Publications by authors named "Daniel Chandramohan"

206 Publications

The Anti-Circumsporozoite Antibody Response Of Children To Seasonal Vaccination With The Rts,S/As01e Malaria Vaccine.

Clin Infect Dis 2021 Dec 11. Epub 2021 Dec 11.

London School of Hygiene and Tropical Medicine, London, UK.

Background: A trial in young African children showed that combining seasonal vaccination with the RTS,S/AS01E vaccine with seasonal malaria chemoprevention reduced the incidence of uncomplicated and severe malaria substantially compared to either intervention given alone. This paper reports the anti-circumsporozoite antibody response to seasonal RTS,S/AS01E vaccination in children in this trial.

Methods: Sera from a randomly selected sub-set of children collected before and one month after three priming doses of RTS,S/AS01E and before and one month after two seasonal booster doses were tested for anti-circumsporozoite antibodies by ELISA. The association between post vaccination antibody titer and incidence of malaria was explored.

Results: A strong anti-circumsporozoite antibody response to three priming doses of RTS,S/AS01E was seen (Geometric Mean Titer, GMT 368.9 EU/ml) but titers fell markedly prior to the first booster dose. A strong antibody response to an annual, pre-malaria transmission season booster dose was observed in primed children but this was lower than after the primary vaccination series and lower after the second than after the first booster dose (ratio of geometric mean rise 0.66 [95% CI: 0.57, 0.77]). Children whose antibody response was in the upper tercile post-vaccination had a lower incidence of malaria during the following year than children in the lowest tercile (hazard ratio 0.43 [95% CI 0.28,0.66].

Conclusion: Seasonal vaccination with RTS,S/AS01E induced a strong booster antibody response which was lower after the second than after the first booster dose. However, the diminished antibody response to the second booster dose was not associated with diminished efficacy.
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http://dx.doi.org/10.1093/cid/ciab1017DOI Listing
December 2021

Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.

EClinicalMedicine 2021 Nov 25;41:101160. Epub 2021 Oct 25.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.

Background: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections.

Methods: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789.

Findings: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57).

Interpretation: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections.

Funding: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.
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http://dx.doi.org/10.1016/j.eclinm.2021.101160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556518PMC
November 2021

Impact of mass administration of azithromycin as a preventive treatment on the prevalence and resistance of nasopharyngeal carriage of Staphylococcus aureus.

PLoS One 2021 13;16(10):e0257190. Epub 2021 Oct 13.

Institut de Recherche en Sciences de la Santé (IRSS), Direction Régionale de l'Ouest (DRO), Bobo-Dioulasso, Burkina Faso.

Staphylococcus aureus is a major cause of serious illness and death in children, indicating the need to monitor prevalent strains, particularly in the vulnerable pediatric population. Nasal carriage of S. aureus is important as carriers have an increased risk of serious illness due to systemic invasion by this pathogen and can transmit the infection. Recent studies have demonstrated the effectiveness of azithromycin in reducing the prevalence of nasopharyngeal carrying of pneumococci, which are often implicated in respiratory infections in children. However, very few studies of the impact of azithromycin on staphylococci have been undertaken. During a clinical trial under taken in 2016, nasal swabs were collected from 778 children aged 3 to 59 months including 385 children who were swabbed before administration of azithromycin or placebo and 393 after administration of azithromycin or placebo. Azithromycin was given in a dose of 100 mg for three days, together with the antimalarials sulfadoxine-pyrimethamine and amodiaquine, on four occasions at monthly intervals during the malaria transmission season. These samples were cultured for S. aureus as well as for the pneumococcus. The S. aureus isolates were tested for their susceptibility to azithromycin (15 g), penicillin (10 IU), and cefoxitine (30 g) (Oxoid Ltd). S. aureus was isolated from 13.77% (53/385) swabs before administration of azithromycin and from 20.10% (79/393) six months after administration (PR = 1.46 [1.06; 2.01], p = 0.020). Azithromycin resistance found in isolates of S. aureus did not differ significantly before and after intervention (26.42% [14/53] vs 16.46% [13/79], (PR = 0.62 [0.32; 1.23], p = 0.172). Penicillin resistance was very pronounced, 88.68% and 96.20% in pre-intervention and in post-intervention isolates respectively, but very little Methicillin Resistance (MRSA) was detected (2 cases before and 2 cases after intervention). Monitoring antibiotic resistance in S. aureus and other bacteria is especially important in Burkina Faso due to unregulated consumption of antibiotics putting children and others at risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257190PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513893PMC
November 2021

Exploring Barriers and Facilitators of Adherence to Artemisinin-Based Combination Therapies for the Treatment of Uncomplicated Malaria in Children in Freetown, Sierra Leone.

Healthcare (Basel) 2021 Sep 18;9(9). Epub 2021 Sep 18.

