan="1">1159/3715 (31)</td><td align="left" rowspan="1" colspan="1">491/1756 (28)</td><td align="left" rowspan="1" colspan="1">105/446 (24)</td><td align="left" rowspan="1" colspan="1">2279/7056 (32)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Infection with >1 respiratory virus</td><td align="left" rowspan="1" colspan="1">108/550 (19)</td><td align="left" rowspan="1" colspan="1">47/585 (8)</td><td align="left" rowspan="1" colspan="1">211/3715 (6)</td><td align="left" rowspan="1" colspan="1">85/1756 (5)</td><td align="left" rowspan="1" colspan="1">19/446 (4)</td><td align="left" rowspan="1" colspan="1">470/7056 (7)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Pneumococcus<xref rid="t002fn002" ref-type="table-fn">**</xref></td><td align="left" rowspan="1" colspan="1">24/381 (6)</td><td align="left" rowspan="1" colspan="1">48/553 (9)</td><td align="left" rowspan="1" colspan="1">348/3507 (10)</td><td align="left" rowspan="1" colspan="1">166/1655 (10)</td><td align="left" rowspan="1" colspan="1">14/423 (3)</td><td align="left" rowspan="1" colspan="1">600/6519 (9)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>*chi squared test</p></fn><fn id="t002fn002"><p>**On <italic>lyt</italic>A PCR</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec017"><title>Incidence of hospitalisation in HIV-infected and -uninfected patients</title><p>The annual incidence of hospitalisation (per 100,000) for SARI at CHBAH ranged between 325 (95% CI 315–335) in 2012 and 617 (95% CI 603–632) in 2010 and was highest in the 45–64 year age-group; annual range 501 to 1284 (<xref rid="pone.0117716.t003" ref-type="table">Table 3</xref>). HIV-infected individuals experienced an age-adjusted increased relative risk of 13 to 19 times for SARI hospitalisation compared to HIV-uninfected individuals. On sensitivity analysis, assuming that all patients not tested for HIV were HIV-uninfected, the trend towards a higher incidence of SARI hospitalisations in HIV-infected individuals remained in all age groups and years.</p><table-wrap id="pone.0117716.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.t003</object-id><label>Table 3</label><caption><title>Incidence of severe acute respiratory illness (SARI) hospitalisations per 100,000 population by year and HIV status at Chris Hani-Baragwanath Hospital, South Africa.</title></caption><alternatives><graphic id="pone.0117716.t003g" xlink:href="pone.0117716.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Year</th><th align="left" rowspan="1" colspan="1">Age group (years)</th><th align="left" rowspan="1" colspan="1">IR (95% CI) All patients</th><th align="left" rowspan="1" colspan="1">IR (95% CI) HIV infected</th><th align="left" rowspan="1" colspan="1">IR (95% CI) HIV uninfected</th><th align="left" rowspan="1" colspan="1">RR (95% CI) HIV infected vs HIV uninfected</th><th align="left" rowspan="1" colspan="1">RR (95% CI) HIV infected vs HIV uninfected sensitivity analysis∫</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">2009</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">126 (112–141)</td><td align="left" rowspan="1" colspan="1">1833 (1496–2227)</td><td align="left" rowspan="1" colspan="1">82 (71–96)</td><td align="left" rowspan="1" colspan="1">22.1 (17.2–28.4)</td><td align="left" rowspan="1" colspan="1">6.9 (4.8–9.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">283 (261–308)</td><td align="left" rowspan="1" colspan="1">2005 (1806–2223)</td><td align="left" rowspan="1" colspan="1">110 (95–126)</td><td align="left" rowspan="1" colspan="1">18.2 (15.3–21.8)</td><td align="left" rowspan="1" colspan="1">12.3 (10.4–14.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">846 (818–875)</td><td align="left" rowspan="1" colspan="1">2947 (2845–3053)</td><td align="left" rowspan="1" colspan="1">101 (90–114)</td><td align="left" rowspan="1" colspan="1">29.0 (25.8–32.8)</td><td align="left" rowspan="1" colspan="1">11.8 (10.8–12.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">925 (882–970)</td><td align="left" rowspan="1" colspan="1">4682 (4403–4973)</td><td align="left" rowspan="1" colspan="1">400 (370–432)</td><td align="left" rowspan="1" colspan="1">11.7 (10.6–12.9)</td><td align="left" rowspan="1" colspan="1">8.7 (7.9–9.