Disease In African Children Research Articles

Risk factors for Bordetella pertussis disease in hospitalized children.

IntroductionDespite a resurgence of disease, risk factors for pertussis in children in low and middle-income countries are poorly understood. This study aimed to investigate risk factors for pertussis disease in African children hospitalized with severe LRTI.MethodsA prospective study of children hospitalized with severe LRTI in Cape Town, South Africa was conducted over a one-year period. Nasopharyngeal and induced sputum samples from child and nasopharyngeal sample from caregiver were tested for Bordetella pertussis using PCR (IS481+/hIS1001). History and clinical details were documented.Results460 children with a median age of 8 (IQR 4–18) months were enrolled. B. pertussis infection was confirmed in 32 (7.0%). The adjusted risk of confirmed pertussis was significantly increased if infants were younger than two months [aRR 2.37 (95% CI 1.03–5.42]), HIV exposed but uninfected (aRR 3.53 [95% CI 1.04–12.01]) or HIV infected (aRR 4.35 [95% CI 1.24–15.29]). Mild (aRR 2.27 [95% CI 1.01–5.09]) or moderate (aRR 2.70 [95% CI 1.13–6.45]) under-nutrition in the children were also associated with higher risk. The highest adjusted risk occurred in children whose caregivers had B. pertussis detected from nasopharyngeal swabs (aRR 13.82 [95% CI 7.76–24.62]). Completion of the primary vaccine schedule (three or more doses) was protective (aRR 0.28 [95% CI 0.10–0.75]).ConclusionsHIV exposure or infection, undernutrition as well as detection of maternal nasal B. pertussis were associated with increased risk of pertussis in African children, especially in young infants. Completed primary vaccination was protective. There is an urgent need to improve primary pertussis vaccine coverage in low and middle-income countries. Pertussis vaccination of pregnant women, especially those with HIV infection should be prioritized.

COVID-19 in children: a case series from Nigeria

IntroductionThe global spread of COVID-19 remains unabated in the past few months with a rise in the number of available literature on the novel virus. There are very few paediatric studies and are mainly from developed countries with a paucity of information on the clinical manifestation of COVID-19 disease in African children, including Nigeria.MethodsWe described the clinical presentation, laboratory findings, treatment and outcome in a group of five Nigerian children managed at a COVID-19 isolation and treatment centre in Nigeria.ResultsWe managed a total of five children with an age range of 3 months to 8 years in the last four weeks (16th April to 15th May 2020). Three of the five children were males. All the children had close contact with family members that tested positive for COVID-19. Out of the five children, one had moderate disease, three had mild symptomatic disease, and one was asymptomatic. Two out of the five children had lymphocytosis. Out of the four children who had chest radiograph, two had features of pneumonia.ConclusionCOVID-19 is not uncommon in Nigerian children, and all had a confirmed family member with COVID-19. Besides, contrary to leucopaenia with lymphopaenia observed in the adult’s population, we found lymphocytosis in this cohort and about 50.0% had pneumonic changes on chest radiograph.

Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.

Immunological bases of increased susceptibility to invasive nontyphoidal Salmonella infection in children with malaria and anaemia

Malaria and anaemia are key underlying factors for iNTS disease in African children. Knowledge of clinical and epidemiological risk-factors for iNTS disease has not been paralleled by an in-depth knowledge of the immunobiology of the disease. Herein, we review human and animal studies on mechanisms of increased susceptibility to iNTS in children.

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0–15 years) and 52/256 children (20%; 95%CI 15–25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71–82%), 123/240 (51%; 95%CI 45–58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36–49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8–35.1), dyspnea (OR 4.2; 95%CI 1.5–12.0) and HIV infection (OR 3.3; 95%CI 1.1–10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

Children’s heart disease in sub-Saharan Africa: Challenging the burden of disease

Children with heart disease in Africa have little or no access to treatment of any kind, and cardiac surgical services are virtually absent outside a handful of centres in a few of the wealthier nations. There is little reliable data concerning the prevalence of congenital or acquired heart disease in African children, but there is sufficient information to indicate that the burden of cardiac disease is vast. This major non-communicable disease is largely hidden, overshadowed by the incidence of communicable diseases. There is as yet little evidence of the hoped-for epidemiological transition toward non-communicable diseases amongst children in Africa. The burden of congenital heart disease is only part of the problem, with rheumatic heart disease (RHD) remaining the commonest cardiac problem, related to poor socioeconomic conditions. RHD is the most preventable form of cardiac disease, yet there is little preventive work being done. The many obstacles to developing paediatric cardiac care are discussed, and some possible ways forward are proposed.