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

Medication adherence is an essential step in the malaria treatment cascade. We conducted a qualitative study embedded within a randomized controlled trial comparing the adherence to the recommended dosing of two artemisinin-based combination therapies (ACT) to treat uncomplicated malaria in Freetown, Sierra Leone. This study explored the circumstances and factors that influenced caregiver adherence to the ACT prescribed for their child in the trial. In-depth interviews were conducted with 49 caregivers; all interviews were recorded, transcribed, and translated. Transcripts were coded and aggregated into themes, applying a thematic content approach. We identified four key factors that influenced optimal treatment adherence: (1) health system influences, (2) health services, (3) caregivers' experiences with malaria illness and treatment, and (4) medication characteristics. Specifically, caregivers reported confidence in the health system as facilities were well maintained and care was free. They also felt that health workers provided quality care, leading them to trust the health workers and believe the test results. Ease of medication administration and perceived risk of side effects coupled with caregivers' prior experience treating malaria influenced how medications were administered. To ensure ACTs achieve maximum effectiveness, consideration of these contextual factors and further development of child-friendly antimalarials are needed.
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http://dx.doi.org/10.3390/healthcare9091233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471195PMC
September 2021

Combining malaria vaccination with chemoprevention: a promising new approach to malaria control.

Malar J 2021 Sep 6;20(1):361. Epub 2021 Sep 6.

London School of Hygiene and Tropical Medicine, London, UK.

Malaria control has stalled in a number of African countries and novel approaches to malaria control are needed for these areas. The encouraging results of a recent trial conducted in young children in Burkina Faso and Mali in which a combination of the RTS,S/AS01 malaria vaccine and seasonal malaria chemoprevention led to a substantial reduction in clinical cases of malaria, severe malaria, and malaria deaths compared with the administration of either intervention given alone suggests that there may be other epidemiological/clinical situations in which a combination of malaria vaccination and chemoprevention could be beneficial. Some of these potential opportunities are considered in this paper. These include combining vaccination with intermittent preventive treatment of malaria in infants, with intermittent preventive treatment of malaria in pregnancy (through vaccination of women of child-bearing age before or during pregnancy), or with post-discharge malaria chemoprevention in the management of children recently admitted to hospital with severe anaemia. Other potential uses of the combination are prevention of malaria in children at particular risk from the adverse effects of clinical malaria, such as those with sickle cell disease, and during the final stages of a malaria elimination programme when vaccination could be combined with repeated rounds of mass drug administration. The combination of a pre-erythrocytic stage malaria vaccine with an effective chemopreventive regimen could make a valuable contribution to malaria control and elimination in a variety of clinical or epidemiological situations, and the potential of this approach to malaria control needs to be explored.
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http://dx.doi.org/10.1186/s12936-021-03888-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419817PMC
September 2021

Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention.

N Engl J Med 2021 09 25;385(11):1005-1017. Epub 2021 Aug 25.

From the London School of Hygiene and Tropical Medicine, London (D.C., M.C., I.K., P.S., P.M., B.G.); Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso (I.Z., R.-S.Y., F.N., F.S., C.Z., A.H., A.-A.S., H.T., J.-B.O.); the Malaria Research and Training Center, University of Sciences, Technologies, and Techniques of Bamako, Bamako, Mali (I.S., M.D., A.T., D.I., K.S., M.K., S.T., A.M., I.T., K.D., A. Dolo, A. Djimde, A. Dicko); PATH, Seattle (C.O.); and GlaxoSmithKline Vaccines, Rixensart, Belgium (O.O.-A.).

Background: Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa.

Methods: We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01 was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes.

Results: We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01 (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01 (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01 as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively.

Conclusions: Administration of RTS,S/AS01 was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).
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http://dx.doi.org/10.1056/NEJMoa2026330DOI Listing
September 2021

Effectiveness of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) in Ghana.

BMJ Glob Health 2021 08;6(8)

Department of Disease Control, London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, UK.

Introduction: Ghana adopted the revised WHO recommendation on intermittent preventive treatment in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in 2012. This study has assessed the effectiveness and safety of this policy in Ghana.

Methods: A total of 1926 pregnant women enrolled at antenatal care (ANC) clinics were assessed for birth outcomes at delivery, and placental histology results for malaria infection were obtained from 1642 participants. Association of reduced placental or peripheral malaria, anaemia and low birth weight (LBW) in women who received ≥4 IPTp-SP doses compared with 3 or ≤2 doses was determined by logistic regression analysis.

Results: Among the 1926 participants, 5.3% (103), 19.2% (369), 33.2% (640) and 42.3% (817) of women had received ≤1, 2, 3 or ≥4 doses, respectively. There was no difference in risk of active placental malaria (PM) infection in women who received 3 doses compared with ≥4 doses (adjusted OR (aOR) 1.00, 95% CI 0.47 to 2.14). The risk of overall PM infection was 1.63 (95% CI 1.07 to 2.48) in 2 dose group and 1.06 (95% CI 0.72 to 1.57) in 3 dose group compared with ≥4 dose group. The risk of LBW was 1.55 (95% CI 0.97 to 2.47) and 1.06 (95% CI 0.68 to 1.65) for 2 and 3 dose groups, respectively, compared with the ≥4 dose group. Jaundice in babies was present in 0.16%, and 0% for women who received ≥4 doses of SP.

Conclusion: There was no difference in the risk of PM, LBW or maternal anaemia among women receiving 3 doses compared with ≥4 doses. Receiving ≥3 IPTp-SP doses during pregnancy was associated with a lower risk of overall PM infection compared with 2 doses. As there are no safety concerns, monthly administration of IPTp-SP offers a more practical opportunity for pregnant women to receive ≥3 doses during pregnancy.
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http://dx.doi.org/10.1136/bmjgh-2021-005877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381314PMC
August 2021

Effect of seasonal malaria chemoprevention plus azithromycin on Plasmodium falciparum transmission: gametocyte infectivity and mosquito fitness.

