Epidemiology of Human Seasonal Coronaviruses Among People With Mild and Severe Acute Respiratory Illness in Blantyre, Malawi, 2011-2017.

BACKGROUND: The aim of this study was to characterize the epidemiology of human seasonal coronaviruses (HCoVs) in southern Malawi. METHODS: We tested for HCoVs 229E, OC43, NL63, and HKU1 using real-time polymerase chain reaction (PCR) on upper respiratory specimens from asymptomatic controls and individuals of all ages recruited through severe acute respiratory illness (SARI) surveillance at Queen Elizabeth Central Hospital, Blantyre, and a prospective influenza-like illness (ILI) observational study between 2011 and 2017. We modeled the probability of having a positive PCR for each HCoV using negative binomial models, and calculated pathogen-attributable fractions (PAFs). RESULTS: Overall, 8.8% (539/6107) of specimens were positive for ≥1 HCoV. OC43 was the most frequently detected HCoV (3.1% [191/6107]). NL63 was more frequently detected in ILI patients (adjusted incidence rate ratio [aIRR], 9.60 [95% confidence interval {CI}, 3.25-28.30]), while 229E (aIRR, 8.99 [95% CI, 1.81-44.70]) was more frequent in SARI patients than asymptomatic controls. In adults, 229E and OC43 were associated with SARI (PAF, 86.5% and 89.4%, respectively), while NL63 was associated with ILI (PAF, 85.1%). The prevalence of HCoVs was similar between children with SARI and controls. All HCoVs had bimodal peaks but distinct seasonality. CONCLUSIONS: OC43 was the most prevalent HCoV in acute respiratory illness of all ages. Individual HCoVs had distinct seasonality that differed from temperate settings.

School-Based Malaria Screening and Treatment Reduces Plasmodium falciparum Infection and Anemia Prevalence in Two Transmission Settings in Malawi.

BACKGROUND: In areas highly endemic for malaria, Plasmodium falciparum infection prevalence peaks in school-age children, adversely affecting health and education. School-based intermittent preventive treatment reduces this burden but concerns about cost and widespread use of antimalarial drugs limit enthusiasm for this approach. School-based screening and treatment is an attractive alternative. In a prospective cohort study, we evaluated the impact of school-based screening and treatment on the prevalence of P. falciparum infection and anemia in 2 transmission settings. METHODS: We screened 704 students in 4 Malawian primary schools for P. falciparum infection using rapid diagnostic tests (RDTs), and treated students who tested positive with artemether-lumefantrine. We determined P. falciparum infection by microscopy and quantitative polymerase chain reaction (qPCR), and hemoglobin concentrations over 6 weeks in all students. RESULTS: Prevalence of infection by RDT screening was 37% (9%-64% among schools). An additional 9% of students had infections detected by qPCR. Following the intervention, significant reductions in infections were detected by microscopy (adjusted relative reduction [aRR], 48.8%; P < .0001) and qPCR (aRR, 24.5%; P < .0001), and in anemia prevalence (aRR, 30.8%; P = .003). Intervention impact was reduced by infections not detected by RDT and new infections following treatment. CONCLUSIONS: School-based screening and treatment reduced P. falciparum infection and anemia. This approach could be enhanced by repeating screening, using more-sensitive screening tests, and providing longer-acting drugs. CLINICAL TRIALS REGISTRATION: NCT04858087.

Respiratory Virus-Associated Severe Acute Respiratory Illness and Viral Clustering in Malawian Children in a Setting With a High Prevalence of HIV Infection, Malaria, and Malnutrition.

