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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and <italic>Haemophilus influenzae</italic> Type b Vaccination, 2000–2012</title><author><name sortKey="Wall, Emma C" sort="Wall, Emma C" uniqKey="Wall E" first="Emma C." last="Wall">Emma C. Wall</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Everett, Dean B" sort="Everett, Dean B" uniqKey="Everett D" first="Dean B." last="Everett">Dean B. Everett</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mukaka, Mavuto" sort="Mukaka, Mavuto" uniqKey="Mukaka M" first="Mavuto" last="Mukaka">Mavuto Mukaka</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bar Zeev, Naor" sort="Bar Zeev, Naor" uniqKey="Bar Zeev N" first="Naor" last="Bar-Zeev">Naor Bar-Zeev</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Feasey, Nicholas" sort="Feasey, Nicholas" uniqKey="Feasey N" first="Nicholas" last="Feasey">Nicholas Feasey</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jahn, Andreas" sort="Jahn, Andreas" uniqKey="Jahn A" first="Andreas" last="Jahn">Andreas Jahn</name><affiliation><nlm:aff id="af4"><institution>I-TECH Malawi</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af5"><addr-line>Department for HIV and AIDS</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Lilongwe, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moore, Mike" sort="Moore, Mike" uniqKey="Moore M" first="Mike" last="Moore">Mike Moore</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Oosterhout, Joep J" sort="Van Oosterhout, Joep J" uniqKey="Van Oosterhout J" first="Joep J." last="Van Oosterhout">Joep J. Van Oosterhout</name><affiliation><nlm:aff id="af6"><addr-line>Department of Medicine</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pensalo, Paul" sort="Pensalo, Paul" uniqKey="Pensalo P" first="Paul" last="Pensalo">Paul Pensalo</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baguimira, Kenneth" sort="Baguimira, Kenneth" uniqKey="Baguimira K" first="Kenneth" last="Baguimira">Kenneth Baguimira</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gordon, Stephen B" sort="Gordon, Stephen B" uniqKey="Gordon S" first="Stephen B." last="Gordon">Stephen B. Gordon</name><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Molyneux, Elizabeth M" sort="Molyneux, Elizabeth M" uniqKey="Molyneux E" first="Elizabeth M." last="Molyneux">Elizabeth M. Molyneux</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carrol, Enitan D" sort="Carrol, Enitan D" uniqKey="Carrol E" first="Enitan D." last="Carrol">Enitan D. Carrol</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Department of Women's and Children's Health</addr-line>,<institution>Institute of Translational Medicine, University of Liverpool</institution>,<addr-line>United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="French, Neil" sort="French, Neil" uniqKey="French N" first="Neil" last="French">Neil French</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Molyneux, Malcolm E" sort="Molyneux, Malcolm E" uniqKey="Molyneux M" first="Malcolm E." last="Molyneux">Malcolm E. Molyneux</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Heyderman, Robert S" sort="Heyderman, Robert S" uniqKey="Heyderman R" first="Robert S." last="Heyderman">Robert S. Heyderman</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24496208</idno><idno type="pmc">4001285</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001285</idno><idno type="RBID">PMC:4001285</idno><idno type="doi">10.1093/cid/ciu057</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002315</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002315</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and <italic>Haemophilus influenzae</italic> Type b Vaccination, 2000–2012</title><author><name sortKey="Wall, Emma C" sort="Wall, Emma C" uniqKey="Wall E" first="Emma C." last="Wall">Emma C. Wall</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Everett, Dean B" sort="Everett, Dean B" uniqKey="Everett D" first="Dean B." last="Everett">Dean B. Everett</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mukaka, Mavuto" sort="Mukaka, Mavuto" uniqKey="Mukaka M" first="Mavuto" last="Mukaka">Mavuto Mukaka</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bar Zeev, Naor" sort="Bar Zeev, Naor" uniqKey="Bar Zeev N" first="Naor" last="Bar-Zeev">Naor Bar-Zeev</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Feasey, Nicholas" sort="Feasey, Nicholas" uniqKey="Feasey N" first="Nicholas" last="Feasey">Nicholas Feasey</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jahn, Andreas" sort="Jahn, Andreas" uniqKey="Jahn A" first="Andreas" last="Jahn">Andreas Jahn</name><affiliation><nlm:aff id="af4"><institution>I-TECH Malawi</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af5"><addr-line>Department for HIV and AIDS</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Lilongwe, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moore, Mike" sort="Moore, Mike" uniqKey="Moore M" first="Mike" last="Moore">Mike Moore</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Oosterhout, Joep J" sort="Van Oosterhout, Joep J" uniqKey="Van Oosterhout J" first="Joep J." last="Van Oosterhout">Joep J. Van Oosterhout</name><affiliation><nlm:aff id="af6"><addr-line>Department of Medicine</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pensalo, Paul" sort="Pensalo, Paul" uniqKey="Pensalo P" first="Paul" last="Pensalo">Paul Pensalo</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baguimira, Kenneth" sort="Baguimira, Kenneth" uniqKey="Baguimira K" first="Kenneth" last="Baguimira">Kenneth Baguimira</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gordon, Stephen B" sort="Gordon, Stephen B" uniqKey="Gordon S" first="Stephen B." last="Gordon">Stephen B. Gordon</name><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Molyneux, Elizabeth M" sort="Molyneux, Elizabeth M" uniqKey="Molyneux E" first="Elizabeth M." last="Molyneux">Elizabeth M. Molyneux</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation></author><author><name sortKey="Carrol, Enitan D" sort="Carrol, Enitan D" uniqKey="Carrol E" first="Enitan D." last="Carrol">Enitan D. Carrol</name><affiliation><nlm:aff id="af7"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Department of Women's and Children's