Malar J 2021 Jul 27;20(1):326. Epub 2021 Jul 27.

Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso.

Background: Seasonal malaria chemoprevention (SMC) consists of administration of sulfadoxine-pyrimethamine (SP) + amodiaquine (AQ) at monthly intervals to children during the malaria transmission period. Whether the addition of azithromycin (AZ) to SMC could potentiate the benefit of the intervention was tested through a double-blind, randomized, placebo-controlled trial. The effect of SMC and the addition of AZ, on malaria transmission and on the life history traits of Anopheles gambiae mosquitoes have been investigated.

Methods: The study included 438 children randomly selected from among participants in the SMC + AZ trial and 198 children from the same area who did not receive chemoprevention. For each participant in the SMC + AZ trial, blood was collected 14 to 21 days post treatment, examined for the presence of malaria sexual and asexual stages and provided as a blood meal to An. gambiae females using a direct membrane-feeding assay.

Results: The SMC treatment, with or without AZ, significantly reduced the prevalence of asexual Plasmodium falciparum (LRT X = 69, P < 0.0001) and the gametocyte prevalence (LRT X = 54, P < 0.0001). In addition, the proportion of infectious feeds (LRT X = 61, P < 0.0001) and the prevalence of oocysts among exposed mosquitoes (LRT X = 22.8, P < 0.001) was reduced when mosquitoes were fed on blood from treated children compared to untreated controls. The addition of AZ to SPAQ was associated with an increased proportion of infectious feeds (LRT X = 5.2, P = 0.02), suggesting a significant effect of AZ on gametocyte infectivity. There was a slight negative effect of SPAQ and SPAQ + AZ on mosquito survival compared to mosquitoes fed with blood from control children (LRTX = 330, P < 0.0001).

Conclusion: This study demonstrates that SMC may contribute to a reduction in human to mosquito transmission of P. falciparum, and the reduced mosquito longevity observed for females fed on treated blood may increase the benefit of this intervention in control of malaria. The addition of AZ to SPAQ in SMC appeared to enhance the infectivity of gametocytes providing further evidence that this combination is not an appropriate intervention.
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http://dx.doi.org/10.1186/s12936-021-03855-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314489PMC
July 2021

Nutritional status in young children prior to the malaria transmission season in Burkina Faso and Mali, and its impact on the incidence of clinical malaria.

Malar J 2021 Jun 22;20(1):274. Epub 2021 Jun 22.

Institut de Recherche en Sciences de La Santé, Bobo-Dioulasso, Burkina Faso.

Background: Malaria and malnutrition remain major problems in Sahel countries, especially in young children. The direct effect of malnutrition on malaria remains poorly understood, and may have important implications for malaria control. In this study, nutritional status and the association between malnutrition and subsequent incidence of symptomatic malaria were examined in children in Burkina Faso and Mali who received either azithromycin or placebo, alongside seasonal malaria chemoprevention.

Methods: Mid-upper arm circumference (MUAC) was measured in all 20,185 children who attended a screening visit prior to the malaria transmission season in 2015. Prior to the 2016 malaria season, weight, height and MUAC were measured among 4149 randomly selected children. Height-for-age, weight-for-age, weight-for-height, and MUAC-for-age were calculated as indicators of nutritional status. Malaria incidence was measured during the following rainy seasons. Multivariable random effects Poisson models were created for each nutritional indicator to study the effect of malnutrition on clinical malaria incidence for each country.

Results: In both 2015 and 2016, nutritional status prior to the malaria season was poor. The most prevalent form of malnutrition in Burkina Faso was being underweight (30.5%; 95% CI 28.6-32.6), whereas in Mali stunting was most prevalent (27.5%; 95% CI 25.6-29.5). In 2016, clinical malaria incidence was 675 per 1000 person-years (95% CI 613-744) in Burkina Faso, and 1245 per 1000 person-years (95% CI 1152-1347) in Mali. There was some evidence that severe stunting was associated with lower incidence of malaria in Mali (RR 0.81; 95% CI 0.64-1.02; p = 0.08), but this association was not seen in Burkina Faso. Being moderately underweight tended to be associated with higher incidence of clinical malaria in Burkina Faso (RR 1.27; 95% CI 0.98-1.64; p = 0.07), while this was the case in Mali for moderate wasting (RR 1.27; 95% CI 0.98-1.64; p = 0.07). However, these associations were not observed in severely affected children, nor consistent between countries. MUAC-for-age was not associated with malaria risk.

Conclusions: Both malnutrition and malaria were common in the study areas, high despite high coverage of seasonal malaria chemoprevention and long-lasting insecticidal nets. However, no strong or consistent evidence was found for an association between any of the nutritional indicators and the subsequent incidence of clinical malaria.
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http://dx.doi.org/10.1186/s12936-021-03802-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220741PMC
June 2021

Assessment of syndromic management of curable sexually transmitted and reproductive tract infections among pregnant women: an observational cross-sectional study.

BMC Pregnancy Childbirth 2021 Jan 30;21(1):98. Epub 2021 Jan 30.

Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Background: This study estimated the prevalence of curable sexually transmitted and reproductive tract infections (STIs/RTIs) among pregnant women attending antenatal care (ANC) in rural Zambia, evaluated the effectiveness of syndromic management of STIs/RTIs versus reference-standard laboratory diagnoses, and identified determinants of curable STIs/RTIs during pregnancy.

Methods: A total of 1086 pregnant women were enrolled at ANC booking, socio-demographic information and biological samples were collected, and the provision of syndromic management based care was documented. The Piot-Fransen model was used to evaluate the effectiveness of syndromic management versus etiological testing, and univariate and multivariate logistic regression analyses were used to identify determinants of STIs/RTIs.

Results: Participants had a mean age of 25.6 years and a mean gestational age of 22.0 weeks. Of 1084 women, 700 had at least one STI/RTI (64.6%; 95% confidence interval [CI], 61.7, 67.4). Only 10.2% of infected women received any treatment for a curable STI/RTI (excluding syphilis). Treatment was given to 0 of 56 women with chlamydia (prevalence 5.2%; 95% CI, 4.0, 6.6), 14.7% of participants with gonorrhoea (prevalence 3.1%; 95% CI, 2.2, 4.4), 7.8% of trichomoniasis positives (prevalence 24.8%; 95% CI, 22.3, 27.5) and 7.5% of women with bacterial vaginosis (prevalence 48.7%; 95% CI, 45.2, 51.2). An estimated 7.1% (95% CI, 5.6, 8.7) of participants had syphilis and received treatment. Women < 20 years old were more likely (adjusted odds ratio [aOR] = 5.01; 95% CI: 1.23, 19.44) to have gonorrhoea compared to women ≥30. The odds of trichomoniasis infection were highest among primigravidae (aOR = 2.40; 95% CI: 1.69, 3.40), decreasing with each subsequent pregnancy. Women 20 to 29 years old were more likely to be diagnosed with bacterial vaginosis compared to women ≥30 (aOR = 1.58; 95% CI: 1.19, 2.10). Women aged 20 to 29 and ≥ 30 years had higher odds of infection with syphilis, aOR = 3.96; 95% CI: 1.40, 11.20 and aOR = 3.29; 95% CI: 1.11, 9.74 respectively, compared to women under 20.

Conclusions: Curable STIs/RTIs were common and the majority of cases were undetected and untreated. Alternative approaches are urgently needed in the ANC setting in rural Zambia.
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http://dx.doi.org/10.1186/s12884-021-03573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847014PMC
January 2021

Factors associated with access and adherence to artemisinin-based combination therapy (ACT) for children under five: a secondary analysis of a national survey in Sierra Leone.

Malar J 2021 Jan 21;20(1):56. Epub 2021 Jan 21.

Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: Access and adherence to artemisinin-based combination therapy (ACT) are key challenges to effective malaria treatment. A secondary analysis of the Sierra Leone malaria Knowledge, Attitudes, and Practices (mKAP) survey was conducted to investigate access and adherence to ACT for the treatment of fever in children under-five.

Methods: The mKAP was a nationally representative, two-stage cluster-sample survey, conducted in 2012. Thirty primary sampling units per district were randomly selected using probability proportionate to size, based on national census estimates; 14 households were subsequently randomly selected and enrolled per sampling unit. The analysis was restricted to children under-five with fever in the past two weeks. Factors associated with access and adherence were assessed using multivariate logistic regression.

Results: Of 5169 enrolled households, 1456 reported at least one child under-five with fever in the past two weeks. Of the 1641 children from these households, 982 (59.8%) received any treatment for fever and were analysed for access to ACT; 469 (47.6%) received ACT and 466 were analysed for treatment adherence. Only 222 (47.4%) febrile children received ACT and completed 3-day treatment. In an adjusted analysis, factors associated with ACT access included knowledge of ACT (odds ratio [OR] 2.78, 95% CI 2.02-3.80; p < 0.001), knowledge of insecticide-treated nets (ITNs) (OR 1.84, 95% CI 1.29-2.63; p = 0.001), source of care (public health facility vs. other; OR 1.86, 95% CI 1.27-2.72, p = 0.001), geographic region (East vs. West; OR 2.30, 95% CI 1.20-4.44; p = 0.025), and age (24-59 vs. 0-23 months; OR 1.45, 95% CI 1.07-1.96; p = 0.016). The only factor associated with ACT adherence was time to treatment; children treated within 24 h were less likely to adhere (OR 0.55, 95% CI 0.34-0.89; p = 0.015).

Conclusions: In 2012, access and adherence to ACT remained low in Sierra Leone. Knowledge of ACT and ITNs, and seeking care in the public sector, were most strongly associated with ACT access. National surveys provide important information on anti-malarial access and could be expanded to measure treatment adherence.
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http://dx.doi.org/10.1186/s12936-021-03590-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817959PMC
January 2021

The Duration of Protection from Azithromycin Against Malaria, Acute Respiratory, Gastrointestinal, and Skin Infections When Given Alongside Seasonal Malaria Chemoprevention: Secondary Analyses of Data from a Clinical Trial in Houndé, Burkina Faso, and Bougouni, Mali.