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">624 (562–690)</td><td align="left" rowspan="1" colspan="1">8777 (6488–1152)</td><td align="left" rowspan="1" colspan="1">544 (487–608)</td><td align="left" rowspan="1" colspan="1">16.1 (11.7–21.7)</td><td align="left" rowspan="1" colspan="1">12.1 (8.5–16.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">All (≥5 years)</td><td align="left" rowspan="1" colspan="1">591 (577–606)</td><td align="left" rowspan="1" colspan="1">3072 (2985–3162)</td><td align="left" rowspan="1" colspan="1">179 (171–188)</td><td align="left" rowspan="1" colspan="1">18.1 (17.0–19.3)<xref rid="t003fn003" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1">10 (9.8–11.0)<xref rid="t003fn003" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">2010</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">65 (56–76)</td><td align="left" rowspan="1" colspan="1">876 (670–1126)</td><td align="left" rowspan="1" colspan="1">42 (35–52)</td><td align="left" rowspan="1" colspan="1">20.5 (14.7–28.4)</td><td align="left" rowspan="1" colspan="1">8.4 (5.5–12.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">206 (187–226)</td><td align="left" rowspan="1" colspan="1">1665 (149–1858)</td><td align="left" rowspan="1" colspan="1">67 (56–79)</td><td align="left" rowspan="1" colspan="1">24.9 (20.3–30.6)</td><td align="left" rowspan="1" colspan="1">17.5 (14.5–21.3)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">753 (727–779)</td><td align="left" rowspan="1" colspan="1">2576 (248–267)</td><td align="left" rowspan="1" colspan="1">105 (95–117)</td><td align="left" rowspan="1" colspan="1">24.3 (21.8–27.3)</td><td align="left" rowspan="1" colspan="1">13.5 (12.4–14.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">1284 (1237–1334)</td><td align="left" rowspan="1" colspan="1">7025 (671–735)</td><td align="left" rowspan="1" colspan="1">456 (426–488)</td><td align="left" rowspan="1" colspan="1">15.4 (14.2–16.7)</td><td align="left" rowspan="1" colspan="1">12.4 (11.4–13.4)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">1101 (1022–1185)</td><td align="left" rowspan="1" colspan="1">19793 (16749–23169)</td><td align="left" rowspan="1" colspan="1">878 (808–954)</td><td align="left" rowspan="1" colspan="1">22.5 (18.7–26.9)</td><td align="left" rowspan="1" colspan="1">20.5 (16.9–24.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">All (≥5 years)</td><td align="left" rowspan="1" colspan="1">617 (603–632)</td><td align="left" rowspan="1" colspan="1">3175 (3091–3262)</td><td align="left" rowspan="1" colspan="1">194 (186–203)</td><td align="left" rowspan="1" colspan="1">19.3 (18.2–20.4)<xref rid="t003fn003" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1">13.6 (12.9–14.3)<xref rid="t003fn003" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">2011</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">36 (29–44)</td><td align="left" rowspan="1" colspan="1">376 (252–541)</td><td align="left" rowspan="1" colspan="1">25 (20–33)</td><td align="left" rowspan="1" colspan="1">14.4 (9.0–22.7)</td><td align="left" rowspan="1" colspan="1">9.4 (5.5–15.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">150 (134–167)</td><td align="left" rowspan="1" colspan="1">998 (859–115)</td><td align="left" rowspan="1" colspan="1">74 (63–87)</td><td align="left" rowspan="1" colspan="1">13.4 (10.8–16.7)</td><td align="left" rowspan="1" colspan="1">12.6 (10.1–15.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">588 (566–611)</td><td align="left" rowspan="1" colspan="1">1914 (1837–1996)</td><td align="left" rowspan="1" colspan="1">117 (106–130)</td><td align="left" rowspan="1" colspan="1">16.3 (14.7–18.3)</td><td align="left" rowspan="1" colspan="1">14.4 (13.0–16.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">641 (608–677)</td><td align="left" rowspan="1" colspan="1">3056 (2854–3269)</td><td align="left" rowspan="1" colspan="1">282 (259–308)</td><td align="left" rowspan="1" colspan="1">10.8 (9.7–12.1)</td><td align="left" rowspan="1" colspan="1">10 (9.0–11.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">419 (372–470)</td><td align="left" rowspan="1" colspan="1">2490 (1564–3633)</td><td align="left" rowspan="1" colspan="1">389 (344–440)</td><td align="left" rowspan="1" colspan="1">6.3 (3.9–9.5)</td><td align="left" rowspan="1" colspan="1">6 (3.7–9.