Health</addr-line>,<institution>Institute of Translational Medicine, University of Liverpool</institution>,<addr-line>United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="French, Neil" sort="French, Neil" uniqKey="French N" first="Neil" last="French">Neil French</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af3"><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Molyneux, Malcolm E" sort="Molyneux, Malcolm E" uniqKey="Molyneux M" first="Malcolm E." last="Molyneux">Malcolm E. Molyneux</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author><author><name sortKey="Heyderman, Robert S" sort="Heyderman, Robert S" uniqKey="Heyderman R" first="Robert S." last="Heyderman">Robert S. Heyderman</name><affiliation><nlm:aff id="af1"><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><institution>The Liverpool School of Tropical Medicine</institution></nlm:aff></affiliation></author></analytic><series><title level="j">Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America</title><idno type="ISSN">1058-4838</idno><idno type="eISSN">1537-6591</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Culture positive bacterial meningitis has fallen over a 12-year period in urban Malawi following Hib vaccination. Hib, NTS, and pneumococcal meningitis have fallen significantly in children. Pneumococcal meningitis has not fallen in adults; NTS and pneumococcal meningitis are seasonal.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Edmond, K" uniqKey="Edmond K">K Edmond</name></author><author><name sortKey="Clark, A" uniqKey="Clark A">A Clark</name></author><author><name sortKey="Korczak, Vs" uniqKey="Korczak V">VS Korczak</name></author><author><name sortKey="Sanderson, C" uniqKey="Sanderson C">C Sanderson</name></author><author><name sortKey="Griffiths, Uk" uniqKey="Griffiths U">UK Griffiths</name></author><author><name sortKey="Rudan, I" uniqKey="Rudan I">I Rudan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pelkonen, T" uniqKey="Pelkonen T">T Pelkonen</name></author><author><name sortKey="Roine, I" uniqKey="Roine I">I Roine</name></author><author><name sortKey="Monteiro, L" uniqKey="Monteiro L">L 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">Clin. Infect. Dis</journal-id><journal-id journal-id-type="publisher-id">cid</journal-id><journal-id journal-id-type="hwp">cid</journal-id><journal-title-group><journal-title>Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America</journal-title></journal-title-group><issn pub-type="ppub">1058-4838</issn><issn pub-type="epub">1537-6591</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24496208</article-id><article-id pub-id-type="pmc">4001285</article-id><article-id pub-id-type="doi">10.1093/cid/ciu057</article-id><article-id pub-id-type="publisher-id">ciu057</article-id><article-categories><subj-group subj-group-type="heading"><subject>Electronic Article</subject></subj-group></article-categories><title-group><article-title>Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and <italic>Haemophilus influenzae</italic> Type b Vaccination, 2000–2012</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wall</surname><given-names>Emma C.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="author-notes" rid="AN1">a</xref></contrib><contrib contrib-type="author"><name><surname>Everett</surname><given-names>Dean B.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="author-notes" rid="AN1">a</xref></contrib><contrib contrib-type="author"><name><surname>Mukaka</surname><given-names>Mavuto</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="author-notes" rid="AN1">a</xref></contrib><contrib contrib-type="author"><name><surname>Bar-Zeev</surname><given-names>Naor</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="author-notes" rid="AN1">a</xref></contrib><contrib contrib-type="author"><name><surname>Feasey</surname><given-names>Nicholas</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Jahn</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Moore</surname><given-names>Mike</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>van Oosterhout</surname><given-names>Joep J.</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Pensalo</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Baguimira</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gordon</surname><given-names>Stephen B.</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Molyneux</surname><given-names>Elizabeth M.</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Carrol</surname><given-names>Enitan D.</given-names></name><xref ref-type="aff" rid="af7">7</xref><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>French</surname><given-names>Neil</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Molyneux</surname><given-names>Malcolm E.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Heyderman</surname><given-names>Robert S.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Malawi-Liverpool</addr-line><addr-line>-Wellcome Trust Clinical Research Programme</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre, Malawi</addr-line></aff><aff id="af2"><label>2</label><institution>The Liverpool School of Tropical Medicine</institution></aff><aff id="af3"><label>3</label><addr-line>Institute of Infection and Global Health</addr-line>,<institution>University of Liverpool</institution><addr-line>, United Kingdom</addr-line></aff><aff id="af4"><label>4</label><institution>I-TECH Malawi</institution></aff><aff id="af5"><label>5</label><addr-line>Department for HIV and AIDS</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Lilongwe, Malawi</addr-line></aff><aff id="af6"><label>6</label><addr-line>Department of Medicine</addr-line></aff><aff id="af7"><label>7</label><addr-line>Department of Paediatrics</addr-line>,<institution>University of Malawi College of Medicine</institution>,<addr-line>Blantyre</addr-line></aff><aff id="af8"><label>8</label><addr-line>Department of Women's and Children's Health</addr-line>,<institution>Institute of Translational Medicine, University of Liverpool</institution>,<addr-line>United Kingdom</addr-line></aff><author-notes><fn fn-type="con" id="AN1"><label>a</label><p>E. C. W., D. B. E., M. M., and N. B.-Z. contributed equally to this work.</p></fn><corresp>Correspondence: Emma Wall, MBChB, MRCP, DTM&H, MRes, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi (<email>emma.wall@doctors.org.uk</email>).</corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>5</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>4</day><month>2</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>4</day><month>2</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>58</volume><issue>10</issue><fpage>e137</fpage><lpage>e145</lpage><history><date date-type="received"><day>1</day><month>11</month><year>2013</year></date><date date-type="accepted"><day>18</day><month>1</month><year>2014</year></date></history><permissions><copyright-statement>© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.</copyright-statement><copyright-year>2014</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0/">http://creativecommons.org/licenses/by/3.0/</ext-link>), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="ciu057.pdf"></self-uri><abstract abstract-type="precis"><p>Culture positive bacterial meningitis has fallen over a 12-year period in urban Malawi following Hib vaccination. Hib, NTS, and pneumococcal meningitis have fallen significantly in children. Pneumococcal meningitis has not fallen in adults; NTS and pneumococcal meningitis are seasonal.</p></abstract><abstract><p><bold><italic>Background.</italic></bold> We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of <italic>Haemophilus influenzae</italic> type b (Hib) vaccination and the rollout of antiretroviral therapy (ART).</p><p><bold><italic>Methods.</italic></bold> We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012.</p><p><bold><italic>Results.</italic></bold> There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92–.94; <italic>P</italic> < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85–.88; <italic>P</italic> < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97–1.0; <italic>P</italic> = .135) despite rapid scale-up of ART provision. In children aged <5 years, <italic>Streptococcus pneumoniae</italic>, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. <italic>Streptococcus pneumoniae</italic> was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100 000 cases in children aged <14 years, 6 per 100 000 adolescents, and 10 per 100 000 adults.</p><p><bold><italic>Conclusions.</italic></bold> Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic “meningitis belt” in Africa is essential.</p></abstract><kwd-group><kwd>meningitis</kwd><kwd>Africa</kwd><kwd>HIV</kwd><kwd>vaccination</kwd><kwd>antiretroviral therapy</kwd></kwd-group></article-meta></front><body><p>The burden of acute bacterial meningitis (ABM) across sub-Saharan Africa is disproportionally higher than in countries in the developed world [<xref rid="CIU057C1" ref-type="bibr">1</xref>]. The associated mortality is more than twice that of developed countries for both children (25%–36% vs 5%–11%) and adults (54%–70% vs 25%–30%) [<xref rid="CIU057C2" ref-type="bibr">2</xref>–<xref rid="CIU057C5" ref-type="bibr">5</xref>]. Outside the “meningitis belt” where large epidemics of meningococcal meningitis occur every 5–10 years, bacterial meningitis incidence in children in Africa is estimated to be as high as 25 cases per 100 000 children [<xref rid="CIU057C6" ref-type="bibr">6</xref>], compared with 0.56 per 100 000 in children aged 2–10 years in the United States or 1–3 per 100 000 in the United Kingdom [<xref rid="CIU057C7" ref-type="bibr">7</xref>–<xref rid="CIU057C9" ref-type="bibr">9</xref>]. The incidence in well-resourced countries continues to decline with the introduction of meningococcal and pneumococcal vaccines [<xref rid="CIU057C10" ref-type="bibr">10</xref>]. Estimates of meningitis incidence in African adults are lacking, but a higher burden of disease is likely, compared with resource-rich countries, particularly where human immunodeficiency virus (HIV) is highly prevalent [<xref rid="CIU057C5" ref-type="bibr">5</xref>]. In Malawi, where the population prevalence of HIV is estimated to be 11.9% [<xref rid="CIU057C11" ref-type="bibr">11</xref>], inpatient HIV prevalence is 70% in adults, and 85% in adults with bacterial meningitis [<xref rid="CIU057C12" ref-type="bibr">12</xref>]. Of children with ABM in Malawi, 36% are HIV infected [<xref rid="CIU057C13" ref-type="bibr">13</xref>].</p><p>In the last 10 years, numerous public health interventions have been introduced into Malawi, including <italic>Haemophilus influenzae</italic> type b (Hib) vaccination in 2002 [<xref rid="CIU057C14" ref-type="bibr">14</xref>], intensification of malaria control in 2005 [<xref rid="CIU057C15" ref-type="bibr">15</xref>], rapid scale-up of antiretroviral therapy (ART) in 2004, and co-trimoxazole preventive therapy in 2005 [<xref rid="CIU057C16" ref-type="bibr">16</xref>]. These measures have been associated with considerable improvements in under-5 childhood mortality and decreases in the mortality rate of HIV-infected adults from 42% to 17% [<xref rid="CIU057C17" ref-type="bibr">17</xref>, <xref rid="CIU057C18" ref-type="bibr">18</xref>]. However, it is less certain how these interventions have affected the burden of ABM. We have been conducting surveillance for invasive bacterial infections for almost 15 years at the largest district and referral hospital in Malawi. We have taken advantage of these consistently collected data to analyze trends in etiology and disease incidence for ABM over a 12-year period.</p><sec sec-type="methods" id="s2"><title>METHODS</title><sec id="s2a"><title>Setting</title><p>The Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, is a 1250-bed government-funded teaching hospital providing free healthcare that serves approximately 1 million people. The annual admission rate to QECH is 50 000 per year. The diagnostic laboratory at the Malawi-Liverpool-Wellcome Trust (MLW) Clinical Research Programme has provided a routine cerebrospinal fluid (CSF) culture for clinically suspected meningitis at QECH for >10 years.