Meta-analysis: Significant effect of malaria-preventive drugs in children

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Use of preventive antimalarial treatments reduces by half the number of malaria infections, among schoolchildren, as well as reducing anaemia, according to a meta-analysis across seven sub-Saharan African countries.

Preventive treatment also reduces cases of anaemia among schoolchildren by 15% and is associated with improved learning in children older than 10 years. The study was the first meta-analysis of its kind and included 15,000 schoolchildren across seven African countries. It was conducted by an international consortium of 33 researchers from 15 institutions led by UMSOM and the London School of Hygiene & Tropical Medicine.

An estimated 3.4bn people worldwide are at risk of contracting malaria, and 400,000 die from the disease every year, according to the World Health Organisation (WHO). While the WHO recommends providing intermittent preventive treatment to pregnant women, infants and young children in some malaria-endemic areas, they have not issued recommendations for school-age children despite growing evidence that use of these preventive mediations works to prevent infections and improve health.

Malaria is transmitted by mosquitoes infected with a parasite and remains prevalent in Africa, Central and South America, and Southeast Asia. Malaria can cause fevers, headache and chills, as well as anaemia due to the parasite’s destruction of red blood cells. Anaemia can cause severe fatigue, headaches, delayed development and poor performance in school. Malaria can also lead to organ failure and can be fatal if left untreated.

“We have overlooked the burden of malaria in school-age children. The resulting chronic illness and anaemia can impair development and lead to cognitive problems making it tougher to pay attention or learn in school,” says lead author Dr Lauren Cohee, an Instructor of Paediatrics and faculty member in the Malaria Research Programme in the Centre for Vaccine Development and Global Health at the University of Maryland School of Medicine. “Children may also play an important role in disease transmission and by treating their infections, we may have substantial public health consequences on the surrounding populations.”

In the journal article, Cohee and her colleagues pointed out that public health campaigns to provide antimalarial medications to school-aged children may also be a way to improve the health and wellness of children, but to curb the disease spread in communities where malaria is endemic.

For their current study, the school-age malaria study group combined data on 15,658 research participants from 11 different clinical studies that tested malaria preventative medications in children ages 5 to 15 years. The children were from seven different countries in sub-Saharan Africa; 8,437 children were given malaria preventives, and 7,221 participants were either not treated or were given a placebo as a control. Doses of preventive drugs were given as often as once a month or as infrequently as once a year depending on the study. The children were monitored for an average of 43-weeks. Six of the clinical trials evaluated cognitive function between children who received the malaria preventives and those who did not.

Preventive malaria drugs can cause side effects such as nausea, vomiting, upset stomach, headache or weakness, and all 11 studies did report instances of these symptoms. No serious side effects, however, were reported in any of the studies.

Cohee noted that preventive treatment of malaria could be added to existing school-based health programs, including nutrition and deworming, to further promote the overall health of the learner. “Utilising schools as a platform to deliver preventive treatment improves the feasibility of this intervention and builds upon the ever-increasing rates of primary school enrolment across the malaria endemic world,” Cohee said.

“More than 200m children in Africa alone are at risk of becoming infected with malaria and in some regions more than 50% of them will ultimately contract it,” says Dr E Albert Reece, executive vice president for medical affairs, University of Maryland Baltimore, and the John Z and Akiko K Bowers distinguished professor and dean, University of Maryland School of Medicine. “We must continue to promote research-based interventions that will improve the health and wellness of our world’s children.”

Abstract
Background: The burden of malaria infection in sub-Saharan Africa among school-aged children aged 5–15 years is underappreciated and represents an important source of human-to-mosquito transmission of Plasmodium falciparum. Additional interventions are needed to control and eliminate malaria. We aimed to assess whether preventive treatment of malaria might be an effective means of reducing P falciparum infection and anaemia in school-aged children and lowering parasite transmission.
Methods: In this systematic review and two meta-analyses, we searched the online databases PubMed, Embase, Cochrane CENTRAL, and Clinicaltrials.gov for intervention studies published between Jan 1, 1990, and Dec 14, 2018. We included randomised studies that assessed the effect of antimalarial treatment among asymptomatic school-aged children aged 5–15 years in sub-Saharan Africa on prevalence of P falciparum infection and anaemia, clinical malaria, and cognitive function. We first extracted data for a study-level meta-analysis, then contacted research groups to request data for an individual participant data meta-analysis. Outcomes of interest included prevalence of P falciparum infection detected by microscopy, anaemia (study defined values or haemoglobin less than age-adjusted and sex-adjusted values), clinical malaria (infection and symptoms on the basis of study-specific definitions) during follow-up, and code transmission test scores. We assessed effects by treatment type and duration of time protected, and explored effect modification by transmission setting. For study-level meta-analysis, we calculated risk ratios for binary outcomes and standardised mean differences for continuous outcomes and pooled outcomes using fixed-effect and random-effects models. We used a hierarchical generalised linear model for meta-analysis of individual participant data. This study is registered with PROSPERO, CRD42016030197.
Findings: Of 628 studies identified, 13 were eligible for the study-level meta-analysis (n=16 309). Researchers from 11 studies contributed data on at least one outcome (n=15 658) for an individual participant data meta-analysis. Interventions and study designs were highly heterogeneous; overall risk of bias was low. In the study-level meta-analysis, treatment was associated with reductions in P falciparum prevalence (risk ratio [RR] 0·27, 95% CI 0·17–0·44), anaemia (0·77, 0·65–0·91), and clinical malaria (0·40, 0·28–0·56); results for cognitive outcomes are not presented because data were only available for three trials. In our individual participant data meta-analysis, we found treatment significantly decreased P falciparum prevalence (adjusted RR [ARR] 0·46, 95% CI 0·40–0·53; p<0·0001; 15 648 individuals; 11 studies), anaemia (ARR 0·85, 0·77–0·92; p<0·0001; 15 026 individuals; 11 studies), and subsequent clinical malaria (ARR 0·50, 0·39–0·60; p<0·0001; 1815 individuals; four studies) across transmission settings. We detected a marginal effect on cognitive function in children older than 10 years (adjusted mean difference in standardised test scores 0·36, 0·01–0·71; p=0·044; 3962 individuals; five studies) although we found no significant effect when combined across all ages.
Interpretation: Preventive treatment of malaria among school-aged children significantly decreases P falciparum prevalence, anaemia, and risk of subsequent clinical malaria across transmission settings. Policy makers and programme managers should consider preventive treatment of malaria to protect this age group and advance the goal of malaria elimination, while weighing these benefits against potential risks of chemoprevention.
Funding: US National Institutes of Health and Burroughs Wellcome Fund/ASTMH Fellowship.

Authors
Lauren M Cohee, Charles Opondo, Siân E Clarke, Katherine E Halliday, Jorge Cano, Andrea G Shipper, Breanna Barger-Kamate, Abdoulaye Djimde, Seybou Diarra, Aditi Dokras, Moses R Kamya, Pascal Lutumba, Alioune Badara Ly, Joaniter I Nankabirwa, J Kiambo Njagi, Hamma Maiga, Catherine Maiteki-Sebuguzi, Junior Matangila, George Okello, Fabian Rohner, Natalie Roschnik, Saba Rouhani, Mahamadou S Sissoko, Sarah G Staedke, Mahamadou A Thera, Elizabeth L Turner, JP Van Geertruyden, Michael B Zimmerman, Matthew C H Jukes, Simon J Brooker, Elizabeth Allen, Miriam K Laufer, R Matthew Chico

 

University of Maryland School of Medicine material

 

The Lancet Global Health full text

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