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">All (≥5 years)</td><td align="left" rowspan="1" colspan="1">389 (378–401)</td><td align="left" rowspan="1" colspan="1">1934 (1869–2001)</td><td align="left" rowspan="1" colspan="1">134 (127–141)</td><td align="left" rowspan="1" colspan="1">13.1 (12.2–14.0)<xref rid="t003fn003" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1">11.9 (11.1–12.7)<xref rid="t003fn003" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">2012</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">33 (26–41)</td><td align="left" rowspan="1" colspan="1">285 (186–431)</td><td align="left" rowspan="1" colspan="1">25 (19–32)</td><td align="left" rowspan="1" colspan="1">11.6 (6.9–18.8)</td><td align="left" rowspan="1" colspan="1">5.9 (3.1–10.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">134 (119–149)</td><td align="left" rowspan="1" colspan="1">1154 (1002–1323)</td><td align="left" rowspan="1" colspan="1">48 (40–59)</td><td align="left" rowspan="1" colspan="1">23.8 (18.7–30.5)</td><td align="left" rowspan="1" colspan="1">14.6 (11.6–18.4)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">505 (485–527)</td><td align="left" rowspan="1" colspan="1">1665 (1592–1741)</td><td align="left" rowspan="1" colspan="1">94 (84–106)</td><td align="left" rowspan="1" colspan="1">17.6 (15.6–19.9)</td><td align="left" rowspan="1" colspan="1">8.9 (8.1–9.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">501 (472–532)</td><td align="left" rowspan="1" colspan="1">2448 (2271–2635)</td><td align="left" rowspan="1" colspan="1">203 (184–225)</td><td align="left" rowspan="1" colspan="1">12 (10.6–13.6)</td><td align="left" rowspan="1" colspan="1">9 (8.0–10.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">337 (296–381)</td><td align="left" rowspan="1" colspan="1">5260 (4052–6692)</td><td align="left" rowspan="1" colspan="1">252 (217–291)</td><td align="left" rowspan="1" colspan="1">20.8 (15.4–27.8)</td><td align="left" rowspan="1" colspan="1">16.6 (12.1–22.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">All (≥5 years)</td><td align="left" rowspan="1" colspan="1">325 (315–335)</td><td align="left" rowspan="1" colspan="1">1703 (1642–1766)</td><td align="left" rowspan="1" colspan="1">99 (93–105)</td><td align="left" rowspan="1" colspan="1">15.8 (14.7–17.1)<xref rid="t003fn003" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1">9.6 (8.9–10.3)<xref rid="t003fn003" ref-type="table-fn">*</xref></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>IR—incidence rate, RR—relative risk, CI—confidence interval, HIV—human immunodeficiency virus</p></fn><fn id="t003fn002"><p>Significant relative risk value at p<0.05 are in bold ∫Assuming that all patients not tested for HIV are HIV negative</p></fn><fn id="t003fn003"><p>*Age-adjusted</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec018"><title>Characteristics of HIV-infected patients and factors associated with HIV infection</title><p>Compared to HIV-uninfected cases, using multivariable analysis, in addition to other factors, HIV-infected subjects were more likely to be receiving tuberculosis treatment at admission (OR 1.7; 95%CI: 1.1–2.7), have pneumococcal infection (OR 2.4; 95%CI: 1.7–3.3), be hospitalised for >7 days (OR 1.7; 95%CI: 1.2–2.3 as compared to <2 days), and had a higher case-fatality ratio (OR1.7; 95%CI: 1.2–2.3; <xref rid="pone.0117716.t001" ref-type="table">Table 1</xref>). In contrast, HIV-infected subjects were less likely to have an underlying medical condition (OR 0.3; 95%CI: 0.2–0.3), or be infected with influenza (OR 0.6; 95%CI: 0.5–0.8).</p><p>Only 1455 (31%) of 4663 HIV-infected patients had available CD4+ T cell count data, of whom 68% (987) had CD4+ T-lymphocyte cell counts <200/mm3. The case-fatality ratio was significantly higher in HIV-infected subjects with severe immunosuppression (12%, 117/983) than those with CD4+ T-lymphocyte count of >200/mm3 (5%, 22/462, p<0.001). Of those with available data, 41% (1083/2629) reported currently receiving ART and 34% (1566/4569) reported receiving prophylaxis with trimethoprim-sulfamethoxazole. The case-fatality ratio was similar in individuals receiving (7%, 80/1075) and not receiving ART (vs. 8%, 121/1536, p = 0.681). The proportion of patients with CD4+ T-lymphocyte cell counts <200/mm3 was higher in patients not receiving ART (388/571, 68%) as compared to patients receiving ART (221/392, 56%).