Genetic variants associated with non-typhoidal Salmonella bacteraemia in African children

BackgroundNon-typhoidal Salmonella (NTS) causes invasive and frequently fatal disease in African children. Existing strategies to prevent, diagnose, and treat NTS disease are inadequate. An improved understanding of the biology of invasive Salmonella infection will facilitate the development of novel NTS control measures. Despite evidence in mice and man showing a clear role for host genetics in NTS susceptibility, there are no published studies investigating host genetic susceptibility to NTS in African populations. MethodsWe conducted a genome-wide association study (SNP Array 6.0, Affymetrix, CA, USA) of NTS bacteraemia in Kenyan children, with replication in Malawian children. We assessed the function of NTS-associated variants in an expression quantitative trait locus (eQTL) dataset of interferon γ (IFNγ) and lipopolysaccharide-stimulated monocytes from 432 healthy European adults. Serum IFNγ (Bio-Plex immunoassay, Bio-Rad Laboratories, CA, USA) in Malawian NTS cases (n=106) during acute disease was correlated with genotype by linear regression. FindingsAfter whole-genome imputation and quality control, 180 Kenyan cases and 2677 controls were included in an association analysis at 7 951 614 (additive model) and 4 669 537 (genotypic model) loci. After quality control, 143 Malawian cases and 336 controls were included in the replication analysis. An intronic variant in STAT4 was associated (recessive model) with NTS in both Kenyan and Malawian children (Kenya p=5·6 × 10−9, Malawi p=0·02, combined p=1·4 × 10−9; odds ratio 7·2, 95% CI 3·8–13·5). The NTS-associated variant was an eQTL for STAT4 expression in IFNγ-stimulated monocytes (p=9·59 × 10−6), the NTS risk allele being associated with lower STAT4 expression. In Malawian children with NTS bacteraemia, the same NTS risk allele was associated with lower serum concentrations of IFNγ (p=0·02) at presentation. InterpretationSTAT4 is highly plausible as a susceptibility locus for invasive NTS disease. STAT4 mediates IFNγ release in T cells and natural killer cells in response to interleukin 12 (IL12). Individuals with rare mutations elsewhere in the IL12–IFNγ axis are at risk of disseminated NTS infection. We provide the first evidence, to our knowledge, of a host genetic determinant of NTS disease in African children, and of a STAT4 variant conferring susceptibility to an infectious disease in man. FundingWellcome Trust.

Variation in the circumsporozoite protein of Plasmodium falciparum: vaccine development implications.

The malaria vaccine candidate RTS,S/AS01 is based on immunogenic regions of Plasmodium falciparum circumsporozoite protein (CSP) from the 3D7 reference strain and has shown modest efficacy against clinical disease in African children. It remains unclear what aspect(s) of the immune response elicited by this vaccine are protective. The goals of this study were to measure diversity in immunogenic regions of CSP, and to identify associations between polymorphism in CSP and the risk of P. falciparum infection and clinical disease. The present study includes data and samples from a prospective cohort study designed to measure incidence of malaria infection and disease in children in Bandiagara, Mali. A total of 769 parasite-positive blood samples corresponding to both acute clinical malaria episodes and asymptomatic infections experienced by 100 children were included in the study. Non-synonymous SNP data were generated by 454 sequencing for the T-cell epitopes, and repeat length data were generated for the B-cell epitopes of the cs gene. Cox proportional hazards models were used to determine the effect of sequence variation in consecutive infections occurring within individuals on the time to new infection and new clinical malaria episode. Diversity in the T-cell epitope-encoding regions Th2R and Th3R remained stable throughout seasons, between age groups and between clinical and asymptomatic infections with the exception of a higher proportion of 3D7 haplotypes found in the oldest age group. No associations between sequence variation and hazard of infection or clinical malaria were detected. The lack of association between sequence variation and hazard of infection or clinical malaria suggests that naturally acquired immunity to CSP may not be allele-specific.

Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa

BackgroundImproved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).MethodsThe study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.ResultsWe identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.ConclusionsRNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Genomic polymorphism of CD209 gene is associated with sickle cell disease in African children (HUM2P.328)

Abstract Sickle cell disease (SCD) presents with multiple complications and marked variability in severity among individuals and possible underlying differences in ethnic-specific disease pathogenesis. The CD209 gene otherwise called DC-SIGN encodes a transmembrane receptor and is expressed on the surface of dendritic cells with multiple studies showing association between its variants and susceptibility to infections. In SCD, vaso-occlusive crises and infections are common occurrences, and the role of CD209 is currently unknown. We examined the genotypic and allelic diversity of CD209 gene and determined its association with SCD in African children. Genomic DNA from 145 children (HbSS) and 244 controls (HbAA) were analyzed for polymorphic variants of CD209 by PCR-RFLP. All SNPs follow Hardy-Weinberg equilibrium (P&amp;gt;0.05). There was a significant difference in both genotypic and allelic frequencies (P=0.004 and P=0.015 respectively) of a promoter variant in CD209, DC-SIGN1-336 between SCD and controls. Additionally, genotype GG variant is less frequent (10.3% versus 22.1%) and significantly associated with sickle cell disease (OR=0.3868; P=0.0010) and this reduced frequency reveals an impaired or reduced capacity to mount an immune response to infectious pathogens. The implications of this finding for delineating disease co-morbidity or as genetic modifiers of SCD pathophysiology, and its significance in African American children with SCD will be explored

Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: protocol for a systematic review.

BackgroundReports from Africa have suggested that pneumocystis pneumonia (PCP) is a less important cause of morbidity than in the developed world. However, more recent studies have shown high seroprevalence rates of P. jirovecii in healthy individuals with HIV as well as high rates of clinical disease in African children. This suggests that PCP may be more common in Africa than was previously recognised. Understanding the contribution of PCP to disease in HIV-infected individuals in sub-Saharan Africa (SSA) has important implications for diagnosis, management and resource allocation. We therefore propose to conduct a systematic review and meta-analysis in order to investigate the burden of PCP in this population.Methods and designWe plan to search electronic databases and reference lists of relevant articles published from 1995 to May 2013 using broad terms for pneumocystis, HIV/AIDS and sub-Saharan Africa. Studies will be included if they provide clear diagnostic criteria for PCP and well-defined study populations or mortality data (denominator). A novel quality score assessment tool has been developed to ensure fidelity to inclusion criteria, minimise risk of selection bias between reviewers and to assess quality of outcome ascertainment. This will be applied to eligible full-text articles. We will extract data using a standardised form and perform descriptive and quantitative analysis to assess PCP prevalence, mortality and case fatality, as well as the quality of included studies. This review protocol has been published in the PROSPERO International Prospective Register of systematic reviews, registration number CRD42013005530.DiscussionOur planned review will contribute to the diagnosis and management of community-acquired pneumonia in HIV-infected individuals in SSA by systematically assessing the burden of PCP in this population. We also describe a novel quality assessment tool that may be applied to other prevalence reviews.

Morbidity After Antiretroviral Therapy Initiation in HIV-1–Infected Children in West Africa

Although 90% of HIV-1-infected children live in sub-Saharan Africa, morbidity data after highly active antiretroviral therapy (HAART) initiation in these settings are limited. The objective of this study was to document the incidence of AIDS-defining events and non-AIDS-defining diseases in African children receiving HAART. Incidences rates (IRs) of AIDS-defining events and 10 other common diseases were estimated overall and by current CD4-strata (<15%, 15 - <25% and ≥25%) from 2 prospective cohorts of African children. One hundred eighty-eight children contributing to 355 children-years were included. The documented morbidity IRs per 100 children-years were upper respiratory infections, 100 (87-114); infectious diarrhea, 37 (31-44); World Health Organization (WHO) stage 2 events, 22.9 (18.2-28.1); and WHO stage 3/4 events, 12.3 (9.1-16.7). IRs of WHO stage 2 events, severe bacterial infections, infectious diarrhea and pneumonia decreased linearly across all CD4%-strata, whereas WHO stage 3/4 events and viral infections occurred mostly when CD4% <15%. Overall, IRs decreased during the first 2 years on HAART except for upper respiratory infection, mycosis and oral candidiasis. This incidence of AIDS- and non-AIDS-defining diseases declined substantially after HAART in 2 African cohorts, although estimates remained high compared with high-resource settings. Without renewed efforts to increase antiretroviral scale-up, children in developing countries will continue to have a high burden of infections.

Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African Children

Respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Disease severity has been linked to host immune responses and polymorphisms in genes associated with innate immunity. A large-scale genetics study of single nucleotide polymorphisms (SNPs) in children in the Netherlands identified SNPs in the vitamin D receptor (VDR) and JUN genes which have a strong association with an increased risk of developing bronchiolitis following the first respiratory syncytial virus (RSV) infection. The Toll-like receptor 4 (TLR4) gene has two SNPs which have been associated previously with RSV disease severity in various populations. The aim of this study was to determine if these SNPs may be associated with RSV disease in African children in South Africa. RSV patient (n = 296) and control (n = 113) groups were established (median ages: 3 and 3.5 months) and DNA extracted from the collected specimens. Real-time polymerase chain reaction using hydrolysis probes was used to screen for SNPs in the VDR (Thr1Meth; rs10735810), TLR4 (Asp299Gly; rs4986790 and Thr399Ile; rs4986791) and JUN (c.750G/A; rs11688) genes. Carriers of the VDR (Thr1Meth) SNP minor T allele were more prone to RSV disease than individuals in the control group. The TLR4 (Asp299Gly), TLR4 (Thr399Ile), and JUN (c.750G/A) SNPs showed no significant association with RSV disease. It is concluded that children carrying the minor T allele of the VDR (Thr1Meth) SNP may be predisposed to RSV disease, as this SNP was identified as a risk factor for severe RSV disease in South African children, confirming the findings in the Netherlands.

Nontyphoidal salmonellosis in Africa

This review aims to identify and highlight important data published in the past 12 months which provide new information on nontyphoidal salmonellosis in Africa. Recent reviews and clinical studies continue to emphasize the challenges of diagnosis and management of invasive nontyphoidal Salmonellae (NTS) disease as a major cause of mortality in African children and HIV-infected African adults. New observational evidence of the association between malaria and NTS disease in African children has been published. An improved understanding of disease pathogenesis has been provided with evidence of persistent intracellular infection in HIV-infected adults. Multidrug resistance of NTS is now widespread in the region. A novel variant of NTS has emerged which is now a common cause of invasive disease in African populations, and it shows evidence of adaptation to human host and has acquired virulence plasmids along with multidrug resistance. Recent studies have provided original data of the importance of humoral immunity in African children, which informs the development of vaccine. NTS are a major cause of invasive disease in Africa. Recent studies provide a range of helpful insights and novel data which could inform strategies for improving management and especially prevention of this neglected disease.

Burden and Epidemiology of Rotavirus Diarrhea in Selected African Countries: Preliminary Results from the African Rotavirus Surveillance Network

Severe rotavirus diarrhea in children <5 years of age is a major public health problem; however, limited regional and country specific data on rotavirus disease burden are available from sub-Saharan Africa. In June 2006, the World Health Organization Regional Office for Africa initiated rotavirus surveillance in selected African countries. With use of standardized methodology developed by the World Health Organization, children <5 years of age who were hospitalized with severe diarrhea were enrolled, and stool specimens were collected for detection of rotavirus strains with use of a commercial enzyme immunoassay. Rotavirus strains were further characterized for G and P types with use of a reverse-transcriptase polymerase chain reaction. From June 2006 through December 2008, rotavirus surveillance was established at 14 sites in 11 African countries. Of 5461 stool samples collected from children enrolled in 8 countries with 1 or 2 complete years of data, 2200 (40%) were positive for rotavirus. Ninety percent of all rotavirus hospitalizations occurred among children aged 3-12 months. Predominant types included G1P[8] (21%), G2P[4] (7%), and P [8] (29%); however, unusual types were also detected, including G8P[6] (5%), G8P[8] (1%), G12P[6] (1%), and G12P[6] (1%). A high percentage of mixed rotavirus infections was also detected. These preliminary results indicate that rotavirus is a major cause of severe diarrheal disease in African children.

Importance of antibody and complement for oxidative burst and killing of invasive nontyphoidal Salmonella by blood cells in Africans.

