Substantial misdiagnosis of severe malaria in African children

Abstract

WHO has estimated that nearly 2000 African children die each day as a result of severe falciparum malaria,1WHOWorld Malaria Report 2021.https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021Date: Dec 6, 2021Date accessed: August 12, 2022Google Scholar a depressing figure that has changed little since 2015. This terrible death toll is a major justification for the substantial global investments in malaria control. Yet there is little research on severe malaria in humans. The pathobiology and clinical management of the lethal infection are seldom discussed in the interminable international meetings on malaria. The only substantial change in policies in recent years has been WHO's ill-advised and unwarranted moratorium on pre-referral rectal artesunate.2Watson JA Warsame M Peto TJ et al.Stopping prereferral rectal artesunate—a grave error.BMJ Glob Health. 2022; 7e010006Crossref Scopus (2) Google ScholarIn areas of high malaria transmission (ie, much of sub-Saharan Africa) malaria is ubiquitous. Finding malaria parasites in a blood smear or a positive rapid diagnostic test (RDT) in a sick child does not necessarily mean that malaria is the cause of the illness. Yet severe malaria is the usual diagnosis in a hospitalised febrile African child with a positive blood smear or RDT. Differentiating severe bacterial infections from severe malaria is difficult, and the two commonly coexist.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar For this reason, it is recommended that all children with suspected severe malaria should receive both parenteral artesunate and parenteral antibiotics.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar Unfortunately this advice is often not followed, or the antibiotics are delayed until the child deteriorates—by which time it might be too late. If children do not receive effective antibiotics immediately, and they would do so if the malaria test was negative, then the positive malaria blood test becomes, perversely, a risk factor for dying from bacterial sepsis. The magnitude of the problem is illustrated by recent analyses of data from leading severe malaria research centres.4Watson JA Uyoga S Wanjiku P et al.Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations.Sci Transl Med. 2022; 14eabn5040Crossref PubMed Scopus (4) Google Scholar, 5Watson JA Ndila CM Uyoga S et al.Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision.eLife. 2021; 10e69698Crossref Google Scholar These analyses provide strong evidence that about a third of African children diagnosed with severe malaria have another cause (probably bacterial infections) of their potentially lethal illness. Simple blood tests can help identify these misdiagnosed children (table), but the implication for clinical management is clear: all children with suspected severe malaria must immediately receive both parenteral artesunate and broad-spectrum antibiotics.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar In the community, where parenteral drug administration is not possible, pre-referral rectal artesunate should be given. Pre-referral rectal formulations of broad-spectrum antibiotics should be developed.TableBlood tests and outcomes in African children with probable misdiagnosed severe falciparum malaria compared with African children with true severe falciparum malaria4Watson JA Uyoga S Wanjiku P et al.Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations.Sci Transl Med. 2022; 14eabn5040Crossref PubMed Scopus (4) Google Scholar, 5Watson JA Ndila CM Uyoga S et al.Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision.eLife. 2021; 10e69698Crossref Google ScholarValuesParasite countsLowerHaemoglobinHigherWhite blood cell countsHigherPlatelet countsHigherPlasma PfHRP2 concentrationsLowerMalaria pigment containing neutrophilsLessPositive blood culturesMoreMortalityHigher Open table in a new tab We declare no competing interests. WHO has estimated that nearly 2000 African children die each day as a result of severe falciparum malaria,1WHOWorld Malaria Report 2021.https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021Date: Dec 6, 2021Date accessed: August 12, 2022Google Scholar a depressing figure that has changed little since 2015. This terrible death toll is a major justification for the substantial global investments in malaria control. Yet there is little research on severe malaria in humans. The pathobiology and clinical management of the lethal infection are seldom discussed in the interminable international meetings on malaria. The only substantial change in policies in recent years has been WHO's ill-advised and unwarranted moratorium on pre-referral rectal artesunate.2Watson JA Warsame M Peto TJ et al.Stopping prereferral rectal artesunate—a grave error.BMJ Glob Health. 2022; 7e010006Crossref Scopus (2) Google Scholar In areas of high malaria transmission (ie, much of sub-Saharan Africa) malaria is ubiquitous. Finding malaria parasites in a blood smear or a positive rapid diagnostic test (RDT) in a sick child does not necessarily mean that malaria is the cause of the illness. Yet severe malaria is the usual diagnosis in a hospitalised febrile African child with a positive blood smear or RDT. Differentiating severe bacterial infections from severe malaria is difficult, and the two commonly coexist.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar For this reason, it is recommended that all children with suspected severe malaria should receive both parenteral artesunate and parenteral antibiotics.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar Unfortunately this advice is often not followed, or the antibiotics are delayed until the child deteriorates—by which time it might be too late. If children do not receive effective antibiotics immediately, and they would do so if the malaria test was negative, then the positive malaria blood test becomes, perversely, a risk factor for dying from bacterial sepsis. The magnitude of the problem is illustrated by recent analyses of data from leading severe malaria research centres.4Watson JA Uyoga S Wanjiku P et al.Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations.Sci Transl Med. 2022; 14eabn5040Crossref PubMed Scopus (4) Google Scholar, 5Watson JA Ndila CM Uyoga S et al.Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision.eLife. 2021; 10e69698Crossref Google Scholar These analyses provide strong evidence that about a third of African children diagnosed with severe malaria have another cause (probably bacterial infections) of their potentially lethal illness. Simple blood tests can help identify these misdiagnosed children (table), but the implication for clinical management is clear: all children with suspected severe malaria must immediately receive both parenteral artesunate and broad-spectrum antibiotics.3WHOSevere malaria.Trop Med Int Health. 2014; 19: 7-131PubMed Google Scholar In the community, where parenteral drug administration is not possible, pre-referral rectal artesunate should be given. Pre-referral rectal formulations of broad-spectrum antibiotics should be developed. We declare no competing interests.