</p></sec><sec id="sec019"><title>Factors associated with mortality</title><p>The overall case fatality ratio was 7% (514/7154), with a median age of 42 years (interquartile range 23–74) in those who died. The case-fatality ratio was 1.5 times greater amongst HIV-infected (8%) as compared to HIV-uninfected (5%) individuals with SARI (<xref rid="pone.0117716.t004" ref-type="table">Table 4</xref>). On multivariable analysis, independent risk indicators associated with death included increasing age group, HIV infection (OR 1.8 95%CI: 1.3–2.4), receipt of mechanical ventilation (OR 6.5; 95%CI: 1.3–32.0) and receiving supplementary-oxygen therapy (OR 2.6; 95%CI: 2.1–3.2) (<xref rid="pone.0117716.t004" ref-type="table">Table 4</xref>).</p><table-wrap id="pone.0117716.t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0117716.t004</object-id><label>Table 4</label><caption><title>Factors associated with death amongst patients aged ≥5 years hospitalised with severe acute respiratory illness (SARI) at four sentinel surveillance sites, South Africa, 2009–2012<xref rid="t004fn002" ref-type="table-fn">†</xref>.</title></caption><alternatives><graphic id="pone.0117716.t004g" xlink:href="pone.0117716.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Characteristics</th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Case-fatality ratio (%)</th><th align="left" rowspan="1" colspan="1">Univariable analysis</th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Multivariable analysis<xref rid="t004fn002" ref-type="table-fn">†</xref></th><th align="left" rowspan="1" colspan="1"></th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">p</th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">p</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Demographic characteristics</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Age group (years)</td><td align="left" rowspan="1" colspan="1">5–14</td><td align="left" rowspan="1" colspan="1">12/577 (2)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">15–24</td><td align="left" rowspan="1" colspan="1">28/594 (5)</td><td align="left" rowspan="1" colspan="1">2.3 (1.2–4.6)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3.0 (1.2–7.5)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">25–44</td><td align="left" rowspan="1" colspan="1">255/3760 (7)</td><td align="left" rowspan="1" colspan="1">3.4 (1.9–6.2)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3.4 (1.5–7.9)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">45–64</td><td align="left" rowspan="1" colspan="1">171/1774 (10)</td><td align="left" rowspan="1" colspan="1">5.0 (2.8–9.1)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">5.9 (2.5–13.7)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥65</td><td align="left" rowspan="1" colspan="1">48/449 (11)</td><td align="left" rowspan="1" colspan="1">5.6 (3.0–10.7)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">9.1 (3.7–22.2)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Race</td><td align="left" rowspan="1" colspan="1">Other race</td><td align="left" rowspan="1" colspan="1">6/187 (3)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.038</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.033</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Black African</td><td align="left" rowspan="1" colspan="1">508/6959 (7)</td><td align="left" rowspan="1" colspan="1">2.4 (1.0–5.4)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3.5 (1.1–11.2)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Site</td><td align="left" rowspan="1" colspan="1">CHBAH</td><td align="left" rowspan="1" colspan="1">371/5424 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.016</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Matikwana/Mapulaneng</td><td align="left" rowspan="1" colspan="1">77/948 (8)</td><td align="left" rowspan="1" colspan="1">1.2 (0.9–1.6)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.8 (1.3–2.6)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Edendale</td><td align="left" rowspan="1" colspan="1">55/554 (10)</td><td align="left" rowspan="1" colspan="1">1.5 (1.1–2.0)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.6 (1.1–2.4)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Klerksdorp</td><td align="left" rowspan="1" colspan="1">11/228 (5)</td><td align="left" rowspan="1" colspan="1">0.7 (0.4–1.3)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.9 (0.5–1.8)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Underlying medical conditions</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">HIV status</td><td align="left" rowspan="1" colspan="1">Negative</td><td align="left" rowspan="1" colspan="1">87/1660 (5)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Positive</td><td align="left" rowspan="1" colspan="1">352/4642 (8)</td><td align="left" rowspan="1" colspan="1">1.5 (1.2–1.9)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.8 (1.3–2.4)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Underlying medical condition<xref rid="t004fn003" ref-type="table-fn">*</xref></td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">456/6281 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.52</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">58/871 (6)</td><td align="left" rowspan="1" colspan="1">0.9 (0.7–1.2)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Underlying tuberculosis</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">475/6854 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">36/274 (13)</td><td align="left" rowspan="1" colspan="1">2.0 (1.4–2.9)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2.0 (1.3–3.0)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Infectious agents identified</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Pneumococcus<xref rid="t004fn004" ref-type="table-fn">**</xref></td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">413/5885(7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.187</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">50/597 (8)</td><td align="left" rowspan="1" colspan="1">1.2 (0.9–1.6)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">473/6413 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.014</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">29/616 (5)</td><td align="left" rowspan="1" colspan="1">0.6 (0.4–0.9)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Clinical presentation and course</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of symptoms prior to admission</td><td align="left" rowspan="1" colspan="1">< 2 days</td><td align="left" rowspan="1" colspan="1">56/1122 (5)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.003</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.039</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">≥ 2 days</td><td align="left" rowspan="1" colspan="1">441/5899 (7)</td><td align="left" rowspan="1" colspan="1">1.5 (1.2–2.0)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.4 (1.0–2.0)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">ICU admission</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">511/7133 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.01</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">3/11 (27)</td><td align="left" rowspan="1" colspan="1">4.9 (1.3–18.4)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Mechanical ventilation</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">510/7135 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.022</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">4/11 (36)</td><td align="left" rowspan="1" colspan="1">7.4 (2.2–25.4)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">6.5 (1.3–32.0)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Oxygen therapy</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">215/4466 (5)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">299/2677 (11)</td><td align="left" rowspan="1" colspan="1">2.5 (2.1–3.0)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2.6 (2.1–3.2)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Antibiotics prescribed on admission</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">19/215 (9)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.349</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">484/6760 (7)</td><td align="left" rowspan="1" colspan="1">0.8 (0.5–1.3)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of hospitalisation (days)</td><td