Clin Infect Dis 2021 10;73(7):e2379-e2386

Malaria Research and Training Center, University of Science, Techniques, and Technologies of Bamako, Bamako, Mali.

Background: Mass drug administration (MDA) with azithromycin (AZ) is being considered as a strategy to promote child survival in sub-Saharan Africa, but the mechanism by which AZ reduces mortality is unclear. To better understand the nature and extent of protection provided by AZ, we explored the profile of protection by time since administration, using data from a household-randomized, placebo-controlled trial in Burkina Faso and Mali.

Methods: Between 2014 and 2016, 30 977 children aged 3-59 months received seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine and either AZ or placebo monthly, on 4 occasions each year. Poisson regression with gamma-distributed random effects, accounting for the household randomization and within-individual clustering of illness episodes, was used to compare incidence of prespecified outcomes between SMC+AZ versus SMC+placebo groups in fixed time strata post-treatment. The likelihood ratio test was used to assess evidence for a time-treatment group interaction.

Results: Relative to SMC+placebo, there was no evidence of protection from SMC+AZ against hospital admissions and deaths. Additional protection from SMC+AZ against malaria was confined to the first 2 weeks post-administration (protective efficacy (PE): 24.2% [95% CI: 17.8%, 30.1%]). Gastroenteritis and pneumonia were reduced by 29.9% [21.7; 37.3%], and 34.3% [14.9; 49.3%], respectively, in the first 2 weeks postadministration. Protection against nonmalaria fevers with a skin condition persisted up to 28 days: PE: 46.3% [35.1; 55.6%].

Conclusions: The benefits of AZ-MDA are broad-ranging but short-lived. To maximize impact, timing of AZ-MDA must address the challenge of targeting asynchronous morbidity and mortality peaks from different causes.
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http://dx.doi.org/10.1093/cid/ciaa1905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492219PMC
October 2021

Vitamin D for Growth and Rickets in Stunted Children: A Randomized Trial.

Pediatrics 2021 01 18;147(1). Epub 2020 Dec 18.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, United Kingdom;

Background And Objectives: Vitamin D is essential for healthy development of bones, but little is known about the effects of supplementation in young stunted children. Our objective was to assess the effect of vitamin D supplementation on risk of rickets and linear growth among Afghan children.

Methods: In this double-blind, placebo-controlled trial, 3046 children ages 1 to 11 months from inner-city Kabul were randomly assigned to receive oral vitamin D (100 000 IU) or placebo every 3 months for 18 months. Rickets Severity Score was calculated by using wrist and knee radiographs for 631 randomly selected infants at 18 months, and rickets was defined as a score >1.5. Weight and length were measured at baseline and 18 months by using standard techniques, and scores were calculated.

Results: Mean (95% confidence interval [CI]) serum 25-hydroxyvitamin D (seasonally corrected) and dietary calcium intake were insufficient at 37 (35-39) nmol/L and 372 (327-418) mg/day, respectively. Prevalence of rickets was 5.5% (placebo) and 5.3% (vitamin D): odds ratio 0.96 (95% CI: 0.48 to 1.92); = .9. The mean difference in height-for-age score was 0.05 (95% CI: -0.05 to 0.15), = .3, although the effect of vitamin D was greater for those consuming >300 mg/day of dietary calcium (0.14 [95% CI: 0 to 0.29]; = .05). There were no between-group differences in weight-for-age or weight-for-height scores.

Conclusions: Except in those with higher calcium intake, vitamin D supplementation had no effect on rickets or growth.
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http://dx.doi.org/10.1542/peds.2020-0815DOI Listing
January 2021

Infant sex modifies associations between placental malaria and risk of malaria in infancy.

Malar J 2020 Dec 3;19(1):449. Epub 2020 Dec 3.

Department of Medicine, Stanford University, Stanford, USA.

Background: Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.

Methods: Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0-20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM.

Results: There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.

Conclusion: PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622.
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http://dx.doi.org/10.1186/s12936-020-03522-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713316PMC
December 2020

Epidemiology of malaria among pregnant women during their first antenatal clinic visit in the middle belt of Ghana: a cross sectional study.

Malar J 2020 Oct 23;19(1):381. Epub 2020 Oct 23.

Kintampo Health Research Centre, Ghana Health Service, PO Box 200, Kintampo, Ghana.

Background: Malaria during pregnancy may result in unfavourable outcomes in both mothers and their foetuses. This study sought to document the current burden and factors associated with malaria and anaemia among pregnant women attending their first antenatal clinic visit in an area of Ghana with perennial malaria transmission.

Methods: A total of 1655 pregnant women aged 18 years and above with a gestational age of 13-22 weeks, who attended an antenatal care (ANC) clinic for the first time, were consented and enrolled into the study. A structured questionnaire was used to collect socio-demographic and obstetric data and information on use of malaria preventive measures. Venous blood (2 mL) was collected before sulfadoxine-pyrimethamine administration. Malaria parasitaemia and haemoglobin concentration were determined using microscopy and an automated haematology analyser, respectively. Data analysis was carried out using Stata 14.

