title: Viral CNS infections in children from a malaria-endemic area  of Malawi: a prospective cohort study.
abstract: BACKGROUND
  Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia.
  
  
  METHODS
  We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection.
  
  
  RESULTS
  Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and 34 (13%) of 262 with neither (p<0·0001). Logistic regression showed children with a viral CNS infection had a significantly higher mortality than did those who did not have a viral CNS infection (p=0·001).
  
  
  CONCLUSIONS
  Viral CNS infections are an important cause of hospital admission and death in children in Malawi, including in children whose coma might be attributed solely to cerebral malaria. Interaction between viral infection and parasitaemia could increase disease severity.
  
  
  BACKGROUND
  Wellcome Trust, US National Institutes of Health, and UK Medical Research Council.
authors.forename: Macpherson
authors.initials: M
authors.lastname: Mallewa
authors.forename: Pam
authors.initials: P
authors.lastname: Vallely
authors.forename: Brian
authors.initials: B
authors.lastname: Faragher
authors.forename: Dan
authors.initials: D
authors.lastname: Banda
authors.forename: Paul
authors.initials: P
authors.lastname: Klapper
authors.forename: Mavuto
authors.initials: M
authors.lastname: Mukaka
authors.forename: Harriet
authors.initials: H
authors.lastname: Khofi
authors.forename: Paul
authors.initials: P
authors.lastname: Pensulo
authors.forename: Terrie
authors.initials: T
authors.lastname: Taylor
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
mesh_terms: D000293:Adolescent; D020805:Central Nervous System Viral Diseases / Q000134:cerebrospinal fluid / Q000453:epidemiology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D060085:Coinfection / Q000453:epidemiology; D019353:Endemic Diseases; D005260:Female; D015658:HIV Infections / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000097:blood / Q000134:cerebrospinal fluid / Q000453:epidemiology*; D016778:Malaria, Falciparum / Q000097:blood / Q000134:cerebrospinal fluid / Q000453:epidemiology*; D008295:Malawi / Q000453:epidemiology; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics / Q000302:isolation & purification*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies
references.citation: J Infect Dis. 2005 Jan 15;191(2):234-7
references.pmid: 15609233
references.citation: Cell. 1995 Feb 24;80(4):593-601
references.pmid: 7532548
references.citation: J Infect Dis. 2012 Jan 1;205(1):106-10
references.pmid: 22075766
references.citation: Lancet. 1974 Jul 13;2(7872):81-4
references.pmid: 4136544
references.citation: Invest Ophthalmol Vis Sci. 1999 Jan;40(1):90-5
references.pmid: 9888431
references.citation: Lancet. 1997 Jun 7;349(9066):1650-4
references.pmid: 9186382
references.citation: Neurology. 2012 Sep 18;79(12):1268-72
references.pmid: 22914840
references.citation: Lancet Infect Dis. 2010 Dec;10(12):835-44
references.pmid: 20952256
references.citation: Jpn J Infect Dis. 2003 Oct-Dec;56(5-6):193-9
references.pmid: 14695429
references.citation: Am J Trop Med Hyg. 2006 Dec;75(6):1148-50
references.pmid: 17172383
references.citation: J Clin Microbiol. 2007 Jun;45(6):1858-66
references.pmid: 17446325
references.citation: J Med Virol. 2012 Jul;84(7):1080-3
references.pmid: 22585725
references.citation: Nat Med. 2004 Feb;10(2):143-5
references.pmid: 14745442
references.citation: Epidemiol Infect. 1993 Oct;111(2):357-71
references.pmid: 8405162
references.citation: J Virol Methods. 1993 Oct;44(2-3):155-65
references.pmid: 8263112
references.citation: J Med Virol. 2010 Oct;82(10):1669-78
references.pmid: 20827763
references.citation: Emerg Infect Dis. 2007 Jan;13(1):136-9
references.pmid: 17370529
references.citation: Clin Infect Dis. 2003 Mar 15;36(6):731-42
references.pmid: 12627357
references.citation: PLoS Negl Trop Dis. 2010 Oct 26;4(10):e854
references.pmid: 21049060
references.citation: J Med Virol. 2002 Aug;67(4):555-62
references.pmid: 12116004
references.citation: Pediatrics. 1978 May;61(5):720-7
references.pmid: 662510
references.citation: Acta Paediatr Scand. 1970 May;59(3):310-6
references.pmid: 4315516
references.citation: Am J Pathol. 1985 Jun;119(3):385-401
references.pmid: 3893148
references.citation: Rev Med Virol. 2012 May;22(3):144-55
references.pmid: 22052666
references.citation: J Microbiol Immunol Infect. 2003 Mar;36(1):37-40
references.pmid: 12741731
references.citation: Eur J Clin Microbiol Infect Dis. 2011 Dec;30(12):1561-9
references.pmid: 21573818
references.citation: Lancet. 2002 Jul 20;360(9328):211-8
references.pmid: 12133656
references.citation: Lancet Neurol. 2010 Nov;9(11):1097-105
references.pmid: 20965438
references.citation: J Infect. 2003 Jul;47(1):59-64
references.pmid: 12850164
references.citation: Virol J. 2008 Mar 27;5:47
references.pmid: 18371229
references.citation: Q J Med. 1989 May;71(265):441-59
references.pmid: 2690177
references.citation: Future Microbiol. 2011 Mar;6(3):349-55
references.pmid: 21449844
references.citation: J Clin Microbiol. 1989 Jun;27(6):1174-9
references.pmid: 2546971
references.citation: J Virol. 2002 Jan;76(1):427-31
references.pmid: 11739709
references.citation: Dev Med Child Neurol. 1995 Sep;37(9):807-13
references.pmid: 7589863
references.citation: QJM. 1999 Mar;92(3):151-7
references.pmid: 10326074
references.citation: J Neurovirol. 2006 Jun;12(3):235-40
references.pmid: 16877305
references.citation: Lancet. 2011 Oct 8;378(9799):1316-23
references.pmid: 21903251
references.citation: Pediatr Infect Dis J. 2013 Feb;32(2):e54-61
references.pmid: 22914560
references.citation: Methods Mol Med. 1999;20:67-79
references.pmid: 21390729
references.citation: Lancet. 2011 Oct 8;378(9799):1281-2
references.pmid: 21903254