</p></sec><sec id="s2b"><title>Patients</title><p>Since 2000, all adults (aged ≥20 years) and children and adolescents presenting with a clinical suspicion of meningitis routinely underwent lumbar puncture (LP): 5–10 mL of CSF from adults and adolescents, and 1–2 mL from children. LP was withheld in patients with clear contraindications to the procedure [<xref rid="CIU057C19" ref-type="bibr">19</xref>], but this was rare. Indications for LP did not change during the study period. Culture-positive isolates were divided into clinically relevant age groups: neonates (0 to <3 months of age), Expanded Program on Immunization (EPI)–eligible children (aged 3 months to <5 years), older children (aged 5–14 years), adolescents (aged 15–19 years), and adults (aged ≥20 years). Neonatal data were not analyzed as a separate group in this study as neonatal meningitis is epidemiologically distinct from community-acquired meningitis. However, these children were included in the overall trend analysis due to a small number of isolates having no patient age assigned. This study conforms to institutional guidelines and practices. Data collection was approved by the University of Malawi College of Medicine Research Ethics Committee.</p></sec><sec id="s2c"><title>Pathogen Isolation and Identification</title><p>Gram stain was performed if the CSF white cell count (WCC) was >10 cells/µL. India ink stain was performed on adult CSF samples. All samples were cultured on sheep blood and chocolate agar for 48 hours under aerobic and microaerophilic conditions. Bacteria and fungi were identified using standard methods [<xref rid="CIU057C20" ref-type="bibr">20</xref>]. Antibiotic susceptibilities of all bacterial isolates were determined by the disc diffusion method (Oxoid, United Kingdom) using standard guidelines [<xref rid="CIU057C21" ref-type="bibr">21</xref>]. CSF biochemistry was determined using a Beckman Coulter CX5 Synchron Pro analyzer from 2009 onward.</p><p>Cryptococcal culture rates on blood agar were reported. Mycobacterial CSF culture was not performed. All diagnostic testing at the MLW Clinical Research Programme laboratory was quality controlled as part of internationally recognized quality control programs.</p></sec><sec id="s2d"><title>National HIV Intervention Strategies</title><p>In Blantyre, ART rollout began from QECH to health centers in 2004. ART Scale-up data were obtained from the Malawi Ministry of Health [<xref rid="CIU057C22" ref-type="bibr">22</xref>]. Data on co-trimoxazole preventive therapy usage were not available.</p></sec><sec id="s2e"><title>Rainfall and Temperature</title><p>Rainfall and temperature data were obtained from the Department of Climate Change and Meteorological Services, Malawi, for 2 stations in Blantyre for 2000–2010. The cooler dry season is between May and August, the hot dry season between September and November, and the rainy season between November and April.</p></sec><sec id="s2f"><title>Incidence Rates</title><p>Midyear population estimates were based on projections from the 1998 and 2008 Population and Housing Censuses [<xref rid="CIU057C23" ref-type="bibr">23</xref>]. Incidence was defined as cases number in a defined period divided by population time observed. Changes in incidence over time were plotted.</p></sec><sec id="s2g"><title>Time-Series Analysis</title><p>Time-series decomposition was used to separate long-term trends from seasonal perturbations [<xref rid="CIU057C24" ref-type="bibr">24</xref>]. Symmetric locally weighted moving averages were used, with less weight given to time points (in months) further from the present. A 5-month window was used to detect seasonality:<disp-formula><tex-math id="M1">\documentclass[12pt]{minimal}
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}{}$$\hat Y_t = \displaystyle{1 \over 9}(Y_{t - 2} + 2Y_{t - 1} + 3Y_t + 2Y_{t + 1} + Y_{t + 2} ).$$\end{document}</tex-math></disp-formula></p><p>A 12-month window was used to construct a trend line that would be sensitive to year-to-year changes but dampen noise from seasonal perturbation:<disp-formula><tex-math id="M2">\documentclass[12pt]{minimal}
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\begin{document}
}{}$$\eqalign{\widehat{Y}_t = & \displaystyle{1 \over {24}}(Y_{t - 6} + Y_{t + 6} ) + \displaystyle{1 \over {12}}(Y_t + Y_{t - 1} + Y_{t + 1} + Y_{t - 2} + Y_{t + 2} \cr &+ Y_{t - 3} + Y_{t + 3} + Y_{t - 4} + Y_{t + 4} + Y_{t - 5} + Y_{t + 5}). } $$\end{document}</tex-math></disp-formula>To determine whether seasonal perturbation differed significantly from baseline, data were trend differenced. The distribution of residual fluctuations for each month was compared to baseline with 2-tailed <italic>t</italic> test. To determine the impact of rainfall and temperature, an autoregressive integrated moving average model with exogenous variables (ARMAX) model was used. Models using specifications of the autoregressive and moving average parameters were compared using the absolute percentage error.</p></sec><sec id="s2h"><title>Statistical Methods</title><p>The Kruskal-Wallis test was used to detect globally significant differences in the distribution of nonnormal variables among groups of interest. Where results were significant, pairwise comparisons were done using Mann-Whitney test. Poisson regression was used to derive incident rate ratios (IRRs) and 95% confidence intervals (CIs) over the 12-year period. Disease incidence ratios pre- and postvaccination were derived using binary (post–pre) rate ratios to estimate vaccine efficacy. A <italic>P</italic> value <.05 denoted statistical significance. Statistical and time series analyses were done using Stata software, version 12.1 (StataCorp, College Station, Texas).</p></sec></sec><sec sec-type="results" id="s3"><title>RESULTS</title><sec id="s3a"><title>Trends in Disease and Pathogen Incidence Over Time</title><p>The overall trends in all culture-positive cases of bacterial meningitis in adults, adolescents, and children aged <20 years are described in Figure <xref ref-type="fig" rid="CIU057F1">1</xref><italic>A</italic>. There was a significant annual decline in the total number of CSF isolates between 2000 and 2012 (IRR, 0.93; 95% CI, .92–.94; <italic>P</italic> < .001). This decline was entirely in children and adolescents (IRR, 0.87; 95% CI, .85–.88; <italic>P</italic> < .001); the number of isolates from adults remained unchanged (IRR, 0.99; 95% CI, .97–1.0; <italic>P</italic> = .135).The number of CSF samples received by the laboratory each year remained constant after 2002, and hospital admission rates did not change during the study period, despite an increasing population.