Results: Mean age (SD) and gestational age (SD) of women at enrolment were 27.4 (6.2) years and 16.7 (4.3) weeks, respectively. Overall malaria parasite prevalence was 20.4% (95% CI 18.5-22.4%). Geometric mean parasite density was 442 parasites/µL (95% CI 380-515). Among women with parasitaemia, the proportion of very low (1-199 parasites/µL), low (200-999 parasites/µL), medium (1000-9999 parasites/µL) and high (≥ 10,000 parasites/µL) parasite density were 31.1, 47.0, 18.9, and 3.0%, respectively. Age ≥ 25 years (OR 0.57, 95% CI 0.41-0.79), multigravid (OR 0.50, 95% CI 0.33-0.74), educated to high school level or above (OR 0.53, 95% CI 0.33-0.83) and in household with higher socio-economic status (OR 0.34, 95% CI 0.21-0.54) were associated with a lower risk of malaria parasitaemia. The prevalence of anaemia (< 11.0 g/dL) was 56.0%, and the mean haemoglobin concentration in women with or without parasitaemia was 9.9 g/dL or 10.9 g/dL, respectively.

Conclusion: One out of five pregnant women attending their first ANC clinic visit in an area of perennial malaria transmission in the middle belt of Ghana had Plasmodium falciparum infection. Majority of the infections were below 1000 parasites/µL and with associated anaemia. There is a need to strengthen existing malaria prevention strategies to prevent unfavourable maternal and fetal birth outcomes in this population.
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http://dx.doi.org/10.1186/s12936-020-03457-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585211PMC
October 2020

Seasonal malaria vaccination: protocol of a phase 3 trial of seasonal vaccination with the RTS,S/AS01 vaccine, seasonal malaria chemoprevention and the combination of vaccination and chemoprevention.

BMJ Open 2020 09 15;10(9):e035433. Epub 2020 Sep 15.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Seasonal malaria chemoprevention (SMC), with sulphadoxine-pyrimethamine plus amodiaquine (SP+AQ) is effective but does not provide complete protection against clinical malaria. The RTS,S/AS01 malaria vaccine provides a high level of protection shortly after vaccination, but this wanes rapidly. Such a vaccine could be an alternative or additive to SMC. This trial aims to determine whether seasonal vaccination with RTS,S/AS01 vaccine could be an alternative to SMC and whether a combination of the two interventions would provide added benefits.

Methods And Analysis: This is an individually randomised, double-blind, placebo-controlled trial. 5920 children aged 5-17 months were enrolled in April 2017 in Mali and Burkina Faso. Children in group 1 received three priming doses of RTS,S/AS01 vaccine before the start of the 2017 malaria transmission season and a booster dose at the beginning of two subsequent transmission seasons. In addition, they received SMC SP+AQ placebo on four occasions each year. Children in group 2 received three doses of rabies vaccine in year 1 and hepatitis A vaccine in years 2 and 3 together with four cycles of SMC SP+AQ each year. Children in group 3 received RTS,S/AS01 vaccine and four courses of SMC SP+AQ. Incidence of clinical malaria is determined by case detection at health facilities. Weekly active surveillance for malaria is undertaken in a randomly selected subset of children. The prevalence of malaria is measured in surveys at the end of each transmission season. The primary endpoint is the incidence of clinical malaria confirmed by a positive blood film with a minimum parasite density of 5000 /µL. Primary analysis will be by modified intention to treat defined as children who have received the first dose of the malaria or control vaccine.

Ethics And Dissemination: The protocol was approved by the national ethics committees of Mali and Burkina Faso and the London School of Hygiene and Tropical Medicine. The results will be presented to all stakeholders and published in open access journals.

Trial Registration Number: NCT03143218; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-035433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493088PMC
September 2020

Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Houndé District, Burkina Faso and Bougouni District, Mali.

PLoS Med 2020 08 21;17(8):e1003214. Epub 2020 Aug 21.

Malaria Research and Training Centre, Bamako, Mali.

Background: Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Houndé, Burkina Faso and Bougouni, Mali.

Methods And Findings: The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule.

Conclusion: Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology.

Trial Registration: The AZ-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT02211729.
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http://dx.doi.org/10.1371/journal.pmed.1003214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442230PMC
August 2020

Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial.

BMC Med 2020 08 10;18(1):207. Epub 2020 Aug 10.

Department of Medicine, University of California, San Francisco, USA.

Background: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown.

Methods: We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4 weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12 months of life. All analyses were done by modified intention to treat.

Results: Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p = 0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p = 0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p = 0.93).

Conclusion: Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants.

Trial Registration: ClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016.
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http://dx.doi.org/10.1186/s12916-020-01675-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416391PMC
August 2020

Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.

Lancet Infect Dis 2020 08 29;20(8):943-952. Epub 2020 Apr 29.

Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Obstetrics and Gynecology, Division of Woman and Baby, University Medical Center Utrecht, Utrecht, Netherlands.

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women.

Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013.

Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82).

Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Funding: The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.
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http://dx.doi.org/10.1016/S1473-3099(20)30064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391007PMC
August 2020

Serotype Profile of Nasopharyngeal Isolates of Obtained from Children in Burkina Faso before and after Mass Administration of Azithromycin.

Am J Trop Med Hyg 2020 08 4;103(2):679-683. Epub 2020 Jun 4.

Institut de Recherche en Sciences de la Santé (IRSS), Bobo-Dioulasso, Burkina Faso.