BACKGROUND: We used data from 4 years of pediatric severe acute respiratory illness (SARI) sentinel surveillance in Blantyre, Malawi, to identify factors associated with clinical severity and coviral clustering. METHODS: From January 2011 to December 2014, 2363 children aged 3 months to 14 years presenting to the hospital with SARI were enrolled. Nasopharyngeal aspirates were tested for influenza virus and other respiratory viruses. We assessed risk factors for clinical severity and conducted clustering analysis to identify viral clusters in children with viral codetection. RESULTS: Hospital-attended influenza virus-positive SARI incidence was 2.0 cases per 10 000 children annually; it was highest among children aged <1 year (6.3 cases per 10 000), and human immunodeficiency virus (HIV)-infected children aged 5-9 years (6.0 cases per 10 000). A total of 605 SARI cases (26.8%) had warning signs, which were positively associated with HIV infection (adjusted risk ratio [aRR], 2.4; 95% confidence interval [CI], 1.4-3.9), respiratory syncytial virus infection (aRR, 1.9; 95% CI, 1.3-3.0) and rainy season (aRR, 2.4; 95% CI, 1.6-3.8). We identified 6 coviral clusters; 1 cluster was associated with SARI with warning signs. CONCLUSIONS: Influenza vaccination may benefit young children and HIV-infected children in this setting. Viral clustering may be associated with SARI severity; its assessment should be included in routine SARI surveillance.

Severe Acute Respiratory Illness Deaths in Sub-Saharan Africa and the Role of Influenza: A Case Series From 8 Countries.

BACKGROUND: Data on causes of death due to respiratory illness in Africa are limited. METHODS: From January to April 2013, 28 African countries were invited to participate in a review of severe acute respiratory illness (SARI)-associated deaths identified from influenza surveillance during 2009-2012. RESULTS: Twenty-three countries (82%) responded, 11 (48%) collect mortality data, and 8 provided data. Data were collected from 37 714 SARI cases, and 3091 (8.2%; range by country, 5.1%-25.9%) tested positive for influenza virus. There were 1073 deaths (2.8%; range by country, 0.1%-5.3%) reported, among which influenza virus was detected in 57 (5.3%). Case-fatality proportion (CFP) was higher among countries with systematic death reporting than among those with sporadic reporting. The influenza-associated CFP was 1.8% (57 of 3091), compared with 2.9% (1016 of 34 623) for influenza virus-negative cases (P < .001). Among 834 deaths (77.7%) tested for other respiratory pathogens, rhinovirus (107 [12.8%]), adenovirus (64 [6.0%]), respiratory syncytial virus (60 [5.6%]), and Streptococcus pneumoniae (57 [5.3%]) were most commonly identified. Among 1073 deaths, 402 (37.5%) involved people aged 0-4 years, 462 (43.1%) involved people aged 5-49 years, and 209 (19.5%) involved people aged ≥50 years. CONCLUSIONS: Few African countries systematically collect data on outcomes of people hospitalized with respiratory illness. Stronger surveillance for deaths due to respiratory illness may identify risk groups for targeted vaccine use and other prevention strategies.

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.

Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria?

BACKGROUND: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. METHODS: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. DISCUSSION: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

Surveillance Programme of IN-patients and Epidemiology (SPINE): implementation of an electronic data collection tool within a large hospital in Malawi.

Miguel Sanjoaquin and colleagues describe their experience of setting up an electronic patient records system in a large referral hospital in Blantyre, Malawi.

Protocol for a Magnetic Resonance Imaging (MRI) Study of Participants in the Fever Randomized Controlled Trial: Does fever control prevent brain injury in malaria?

Background: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. Methods: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. Discussion: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

Aggressive antipyretics in central nervous system malaria: Study protocol of a randomized-controlled trial assessing antipyretic efficacy and parasite clearance effects (Malaria FEVER study).

BACKGROUND: Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. METHODS: In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment. DISCUSSION: This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.

School-based screening and treatment may reduce P. falciparum transmission.

In areas where malaria remains entrenched, novel transmission-reducing interventions are essential for malaria elimination. We report the impact screening-and-treatment of asymptomatic Malawian schoolchildren (n = 364 in the rainy season and 341 in the dry season) had on gametocyte-the parasite stage responsible for human-to-mosquito transmission-carriage. We used concomitant household-based surveys to predict the potential reduction in transmission in the surrounding community. Among 253 students with P. falciparum infections at screening, 179 (71%) had infections containing gametocytes detected by Pfs25 qRT-PCR. 84% of gametocyte-containing infections were detected by malaria rapid diagnostic test. While the gametocyte prevalence remained constant in untreated children, treatment with artemether-lumefantrine reduced the gametocyte prevalence (p < 0.0001) from 51.8 to 9.7% and geometric mean gametocyte density (p = 0.008) from 0.52 to 0.05 gametocytes/microliter. In community surveys, 46% of all gametocyte-containing infections were in school-age children, who comprised only 35% of the population. Based on these estimates six weeks after the intervention, the gametocyte burden in the community could be reduced by 25-55% depending on the season and the measure used to characterize gametocyte carriage. Thus, school-based interventions to treat asymptomatic infections may be a high-yield approach to not only improve the health of schoolchildren, but also decrease malaria transmission.