<fig id="CIU057F1" position="float"><label>Figure 1.</label><caption><p>Trends in culture positive isolates over time. <italic>A</italic>, Total numbers of culture-positive cases of bacterial meningitis, 2000–2012, by year. Isolates are subdivided into adults aged >20 years and children and adolescents aged <20 years, compared with all cerebrospinal fluid samples received by the laboratory for analysis (right scale). <italic>B</italic>, Total numbers of culture-positive isolates by year and pathogen in all children and adolescents aged <20 years of <italic>Streptococcus pneumoniae</italic>, nontyphoidal salmonellae (NTS), and <italic>Haemophillus influenzae</italic> (Hib) meningitis. <italic>C</italic>, Total numbers of culture-positive isolates by year and pathogen in age-known Expanded Program on Immunization vaccine-eligible children aged ≥3 months to <5 years of <italic>S. pneumoniae</italic>, NTS, and Hib meningitis. Abbreviations: CSF, cerebrospinal fluid; Hib, <italic>Haemophilus influenzae</italic>; PCV13, 13-valent pneumococcal conjugate vaccine.</p></caption><graphic xlink:href="ciu05701"></graphic></fig></p><p>Specific trends in the most commonly isolated pathogens in children and adolescents are described in Figure <xref ref-type="fig" rid="CIU057F1">1</xref><italic>B</italic>. These data include all children from birth where the age is known, and a small number of children (<5% total) where the age was not documented but admission to a pediatric ward was recorded. Cases of Hib meningitis declined 20-fold from 80 cases per year in 2000 to <4 cases per year in 2012 in all children and adolescents. Following Hib vaccination in 2002, cases declined rapidly in the EPI-eligible, 3 months to <5 years age group (Figure <xref ref-type="fig" rid="CIU057F1">1</xref><italic>C</italic>). In the years immediately preceding and following vaccine introduction, Hib incidence has dropped dramatically; the binary IRR of the fall is 0.11 (95% CI, .08–.14; <italic>P</italic> < .001), providing an estimated vaccine effectiveness of 89% (95% CI, 86%–92%). Childhood nontyphoidal salmonellae (NTS) and pneumococcal meningitis cases have also significantly declined in children in this age group between 2002 and 2012; the IRR over 12 years was 0.85 (95% CI, .81–.89; <italic>P</italic> < .001) for NTS, and 0.88 (95% CI, .85–.91; <italic>P</italic> < .001) for pneumococcus.</p><p>From these data, the overall incidence of culture-positive bacterial meningitis was estimated. Incidence declined from 49.6 per 100 000 in 2002 to 20 per 100 000 in 2012. This decline is driven predominately by the 3 months to <5 years age group (incidence 154.4 in 2002 to 20 in 2012), and the 5-15 years group (incidence 15.7 in 2002 to 8 in 2012), with incidence in adolescents and adults remaining unchanged (Figure <xref ref-type="fig" rid="CIU057F2">2</xref>).
<fig id="CIU057F2" position="float"><label>Figure 2.</label><caption><p>Incidence of culture-positive bacterial meningitis per 100 000 population. <italic>A</italic>, Incidence and all cases of bacterial meningitis, 2000–2012, in all cases and children and adolescents aged <20 years. <italic>B</italic>, Incidence and cases by specific age group (only children for whom age was known are included).</p></caption><graphic xlink:href="ciu05702"></graphic></fig></p><p><ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary Figure 1<italic>A</italic></ext-link>–<italic>D</italic> shows the proportions of all culture-positive isolates per age group. In the age group 3 months to <5 years (<ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary Figure 1</ext-link><italic>A</italic>), there has been a decline of 88% in the total number of microbiologically confirmed pathogens since 2000. Hib meningitis has dramatically declined from >35% of all cases prior to 2002 to 3.5% in 2005, subsequently remaining between 10% and 15%. <italic>Streptococcus pneumoniae</italic> accounted for 30%–50% of cases in 2000–2003, but as Hib cases declined, pneumococcus has consistently accounted for >60% of cases since 2004. The number of pneumococcal isolates in this age group has dropped from a peak of 115 out of 177 cases in 2007 to 16 per 25 cases in 2012. Nontyphoidal salmonellae meningitis caused approximately 23% of cases before 2004, dropping to <10% by 2012. Group B streptococcal meningitis peaked in 2005 at almost 15%, but since 2009 has dropped to <3%. Confirmed meningococcal meningitis has remained consistently at <5%. Pathogens listed as “other” have increased in proportion as the other causes have decreased. This group includes groups A and D streptococci, <italic>Klebsiella pneumoniae</italic>, <italic>Listeria monocytogenes</italic>, <italic>Salmonella enteritidis</italic>, <italic>Staphylococcus aureus</italic>, and <italic>H. influenzae</italic> types a and c and nontypeables.</p><p><italic>Streptococcus pneumoniae</italic> is the predominant bacterial pathogen causing 65% of infections in the 5- to 15-year age group; Hib caused 8.6% and NTS <1% of infections (<ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary Figure 1</ext-link><italic>B</italic>). <italic>Streptococcus pneumoniae</italic> was also the predominant pathogen in all older age groups >15 years; numbers of <italic>Neisseria meningitidis</italic> isolated from adults and adolescents were small (<ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary Figure 1</ext-link><italic>C</italic> and 1<italic>D</italic>). Rapid up-scaling of ART has led to >354 000 adults and >34 000 children starting ART by September 2012 in the Southern Region of Malawi (Figure <xref ref-type="fig" rid="CIU057F3">3</xref>), of which >215 000 adults and >21 000 children were reported to be alive on ART at the end of 2012. However meningitis due to <italic>Cryptococcus neoformans</italic> accounted for significant and consistent numbers of cases, particularly in adults in 2000–2012, with the exception of the under-5 group, in whom cryptococcal meningitis was detected only from 2009 onward (<ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary Figure 2</ext-link>).