align="left" rowspan="1" colspan="1"><2</td><td align="left" rowspan="1" colspan="1">39/523 (7)</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">0.002</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2–7</td><td align="left" rowspan="1" colspan="1">252/4011 (6)</td><td align="left" rowspan="1" colspan="1">0.8 (0.6–1.2)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.5 (0.3–0.7)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">>7</td><td align="left" rowspan="1" colspan="1">219/2552 (9)</td><td align="left" rowspan="1" colspan="1">1.2 (0.8–1.7)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.6 (0.4–1.0)</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t004fn001"><p>OR—Odds ratio, CI—confidence interval, HIV—human immunodeficiency virus, CHBAH—Chris Hani Baragwanath Academic Hospital</p></fn><fn id="t004fn002"><p>†Additional factors evaluated and found to be non-significant on univariable analysis: sex, alcohol, smoking, and infection with adenovirus, enterovirus, rhinovirus, human metapneumovirus, parainfluenza virus 1, 2 and 3 and respiratory syncytial virus</p></fn><fn id="t004fn003"><p>*Asthma, other chronic lung disease, chronic heart disease (valvular heart disease, coronary artery disease, or heart failure excluding hypertension), liver disease (cirrhosis or liver failure), renal disease (nephrotic syndrome, chronic renal failure), diabetes mellitis, immunocompromising conditions excluding HIV infection (organ transplant, immunosuppressive therapy, immunoglobulin deficiency, malignancy), neurological disease (cerebrovascular accident, spinal cord injury, seizures, neuromuscular conditions) or pregnancy. Comorbidities were considered absent in cases for which the medical records stated that the patient had no underlying medical condition or when there was no direct reference to that condition.</p></fn><fn id="t004fn004"><p>**On <italic>lyt</italic>A PCR</p></fn></table-wrap-foot></table-wrap></sec></sec><sec sec-type="conclusions" id="sec020"><title>Discussion</title><p>More than two thirds (>70%) of individuals aged ≥5 years hospitalised with SARI in South Africa are co-infected with HIV, making this by far the most important underlying risk condition for this syndrome even in the era of widespread availability of ART. HIV-infected individuals had a 13–19 times greater incidence of SARI hospitalisation than HIV-uninfected individuals and also experienced prolonged hospitalisation and increased risk of death. The spectrum of viral infectious agents identified from HIV-infected and -uninfected individuals was generally similar, however HIV-infected individuals were more likely to test positive for pneumococcus.</p><p>The overall incidence of SARI hospitalisation ranged from 325–617/100,000, somewhat greater than was described in another high HIV-prevalence setting in Kenya (229/100,000).[<xref rid="pone.0117716.ref015" ref-type="bibr">15</xref>] The incidence of SARI hospitalisation in HIV-uninfected individuals aged ≥5 years ranged from 99–194/100,000 population each year, similar to what has been described from low HIV-prevalence middle income countries such as Bangladesh (110–130/100,000) and Thailand (incidence in all ages 177–580/100,000) and slightly lower than the incidence in US adults (267/100,000).[<xref rid="pone.0117716.ref016" ref-type="bibr">16</xref>–<xref rid="pone.0117716.ref018" ref-type="bibr">18</xref>] Differences in incidence observed in different settings may be related to differences in health-seeking behavior, differing thresholds for hospital admission and case definitions or may reflect real differences. The 13–19 times elevated incidence (1703–3175/100,000) of hospitalised SARI which we observed in HIV-infected individuals was somewhat greater than the 4 times elevated incidence described in HIV-infected adults from Kenya with outpatient and hospitalised ARI.[<xref rid="pone.0117716.ref003" ref-type="bibr">3</xref>] Amongst HIV-infected individuals the peak incidence was in the 25–64 years age group, the age group most affected by HIV. Amongst HIV-uninfected individuals, incidence increased with increasing age, similar to that seen in low HIV-prevalence countries.[<xref rid="pone.0117716.ref018" ref-type="bibr">18</xref>]</p><p>We identified at least one respiratory virus in approximately one-third of all patients, similar to other studies from adults.