Pilot Study of the Addition of Mass Treatment for Malaria to Existing School-Based Programs to Treat Neglected Tropical Diseases.

Malaria and neglected tropical diseases (NTDs), including schistosomiasis and soil transmitted helminths, threaten the health of school aged in sub-Saharan Africa. Established school-based mass drug administration (MDA) programs are used to control NTDs. Recent clinical trials have shown benefit of mass treatment of malaria in schools. The potential of adding malaria treatment to existing NTD programs has not been thoroughly evaluated. We offered malaria treatment with artemether-lumefantrine during routine NTD MDA and developed peer education programs in two primary schools in southern Malawi. We assessed participation, safety, and tolerability of coadministration of artemether-lumefantrine with praziquantel and albendazole. Results were compared with two schools conducting standard NTD MDA with additional monitoring by study staff. A total of 3,387 students (68%) received the standard NTD MDA. Among parents who came to schools on the day of the MDA, malaria treatment was well accepted; 87% of students who received the standard NTD MDA in intervention schools also consented for treatment with artemether-lumefantrine. The most frequent treatment emergent adverse events (AEs) were headache and vomiting. However, AEs were rare and were not more frequent in students who received artemether-lumefantrine in addition to praziquantel and albendazole. In this study, we found that the addition of malaria treatment to NTD MDA is well-received and safe. Such integrated programs may leverage existing infrastructures to reduce intervention costs and could become the framework for further integrated school-based health programs.

Epidemiology of Severe Acute Respiratory Illness and Risk Factors for Influenza Infection and Clinical Severity among Adults in Malawi, 2011-2013.

Data on the epidemiology of severe acute respiratory illness (SARI) in adults from low-income, high human immunodeficiency virus (HIV) prevalence African settings are scarce. We conducted adult SARI surveillance in Blantyre, Malawi. From January 2011 to December 2013, individuals aged ≥ 15 years with SARI (both inpatients and outpatients) were enrolled at a large teaching hospital in Blantyre, Malawi. Nasopharyngeal aspirates were tested for influenza and other respiratory viruses by polymerase chain reaction. We estimated hospital-attended influenza-positive SARI incidence rates and assessed factors associated with influenza positivity and clinical severity (Modified Early Warning Score > 4). We enrolled 1,126 SARI cases; 163 (14.5%) were positive for influenza. Human immunodeficiency virus prevalence was 50.3%. Annual incidence of hospital-attended influenza-associated SARI was 9.7-16.8 cases per 100,000 population. Human immunodeficiency virus was associated with a 5-fold greater incidence (incidence rate ratio 4.91, 95% confidence interval [CI]: 3.83-6.32). On multivariable analysis, female gender, as well as recruitment in hot, rainy season (December to March; adjusted odds ratios (aOR): 2.82, 95% CI: 1.57-5.06) and cool, dry season (April to August; aOR: 2.47, 95% CI: 1.35-4.15), was associated with influenza positivity, whereas influenza-positive patients were less likely to be HIV-infected (aOR: 0.59, 95% CI: 0.43-0.80) or have viral coinfection (aOR: 0.51, 95% CI: 0.36-0.73). Human immunodeficiency virus infection (aOR: 1.86; 95% CI: 1.35-2.56) and recruitment in hot, rainy season (aOR: 4.98, 95% CI: 3.17-7.81) were independently associated with clinical severity. In this high HIV prevalence population, influenza was associated with nearly 15% of hospital-attended SARI. Human immunodeficiency virus infection is an important risk factor for clinical severity in all-cause and influenza-associated SARI. Expanded access to HIV testing and antiretroviral treatment, as well as targeted influenza vaccination, may reduce the burden of SARI in Malawi and other high HIV prevalence settings.