<fig id="CIU057F3" position="float"><label>Figure 3.</label><caption><p>Cumulative numbers of adults and children alive on antiretroviral therapy (ART) per year in the Southern Region of Malawi.</p></caption><graphic xlink:href="ciu05703"></graphic></fig></p></sec><sec id="s3b"><title>Seasonality</title><p>We have previously described seasonal invasive pneumococcal disease trends in Blantyre over the same time period [<xref rid="CIU057C25" ref-type="bibr">25</xref>] and tested if bacterial meningitis is seasonal. Figure <xref ref-type="fig" rid="CIU057F4">4</xref><italic>A</italic> and 4<italic>B</italic> describe the seasonality of meningitis due to <italic>S. pneumoniae</italic> and <italic>Salmonella</italic> Typhimurium. Rainfall and temperature data were available for the 2000–2010 period only.
<fig id="CIU057F4" position="float"><label>Figure 4.</label><caption><p>Seasonality plot of all meningitis cases caused by <italic>Streptococcus pneumoniae</italic> (<italic>A</italic>) and nontyphoidal salmonellae (NTS) (<italic>B</italic>). <italic>A</italic>, Seasonality of <italic>S. pneumoniae. B</italic>, Seasonality of NTS.</p></caption><graphic xlink:href="ciu05704"></graphic></fig></p><p>The mean number of isolates per month of <italic>S. pneumoniae</italic> were significantly and consistently lower than the baseline long-term trend during the wet season between December to April over 10 years, despite the overall fall in isolate numbers (<italic>P</italic> < .05). Using the ARMAX model, rainfall was associated with 28% (95% CI, 13.7%–41.4%; <italic>P</italic> < .001) fewer cases of pneumococcal meningitis. Hot weather was associated with 42.8% (95% CI, 1.8%–87.5%, <italic>P</italic> = .06) more cases of pneumococcal meningitis, but the confidence interval crosses the null point. <italic>Streptococcus pneumoniae</italic> meningitis is therefore a seasonal disease in Malawi occurring in the dry season, particularly hot, dry months. Cases of NTS meningitis were above the mean in August to December and below the mean in January, but the trend did not reach significance. Hib and cryptococcal disease were not seasonal (data not shown).</p></sec><sec id="s3c"><title>CSF Findings by Pathogen</title><p>Significantly lower CSF WCCs were seen in cases of <italic>S. pneumoniae</italic> meningitis compared with <italic>N. meningitidis</italic> meningitis in both adults and children (Table <xref ref-type="table" rid="CIU057TB1">1</xref>). HIV did not influence the CSF WCC in pneumococcal meningitis in adults (median CSF WCC in HIV-positive adults was 435 cells/µL [interquartile range {IQR}, 107–1680 cells/µL]; n = 297), compared with 575 cells/µL (IQR, 196–1740 cells/µL) in HIV-negative adults (n = 44) (<italic>P</italic> = .31). Both NTS and cryptococcal meningitis were associated with lower CSF WCC than <italic>S. pneumoniae</italic> and <italic>N. meningitidis.</italic> CSF protein was significantly higher in bacterial meningitis caused by all pathogens (with the exception of NTS) than in cryptococcal meningitis (<italic>P</italic> < .001). Similarly, CSF glucose levels were significantly lower in <italic>S. pneumoniae</italic> compared with cryptococcus for both adults and children (<italic>P</italic> < .001).