Bacteremia caused by nontyphoidal strains of Salmonella is endemic among African children. Case-fatality rates are high and antibiotic resistance increasing, but no vaccine is currently available. T cells are important for clearance of Salmonella infection within macrophages, but in Africa, invasive Salmonella disease usually manifests in the blood and affects children between 4 months and 2 y of age, when anti-Salmonella antibody is absent. We have previously found a role for complement-fixing bactericidal antibody in protecting these children. Here we show that opsonic activity of antibody and complement is required for oxidative burst and killing of Salmonella by blood cells in Africans. Induction of neutrophil oxidative burst correlated with anti-Salmonella IgG and IgM titers and C3 deposition on bacteria and was significantly lower in African children younger than 2 y compared with older children. Preopsonizing Salmonella with immune serum overcame this deficit, indicating a requirement for antibody and/or complement. Using different opsonization procedures, both antibody and complement were found to be necessary for optimal oxidative burst, phagocytosis and killing of nontyphoidal Salmonella by peripheral blood cells in Africans. Although most strains of African nontyphoidal Salmonella can be killed with antibody and complement alone, phagocytes in the presence of specific antibody and complement can kill strains resistant to killing by immune serum. These findings increase the likelihood that an antibody-inducing vaccine will protect against invasive nontyphoidal Salmonella disease in African children.

Rosai-Dorfman Disease in African children

We present a report of Rosai-Dorfman disease in African children, as well as highlight its familial tendency and draw attention to the different orbito/ocular presentations of this disease. An observational case review was performed. Two siblings, one with multiple subcutaneous eye lid nodules in a 12 year old female, and the younger brother who demonstrated a right fungating

Viewpoint: part 2:Wasting disease in African children: the challenges ahead

Malnutrition is an important contributing factor in 5.6 million children who die annually. Severe acute malnutrition (SAM) is a direct cause in 2.7 million deaths . While the clinical syndrome kwashiorkor has impressed clinician and journalist alike, it are stunting, wasting disease and micronutrient diseases like anaemia, vitamin A and iodine deficiency which contribute most to the large global burden of malnutrition (-related) disease . As discussed in part I of this trilogy, 6 decades of understanding of the pathophysiology of severe malnutrition in children has enabled the world community and WHO to develop evidence-based therapeutic guidelines curing most malnourished children . We tend to have become less dogmatic and in anticipation of the many different, often adverse, environments realise why and how children become malnourished. Jackson and Golden defined the varied clinical presentations of malnutrition as determined by the severity, duration and complexity of interactions of specific macro- and micronutrient deficiencies. Both the impact of the nutrient deficits and susceptibility for infection decrease with age, the young being most vulnerable.

Pre-erythrocytic malaria vaccines: towards greater efficacy

The complex life cycle of the malaria parasite Plasmodium falciparum provides many options for vaccine design. Several new types of vaccine are now being evaluated in clinical trials. Recently, two vaccine candidates that target the pre-erythrocytic stages of the malaria life cycle - a protein particle vaccine with a powerful adjuvant and a prime-boost viral-vector vaccine - have entered Phase II clinical trials in the field and the first has shown partial efficacy in preventing malarial disease in African children. This Review focuses on the potential immunological basis for the encouraging partial protection induced by these vaccines, and it considers ways for developing more effective malaria vaccines.

A prospective comparison of malaria with other severe diseases in African children: prognosis and optimization of management.

The burden of malaria in regions of high endemicity frequently overwhelms hospitals' capacity to provide effective care. A rapid, simple method of identifying children who are at highest risk is vital to reduce mortality among hospitalized children. Multiple regression analysis identified prognostic variables predicting mortality in severely ill children admitted to a Ghanaian teaching hospital. These variables were compared in children with and without malaria. A total of 1492 (90.2%) of 1654 severely ill children referred for assessment had evaluable outcomes. Low Blantyre coma score (BCS), high blood lactate level, and high body mass index were independent predictors of mortality among children with malaria (area under the receiver operating characteristic curve [AUC/ROC], 0.84). In children without malaria, BCS and lactate level also predicted mortality, but the addition of respiratory distress and hematocrit improved the model (AUC/ROC, 0.77). Predictors of mortality in children with malaria differ from those for other severe illnesses and reflect differences in underlying pathophysiological processes.