[<xref rid="pone.0117716.ref019" ref-type="bibr">19</xref>, <xref rid="pone.0117716.ref020" ref-type="bibr">20</xref>] The prevalence of detection of most respiratory viruses was highest in the 5–14 year age-group and decreased with increasing age. Rhinovirus and adenovirus were most commonly detected, followed by influenza. While the detection of influenza virus in persons aged ≥5 years with SARI likely reflects an aetiologic role, the clinical relevance of many of the other respiratory viruses is unclear without a comparison to controls.[<xref rid="pone.0117716.ref003" ref-type="bibr">3</xref>, <xref rid="pone.0117716.ref019" ref-type="bibr">19</xref>]</p><p>Pneumococcus was identified in 9% of individuals overall with the highest detection rate in persons aged 25–64 years, the age group most affected by HIV. While real-time PCR is more sensitive than blood culture for diagnosing pneumococcal SARI, additional cases of pneumococcal co-infection may still have been missed.[<xref rid="pone.0117716.ref021" ref-type="bibr">21</xref>] Healthy adults are rarely colonized with the pneumococcus and previous studies have found the lytA PCR on blood to be negative in healthy children colonized with the pneumococcus [<xref rid="pone.0117716.ref022" ref-type="bibr">22</xref>–<xref rid="pone.0117716.ref024" ref-type="bibr">24</xref>]. For this reason, we feel that detection of this target in the blood of these SARI patients likely serves as a specific marker for pneumococcal disease. Sterile specimen cultures for bacteria were performed uncommonly (<15% of patients) and thus we were not able to compare bacterial culture with PCR results. On multivariable analysis pneumococcus was significantly more likely to be detected in HIV-infected than HIV-uninfected individuals, likely reflecting the very high relative risk of hospitalisation for pneumococcal SARI in HIV-infected adults.[<xref rid="pone.0117716.ref025" ref-type="bibr">25</xref>] Pneumococcal polysaccharide vaccine is used uncommonly in South Africa, but this vaccine is not recommended for HIV-infected adults.[<xref rid="pone.0117716.ref026" ref-type="bibr">26</xref>] Although more recent data suggest that the pneumococcal conjugate vaccine may be effective in HIV-infected adults in Africa, [<xref rid="pone.0117716.ref027" ref-type="bibr">27</xref>] there is no specific recommendation for this vaccine in adults in South Africa. The pneumococcal conjugate vaccine was introduced into the routine childhood immunisation programme in 2009. This may have impacted on the proportion of patients testing positive for pneumococcus over time as a result of indirect protection conferred to unvaccinated adults.[<xref rid="pone.0117716.ref028" ref-type="bibr">28</xref>, <xref rid="pone.0117716.ref029" ref-type="bibr">29</xref>]</p><p>In contrast to pneumococcus, influenza virus was significantly less commonly identified from HIV-infected individuals. We have previously demonstrated, in the same population, that HIV-infected individuals aged 25–44 years have an ~10–20 times increased incidence of hospitalisation for influenza.[<xref rid="pone.0117716.ref030" ref-type="bibr">30</xref>] The relatively lower detection rates in our study likely reflect the fact that HIV-infected individuals have a substantially elevated risk of other important pathogens such as pneumococcus, <italic>Pneumocystis jirovecii</italic> and tuberculosis which contribute to a greater proportion of SARI cases in the HIV-infected, rather than an absolute lower risk in HIV-infected individuals. This has been described for respiratory viral infections in HIV-infected children from South Africa.[<xref rid="pone.0117716.ref031" ref-type="bibr">31</xref>]</p><p>The overall case-fatality ratio was 7%, similar to other studies from Africa and the US.[<xref rid="pone.0117716.ref003" ref-type="bibr">3</xref>, <xref rid="pone.0117716.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0117716.ref018" ref-type="bibr">18</xref>, <xref rid="pone.0117716.ref032" ref-type="bibr">32</xref>, <xref rid="pone.0117716.ref033" ref-type="bibr">33</xref>] Increasing age was a risk factor for death, similar to that observed in developed country settings.