<table-wrap id="CIU057TB1" position="float"><label>Table 1.</label><caption><p>Differences Between Cerebrospinal Fluid (CSF) Laboratory Parameters From Culture-Positive CSF Samples, by Infecting Organism and Age Group</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">CSF Parameter</th><th align="center" rowspan="1" colspan="1"><italic>Spn</italic> Meningitis, Adults (n = 795)</th><th align="center" rowspan="1" colspan="1"><italic>Spn</italic> Meningitis, Children (n = 998)</th><th align="center" rowspan="1" colspan="1">NTS Meningitis, Adults (n = 28)</th><th align="center" rowspan="1" colspan="1">NTS Meningitis, Children (n = 269)</th><th align="center" rowspan="1" colspan="1">NM Meningitis, Adults (n = 17)</th><th align="center" rowspan="1" colspan="1">NM Meningitis, Children (n = 22)</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Median CSF protein, g/L (IQR)</td><td rowspan="1" colspan="1">2.6 (0–4.6) (n = 161)</td><td rowspan="1" colspan="1">2.4 (0.99–3.59) (n = 170)</td><td rowspan="1" colspan="1">1.84 (0.92–3.15) (n = 3)</td><td rowspan="1" colspan="1">1.84 (0–5.31) (n = 26)</td><td rowspan="1" colspan="1">4.53 (3.23–5.54) (n = 4)</td><td rowspan="1" colspan="1">1.87 (1.58–3.20) (n = 4)</td></tr><tr><td rowspan="1" colspan="1">Median CSF glucose, mmol/L (IQR)</td><td rowspan="1" colspan="1">0 (0–0.17) (n = 161)</td><td rowspan="1" colspan="1">0 (0–0.33) (n = 146)</td><td rowspan="1" colspan="1">2.75 (0–3.08) (n = 3)</td><td rowspan="1" colspan="1">0.06 (0–0.44) (n = 25)</td><td rowspan="1" colspan="1">0.08 (0–0.98) (n = 4)</td><td rowspan="1" colspan="1">0.42 (0.14–0.73) (n = 4)</td></tr><tr><td rowspan="1" colspan="1">Median CSF WCC, cells/µL (IQR)</td><td rowspan="1" colspan="1">335 (74–1360)</td><td rowspan="1" colspan="1">407 (130–1360)</td><td rowspan="1" colspan="1">65 (5–700)</td><td rowspan="1" colspan="1">560 (150–2800)</td><td rowspan="1" colspan="1">2320 (155–5920)</td><td rowspan="1" colspan="1">1970 (250–6800)</td></tr></tbody></table><table-wrap-foot><fn><p>Adults are defined as aged >20 years, children as children and adolescents aged <20 years.</p></fn><fn><p>Abbreviations: CSF, cerebrospinal fluid; IQR, interquartile range; NM, <italic>Neisseria meningitidis</italic>; NTS, nontyphoidal salmonellae; <italic>Spn</italic>, <italic>Streptococcus pneumoniae</italic>; WCC, white cell count<italic>.</italic></p></fn></table-wrap-foot></table-wrap></p><p>WCC data were collected for culture-negative CSF specimens from 2007. Between 2007 and 2010, 643 of 8166 (7.8%) adults had a negative culture but had a CSF WCC of >100 cells/µL; 796 of 9431 (8.4%) children had a negative culture but had a CSF WCC of >20 cells/µL. These cases may represent a significant additional meningitis disease burden; we are currently investigating the causes of culture-negative meningitis in our hospital.</p></sec></sec><sec sec-type="discussion" id="s4"><title>DISCUSSION</title><p>Our data indicate that culture-confirmed cases of ABM presenting to the largest secondary and tertiary referral hospital in Malawi have declined steeply over the last 12 years, driven largely by a decline in persons aged 3 months to <5 years. This has occurred prior to the addition of the 13-valent pneumococcal conjugate vaccine (PCV13) to the routine infant schedule in Malawi in 2011 but subsequent to the introduction of Hib vaccine in 2002. Although a similar decline in Hib ABM that was ecologically coincident with Hib vaccine introduction has been observed elsewhere in Africa [<xref rid="CIU057C26" ref-type="bibr">26</xref>, <xref rid="CIU057C27" ref-type="bibr">27</xref>], it is striking that we also observed a decline in cases of pneumococcal and NTS ABM in this age group. Why we have not observed a similar overall decline in the incidence of acute adult ABM, in contrast to childhood disease, is uncertain.</p><p>The decline in childhood cases of <italic>S. pneumoniae</italic> ABM in children aged 3 months to <5 years preceding the introduction of PCV13 has not been observed in other sub-Saharan African facility-based studies [<xref rid="CIU057C28" ref-type="bibr">28</xref>], with the exception of HIV-infected children receiving ART in South Africa [<xref rid="CIU057C29" ref-type="bibr">29</xref>]. We have previously reported a similar decline in cases of pneumococcal bacteremia (IPD) in adults and children [<xref rid="CIU057C25" ref-type="bibr">25</xref>]. During 2000–20012 in Malawi, there have been considerable improvements in general nutrition and the management of childhood illness at primary healthcare levels, which have been linked to a 50% decline in the overall under-5 mortality between 1999 and 2009 [<xref rid="CIU057C30" ref-type="bibr">30</xref>]. Pediatric ABM has been associated with HIV in 36% of cases in Malawi [<xref rid="CIU057C13" ref-type="bibr">13</xref>]. Data on the overall community prevalence of HIV in children are unavailable, but the estimated prevalence of HIV in pregnant women in Southern Malawi has fallen from 19% in 2000 to 14% in 2010 [<xref rid="CIU057C22" ref-type="bibr">22</xref>]. Furthermore, extensive rollout of ART for children and a national prevention of mother-to-child transmission program may be driving down the burden of HIV. We suggest that these factors, together with some improvement in socioeconomic indicators [<xref rid="CIU057C31" ref-type="bibr">31</xref>], are likely to have contributed to the observed decline in childhood ABM, particularly NTS and <italic>S. pneumoniae</italic> meningitis. Although the control of malaria has been shown to improve all-cause mortality in other African settings [<xref rid="CIU057C32" ref-type="bibr">32</xref>], there has not been a sufficiently large decline in childhood malaria in Malawi to contribute substantially to this trend [<xref rid="CIU057C15" ref-type="bibr">15</xref>].