Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi.

BACKGROUND: Cerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi. METHODS: This retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome. RESULTS: A total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007-1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986-1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983-0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993-1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090-1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973-1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome. CONCLUSIONS: In Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome.

The effect of local variation in malaria transmission on the prevalence of sulfadoxine-pyrimethamine resistant haplotypes and selective sweep characteristics in Malawi.

BACKGROUND: Persistence of sulfadoxine-pyrimethamine (SP) resistance has been described in an urban setting in Malawi where malaria transmission is relatively low. Higher malaria transmission is associated with greater genetic diversity and more frequent genetic recombination, which could lead to a more rapid re-emergence of SP-sensitive parasites, as well as more rapid degradation of selective sweeps. In this study, the impact of local variation in malaria transmission on the prevalence of SP-resistant haplotypes and selective sweep characteristics was investigated at an urban site with low parasite prevalence and two rural sites with moderate and high parasite prevalence. METHODS: Samples from three sites with different parasite prevalence were genotyped for resistance markers within pfdhfr-ts and pfdhps and at microsatellites flanking these genes. Expected heterozygosity (He) was estimated to evaluate genetic diversity. RESULTS: No difference in the prevalence of highly resistant DHFR 51I/59R/108N and DHPS 437G/540E was found between sites. Small differences in He flanking pfdhfr-ts and pfdhps were seen between rural-moderate and the other sites, as well as some shared haplotypes between the rural-high and urban-low sites. CONCLUSIONS: The results do not show an effect of local variation in malaria transmission, as inferred from parasite prevalence, on SP-resistant haplotype prevalence.

Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection.

Some children with uncomplicated malaria progress to cerebral malaria despite appropriate treatment; identifying them in advance might improve their care. The objective of this study was to determine if plasma concentrations of a malaria protein, HRP2 (histidine-rich protein 2) would serve this purpose. Cases and controls were children presenting with uncomplicated malaria; the cases (n = 25) developed cerebral malaria, and the controls (n = 125) did not. Mean plasma HRP2 concentrations were significantly higher in the cases, and an HRP2 cutoff was identified that could predict disease progression (sensitivity and specificity, 88% for each). Quantitative measurements of HRP2 may be a useful screening tool.

Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial.

Importance: A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae. Objective: To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher. Design, Setting, and Participants: This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023. Intervention: The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher. Main Outcomes and Measures: The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance. Results: Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07). Conclusions and Relevance: This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia. Trial Registration: ClinicalTrials.gov Identifier: NCT03399318.

Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children.

BACKGROUND: Brain histology and ophthalmoscopy suggest that approximately 25% of children with World Health Organization-defined cerebral malaria (CM) have a nonmalarial cause of death. Misclassification complicates clinical care, confounds studies of association, and may obfuscate successes in malaria control. Retinopathy predicts intracerebral parasite sequestration with >90% sensitivity and specificity, but detecting retinopathy requires well-trained personnel and expensive equipment. METHODS: We investigated the utility of plasma concentrations of parasite histidine-rich protein 2 (pHRP2), a Plasmodium-specific protein, as a predictor of intracerebral parasite sequestration at autopsy and of malaria retinopathy on clinical examination in patients with clinically defined CM. RESULTS: In 64 autopsy cases, 47 of whom had histological evidence of sequestration, the sensitivity and specificity of a plasma pHRP2 level of >1700 ng/mL were 98% and 94%, respectively, and the area under the receiver operating characteristic (AUROC) curve was 0.98. In a separate, prospectively studied group of 101 children with clinically defined CM, of whom 71 had retinopathy, the same pHRP2 cutoff predicted retinopathy-positivity with a sensitivity of 90% and specificity of 87% (AUROC, 0.90). CONCLUSIONS: Elevated plasma pHRP2 concentrations can identify Malawian children with histologically confirmed or retinopathy-positive CM and is a more field-friendly approach to confirming the diagnosis than post mortem sampling or ophthalmoscopy.

Capacity Building in Pediatric Critical Care-Global Health Research and Education: The Blantyre Experience.

Pediatric critical care medicine (PCCM), as it is practiced in high-income countries, is focused on specialized medical care for the most vulnerable pediatric patient populations. However, best practices for provision of that care globally are lacking. Thus, PCCM research and education programming can potentially fill significant knowledge gaps by facilitating the development of evidence-based clinical guidelines that reduce child mortality on a global scale. Malaria remains a leading cause of pediatric mortality worldwide. The Blantyre Malaria Project (BMP) is a research and clinical care collaborative that has focused on reducing the public health burden of pediatric cerebral malaria in Malawi since 1986. In 2017, the requirements of a new research study led to the creation of PCCM services in Blantyre, creating the opportunity to establish a PCCM-Global Health Research Fellowship by BMP in collaboration with the University of Maryland School of Medicine. In this perspective piece, we reflect on the evolution of the PCCM-Global Health research fellowship. Although the specifics of this fellowship are out of the scope of this perspective, we discuss the context allowing for the development of this program and explore some early lessons learned to consider for future capacity-building efforts in the future of PCCM-Global Health research.