[<xref rid="pone.0117716.ref034" ref-type="bibr">34</xref>] However, the median age at death was 42 years (36 years in HIV-infected and 62 years in HIV-uninfected), lower than the median age at death in more developed settings where death is more common in elderly individuals. HIV-infected individuals were 1.5 times more likely to die than HIV-uninfected individuals in contrast to other studies which have found a similar mortality in HIV-infected and -uninfected individuals.[<xref rid="pone.0117716.ref032" ref-type="bibr">32</xref>, <xref rid="pone.0117716.ref035" ref-type="bibr">35</xref>, <xref rid="pone.0117716.ref036" ref-type="bibr">36</xref>] Earlier studies included smaller numbers of cases and may have been underpowered to detect the relatively modest increased relative risk of death. In addition, in other studies, HIV-uninfected individuals may have had a higher proportion of elderly or persons with underlying illness than in our study. Receiving tuberculosis treatment on admission was also a risk factor for death. A study in South African gold miners found that underlying lung damage from tuberculosis was a risk factor for SARI mortality.[<xref rid="pone.0117716.ref037" ref-type="bibr">37</xref>] Patients who died had a shorter duration of hospitalisation, suggesting that death occurred early during admission. A longer duration of symptoms prior to hospitalisation was also associated with increased mortality, thus delayed clinical presentation and subsequent delayed treatment initiation may have contributed to mortality in some cases. Mechanical ventilation and supplementary oxygen therapy were independent predicators of mortality. It is likely that these factors are surrogates for disease severity. Unfortunately, data on oxygen saturation were not available.</p><p>Approximately 40% of patients with available data reported receiving ART on admission. Suggesting that even in the presence of ART, pneumonia remains a common clinical presentation in HIV-infected individuals. More than two thirds of patients with available data had severe immunosuppression on CD4+ T cell count and a low CD4+ T cell count was associated with increased mortality. Data on receipt of ART and CD4+T cell counts was unfortunately available for less than half of all HIV-infected patients and no data on ART compliance or clinical HIV stage was available potentially biasing results. In addition, data on socioeconomic status of patients were not available.</p><p>Additional limitations of our study include that subjects were only tested systematically for ten viruses and pneumococcus. Blood cultures were not performed systematically and we did not test for <italic>P</italic>. <italic>jirovecii</italic> or tuberculosis, important causes of pneumonia in HIV-infected individuals.[<xref rid="pone.0117716.ref036" ref-type="bibr">36</xref>, <xref rid="pone.0117716.ref038" ref-type="bibr">38</xref>] Our study may have underestimated mortality because severely ill cases may have been less likely to consent to inclusion or may have died before or shortly after hospital admission prior to being consented, as has been previously suggested.[<xref rid="pone.0117716.ref039" ref-type="bibr">39</xref>] Our estimates of incidence were only obtained from one surveillance hospital and assumed that all individuals in the community accessed care at CHBH hospital. In addition, we did not account for individuals who did not seek care at all. Therefore our incidence and mortality estimates likely represent a minimum estimate. Nevertheless, the estimates of relative risk by HIV status should be robust, unless patients had differential access to care by HIV-infection status. Missing information for some of the predictors in our logistic regression model may have resulted in a loss of power that may have potentially hindered our ability to assess significance for some of the predictors assessed in our model and could have potentially introduced bias.</p><p>Efforts to promote earlier diagnosis of HIV infection and earlier ART initiation as well as more widespread ART availability may reduce the substantial burden of disease in HIV-infected individuals and improve outcomes in patients with SARI. Pneumococcus and influenza were commonly detected aetiologies. 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