</p><p>Free ART has been provided in Malawi for adults since 2004, and to date nearly 360 000 HIV-infected individuals had been registered in the national ART program in the Southern Region of Malawi; co-trimoxazole prophylaxis has been widely available since 2006 [<xref rid="CIU057C22" ref-type="bibr">22</xref>].The absence of a decline in adult ABM, despite improvements in HIV care including the rollout of ART and co-trimoxazole, coincident with a fall in the incidence of IPD, is therefore surprising [<xref rid="CIU057C25" ref-type="bibr">25</xref>]. We have previously demonstrated high rates of pneumococcal carriage with broad serotype diversity in HIV-infected adults despite the initiation of ART [<xref rid="CIU057C33" ref-type="bibr">33</xref>]. We therefore speculate that persistent defects in immune control in the nasopharynx and potentially the CSF compartment could account for the continuing high incidence of pneumococcal ABM in adults.</p><p>Meningitis is seasonal in many parts of the world [<xref rid="CIU057C34" ref-type="bibr">34</xref>]. A better understanding of these disease patterns and the potential climatic associations are important for public health planning and the interpretation of disease incidence. Malawi is geographically far from countries where epidemic meningitis primarily due to <italic>N. meningitidis,</italic> coincident with the hot, dry season has been described [<xref rid="CIU057C34" ref-type="bibr">34</xref>, <xref rid="CIU057C35" ref-type="bibr">35</xref>]. In Malawi, pneumococcal and NTS meningitis were both seasonal over the last 10 years, peaking in the cold, dry and hot, wet seasons, respectively. Importantly, seasonality was maintained, even as incidence rates have declined. Other African centers beyond the meningitis belt have observed meningitis seasonality in Uganda, but not in Tanzania, although these data are not from centers undertaking long-term surveillance [<xref rid="CIU057C36" ref-type="bibr">36</xref>, <xref rid="CIU057C37" ref-type="bibr">37</xref>].</p><p>Our disease estimates are of minimum incidence, as it is well described that routine surveillance supported by CSF culture alone may underestimate meningitis incidence [<xref rid="CIU057C38" ref-type="bibr">38</xref>]. However, in a high-HIV-prevalence setting, the causes of culture-negative meningitis includes tuberculosis. We did not have access to tuberculosis culture, so incidence estimates including culture-negative cases may be inaccurate and are not presented.</p><p>Our data have several limitations. Several adult and pediatric ABM and IPD clinical trials conducted at our center may have increased case ascertainment. However, following the completion of these studies, the number of CSF samples processed in the laboratory has remained static. There may have been underascertainment of pathogens due to the unavailability of diagnostic nucleic acid detection [<xref rid="CIU057C38" ref-type="bibr">38</xref>]. Although there are no other government-funded facilities where ABM cases are routinely admitted, patients may experience significant delays in the community and die undiagnosed, causing further underascertainment [<xref rid="CIU057C39" ref-type="bibr">39</xref>]. Health centers may have administered parenteral antibiotics prior to transfer to QECH, but documentation and trends are not available. There were no changes in either national or hospital guidelines during this period. Finally, our data set has arisen from 1 center. However, given the similarity of cross-sectional data that have emerged with other regional settings, it is likely that these data are generalizable to other HIV-prevalent African countries.</p><p>In conclusion, rates of ABM have declined significantly in children but not in adults in Malawi. Hib vaccine introduction appears to have resulted in the decline of incidence of Hib in young children, but the highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults, among whom the burden remains high. Long-term surveillance of bacterial meningitis outside the epidemic meningitis belt is essential in Africa.</p></sec><sec sec-type="supplementary-material" id="s5"><title>Supplementary Data</title><p><ext-link ext-link-type="uri" xlink:href="http://cid.oxfordjournals.org/lookup/suppl/doi:10.1093/cid/ciu057/-/DC1">Supplementary materials</ext-link> are available at <italic>Clinical Infectious Diseases</italic> online (<uri xlink:type="simple" xlink:href="http://cid.oxfordjournals.org">http://cid.oxfordjournals.org</uri>). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.</p><supplementary-material id="PMC_1" content-type="local-data"><caption><title>Supplementary Data</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_58_10_e137__index.html"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_ciu057_ciu057supp.docx"></media></supplementary-material></sec></body><back><ack><title>Notes</title><p><bold><italic>Acknowledgments.</italic></bold> The authors thank the Statistics and Data Department at the Malawi-Liverpool-Wellcome Trust (MLW) Clinical Research Programme, particularly Lyness Ndelemani, Malango Msukwa, and Dr Sarah White; the patients and the medical and nursing staff of Queen Elizabeth Central Hospital; the staff of the MLW Microbiology Laboratory, particularly Brigitte Denis, Amanda Walsh, and Lorna Wilson; and Adams Chavula of the Department of Climate Change and Meteorological Services, Malawi, for their contribution to this study.</p><p><bold><italic>Financial support.</italic></bold> The invasive bacterial surveillance service is supported by <funding-source>the Wellcome Trust Major Overseas programme core award</funding-source> (award number <award-id>084679/Z/08/Z</award-id>).</p><p><bold><italic>Potential conflicts of interest.</italic></bold> All authors: No reported conflicts.</p><p>All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. 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