Mass drug administration (MDA) with azithromycin (AZ) has been used successfully to control trachoma. However, several studies have shown that MDA with AZ has led to the emergence of resistance to AZ in The emergence of resistance to AZ has also been observed when this antibiotic was combined with the antimalarials used for seasonal malaria chemoprevention (SMC). The development of antibiotic resistance, including resistance to AZ, is sometimes associated with the emergence of a bacterial clone that belongs to a specific serotype. We hypothesize that the increase in resistance of observed after 3 years of SMC with AZ might be associated with a change in the distribution of pneumococcal serotypes. Therefore, 698 randomly selected isolates from among the 1,468 isolates of obtained during carriage studies undertaken during an SMC plus AZ trial were serotyped. A polymerase chain reaction (PCR) multiplex assay using an algorithm adapted to the detection of the pneumococcal serotypes most prevalent in African countries was used for initial serotyping, and the Quellung technique was used to complement the PCR technique when necessary. Fifty-six serotypes were detected among the 698 isolates of . A swift appearance and disappearance of many serotypes was observed, but some serotypes including 6A, 19F, 19A, 23F, and 35B were persistent. The distribution of serotypes between isolates obtained from children who had received AZ or placebo was similar. An increase in AZ resistance was seen in several serotypes following exposure to AZ. Mass drug administration with AZ led to the emergence of resistance in pneumococci of several different serotypes and did not appear to be linked to the emergence of a single serotype.
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http://dx.doi.org/10.4269/ajtmh.19-0944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410481PMC
August 2020

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BMC Med 2020 06 2;18(1):138. Epub 2020 Jun 2.

Institut Pasteur du Cambodge, Phnom Penh, Cambodia.

Background: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection.

Methods: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013.

Results: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001).

Conclusions: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.
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http://dx.doi.org/10.1186/s12916-020-01592-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263905PMC
June 2020

District-level approach for tailoring and targeting interventions: a new path for malaria control and elimination.

Malar J 2020 Mar 30;19(1):125. Epub 2020 Mar 30.

Malaria Elimination Initiative, Global Health Group, University of California, San Francisco, CA, 94158, USA.

Despite huge investments and implementation of effective interventions for malaria, progress has stalled, with transmission being increasingly localized among difficult-to-reach populations and outdoor-biting vectors. Targeting difficult pockets of transmission will require the development of tailored and targeted approaches suited to local context, drawing from insights close to the frontlines. Districts are best placed to develop tailored, locally appropriate approaches. We propose a reorganization of how malaria services are delivered. Firstly, enabling district health officers to serve as conduits between technical experts in national malaria control programmes and local community leaders with knowledge specific to local, at-risk populations; secondly, empowering district health teams to make malaria control decisions. This is a radical shift that requires the national programme to cede some control. Shifting towards a district or provincial level approach will necessitate deliberate planning, and repeated, careful assessment, starting with piloting and learning through experience. Donors will need to alter current practice, allowing for flexible funding to be controlled at sub-national levels, and to mix finances between case management, vector control and surveillance, monitoring and evaluation. System-wide changes proposed are challenging but may be necessary to overcome stalled progress in malaria control and elimination and introduce targeted interventions tailored to the needs of diverse malaria affected populations.
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http://dx.doi.org/10.1186/s12936-020-03185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106871PMC
March 2020

Effect of adding azithromycin to the antimalarials used for seasonal malaria chemoprevention on the nutritional status of African children.

Trop Med Int Health 2020 06 16;25(6):740-750. Epub 2020 Apr 16.

Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso.

Objectives: Mass administration of azithromycin has reduced mortality in children in sub-Saharan Africa but its mode of action is not well characterised. A recent trial found that azithromycin given alongside seasonal malaria chemoprevention was not associated with a reduction in mortality or hospital admissions in young children. We investigated the effect of azithromycin on the nutritional status of children enrolled in this study.

Methods: A total of 19 578 children in Burkina Faso and Mali were randomised to receive either azithromycin or placebo alongside seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine monthly for three malaria transmission seasons (2014-2016). After each transmission season, anthropometric measurements were collected from approximately 4000 randomly selected children (2000 per country) at a cross-sectional survey and used to derive nutritional status indicators. Binary and continuous outcomes between treatment arms were compared by Poisson and linear regression.

Results: Nutritional status among children was poor in both countries with evidence of acute and chronic malnutrition (24.9-33.3% stunted, 15.8-32.0% underweight, 7.2-26.4% wasted). There was a suggestion of improvement in nutritional status in Burkina Faso and deterioration in Mali over the study period. At the end of each malaria transmission season, nutritional status of children did not differ between treatment arms (seasonal malaria chemoprevention plus azithromycin or placebo) in either the intention-to-treat or per-protocol analyses (only children with at least three cycles of SMC in the current intervention year).

Conclusions: The addition of azithromycin to seasonal malaria chemoprevention did not result in an improvement of nutritional outcomes in children in Burkina Faso and Mali.
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http://dx.doi.org/10.1111/tmi.13390DOI Listing
June 2020

Evaluation of Implementation of Intermittent Screening and Treatment for Control of Malaria in Pregnancy in Jharkhand, India.

Am J Trop Med Hyg 2020 06;102(6):1343-1350

National Institute for Malaria Research, Delhi, India.