Overdiagnosis of Malaria Illness in an Endemic Setting: A Facility-Based Surveillance Study in Malawi.

In endemic settings where asymptomatic malaria infections are common, malaria infection can complicate fever diagnosis. Factors influencing fever misdiagnosis, including accuracy of malaria rapid diagnostic tests (mRDTs) and the malaria-attributable fraction of fevers (MAF), require further investigation. We conducted facility-based surveillance in Malawi, from January 2012 through December 2013 in settings of high perennial (Chikhwawa), high seasonal (Thoylo), and moderate seasonal (Ndirande) malaria transmission. Consecutive patients presenting to outpatient departments were screened; those with suspected malaria illness were tested by mRDT or routine thick-smear microscopy. Test positivity rates (TPRs), positive predictive value (PPVs) of mRDTs, and MAFs were calculated by site, age, and season. Of 41,471 patients, 10,052 (24.2%) tested positive for malaria. The TPR was significantly greater in Chikhwawa (29.9%; 95% CI, 28.6-30.0) compared with Thyolo (13.2%; 95% CI, 12.5-13.7) and Ndirande (13.1%; 95% CI, 12.2-14.4). The overall PPV was 77.8% (95% CI, 76.8-78.7); it was lowest among infants (69.9%; 95% CI, 65.5-74.2) and highest among school-age children (81.9%; 95% CI, 80.3-83.4). Malaria infection accounted for about 50% of fevers in children younger than 5 years old with microscopy-confirmed Plasmodium falciparum infection, and less than 20% of such fevers in school-age children. Outpatient settings in Malawi had a high burden of malaria illness, but also possible overdiagnosis of malaria illness. Interventions to reduce malaria transmission and rapid testing for other common febrile illness may improve diagnostic clarity among outpatients in malaria endemic settings.

Prevalence and Clinical Management of Non-malarial Febrile Illnesses among Outpatients in the Era of Universal Malaria Testing in Malawi.

Increasing access to rapid diagnostic tests for malaria (mRDTs) has raised awareness of the challenges healthcare workers face in managing non-malarial febrile illnesses (NMFIs). We examined NMFI prevalence, clinical diagnoses, and prescribing practices in outpatient clinics across different malaria transmission settings in Malawi. Standardized facility-based malaria surveillance was conducted at three facilities one of every 4 weeks over 2 years. Information on demographics, presenting symptoms, temperature, clinical diagnosis, and treatment were collected from outpatients presenting with malaria-like symptoms. Of the 25,486 patients with fever, 69% had NMFI. Non-malarial febrile illness prevalence was lower in 5- to 15-year-old patients (55%) than in children < 5 years (72%) and adults > 15 years of age (77%). The most common clinical diagnoses among febrile patients with negative mRDTs in all age-groups and settings were respiratory infections (46%), sepsis (29%), gastroenteritis (13%), musculoskeletal pain (9%), and malaria (5%). Antibiotic prescribing was high in all age-groups and settings. Trimethoprim-sulfamethoxazole (40%) and amoxicillin (29%) were the most commonly prescribed antibiotics and were used for nearly all clinical diagnoses. In these settings with minimal access to diagnostic tools, patients with fever and a negative mRDT received a limited number of clinical diagnoses. Many were likely to be inaccurate and were associated with the inappropriate use of the limited range of available antibiotics. Prescription and diagnostic practices for NMFIs in the facilities require research and policy input. Resource-limited malaria-endemic countries urgently need more point-of-care diagnostic tools and evidence-based diagnosis and treatment algorithms to provide effective and cost-efficient care.

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.

Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/µl) and uncomplicated malaria (3,700/µl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/µl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.

Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children.

We investigated the benefit of 2 candidate adjunctive therapies in bacterial meningitis: glycerol, which has shown promise in earlier studies, and acetaminophen, which is reportedly beneficial in adult septicemia. In a hospital in Blantyre, Malawi, we enrolled 360 children aged ≥ 2 months with proven bacterial meningitis (36% HIV infected) in a double-blind, randomized, placebo-controlled trial of glycerol and acetaminophen in a 2 × 2 factorial design. Of 4 groups, first group received oral glycerol, second received rectal acetaminophen, third received both therapies and the fourth received placebos only. Adjuvant therapies were given for the first 48 hours of antibiotic therapy. Endpoints were mortality and neurological sequelae. Baseline findings were similar across all groups, except that many children had prior antibiotics in the acetaminophen group and many were anemic in the acetaminophen and glycerol group. Outcomes were similar for all groups. We found no benefit from oral glycerol or rectal acetaminophen in, mostly pneumococcal, meningitis in Malawian children.

Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study.

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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Wellcome Trust, US National Institutes of Health, and UK Medical Research Council.