This study evaluated intermittent screening and treatment during pregnancy (ISTp) for malaria using rapid diagnostic tests (RDTs) at antenatal care (ANC) compared with passive case detection within the routine health system. The mixed-method evaluation included two cross-sectional household surveys (pre- and post-implementation of ISTp), in-depth interviews with health workers, and focus group discussions (FGDs) with pregnant women. Differences in proportions between surveys for a number of outcomes were tested; 553 and 534 current and recently pregnant women were surveyed (pre- and post-implementation, respectively). In-depth interviews were conducted with 29 health providers, and 13 FGDs were held with pregnant women. The proportion of pregnant women who received an RDT for malaria at ANC at least once during their pregnancy increased from pre- to post-implementation (19.2%; 95% CI: 14.9, 24.3 versus 42.5%; 95% CI: 36.6, 48.7; < 0.0001), and the proportion of women who had more than one RDT also increased (16.5%; 95% CI: 13.1, 20.5 versus 27.7%; 95% CI: 23.0, 33.0; = 0.0008). Post-implementation, however, only 8% of women who had completed their pregnancy received an RDT on three visits to ANC. Health workers were positive about ISTp mainly because of their perception that many pregnant women with malaria were asymptomatic. Health workers perceived pregnant women to have reservations about ISTp because of their dislike of frequent blood withdrawal, but pregnant women themselves were more positive. Intermittent screening and treatment during pregnancy was not sufficiently adopted by health workers to ensure the increased detection of malaria infections achievable with this strategy in this setting.
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http://dx.doi.org/10.4269/ajtmh.19-0514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253127PMC
June 2020

Evaluation of a capacity building intervention on malaria treatment for under-fives in rural health facilities in Niger State, Nigeria.

Malar J 2020 Feb 24;19(1):90. Epub 2020 Feb 24.

Disease Control Department, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.

Background: Despite the uptake of parasitological testing into policy and practice, appropriate prescription of anti-malarials and artemisinin-based combination therapy (ACT) in accordance with test results is variable. This study describes a National Malaria Control Programme-led capacity building intervention which was implemented in 10 States of Nigeria. Using the experience of Niger State, this study assessed the effect on malaria diagnosis and prescription practices among febrile under-fives in rural health facilities.

Methods: The multicomponent capacity building intervention consisted of revised case management manuals; cascade training from national to state level carried out at the local government area (LGA) level; and on the job capacity development through supportive supervision. The evaluation was conducted in 28, principally government-owned, health facilities in two rural LGAs of Niger State, one in which the intervention case management of malaria was implemented and the other acted as a comparison area with no implementation of the intervention. Three outcomes were considered in the context of rapid diagnostic testing (RDT) for malaria which were: the prevalence of RDT testing in febrile children; appropriate treatment of RDT-positive children; and appropriate treatment of RDT-negative children. Outcomes were compared post-intervention between intervention and comparison areas using multivariate logistic regression.

Results: The intervention did not improve appropriate management of under-fives in intervention facilities above that seen for under-fives in comparison facilities. Appropriate treatment with artemisinin-based combinations of RDT-positive and RDT-negative under-fives was equally high in both areas. However, appropriate treatment of RDT-negative children, when defined as receipt of no ACT or any other anti-malarials, was better in comparison areas. In both areas, a small number of RDT-positives were not given ACT, but prescribed an alternative anti-malarial, including artesunate monotherapy. Among RDT-negatives, no under-fives were prescribed artesunate as monotherapy.

Conclusion: In a context of significant stock-outs of both ACT medicines and RDTs, under-fives were not more appropriately managed in intervention than comparison areas. The malaria case management intervention implemented through cascade training reached only approximately half of health workers managing febrile under-fives in this setting. Implementation studies on models of cascade training are needed to define what works in what context.
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http://dx.doi.org/10.1186/s12936-020-03167-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041190PMC
February 2020

Proactive case detection of common childhood illnesses by community health workers: a systematic review.

BMJ Glob Health 2019 15;4(6):e001799. Epub 2019 Dec 15.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Identifying design features and implementation strategies to optimise community health worker (CHW) programmes is important in the context of mixed results at scale. We systematically reviewed evidence of the effects of proactive case detection by CHWs in low-income and middle-income countries (LMICs) on mortality, morbidity and access to care for common childhood illnesses.

Methods: Published studies were identified via electronic databases from 1978 to 2017. We included randomised and non-randomised controlled trials, controlled before-after studies and interrupted time series studies, and assessed their quality for risk of bias. We reported measures of effect as study investigators reported them, and synthesised by outcomes of mortality, disease prevalence, hospitalisation and access to treatment. We calculated risk ratios (RRs) as a principal summary measure, with CIs adjusted for cluster design effect.

Results: We identified 14 studies of 11 interventions from nine LMICs that met inclusion criteria. They showed considerable diversity in intervention design and implementation, comparison, outcomes and study quality, which precluded meta-analysis. Proactive case detection may reduce infant mortality (RR: 0.52-0.94) and increase access to effective treatment (RR: 1.59-4.64) compared with conventional community-based healthcare delivery (low certainty evidence). It is uncertain whether proactive case detection reduces mortality among children under 5 years (RR: 0.04-0.80), prevalence of infectious diseases (RR: 0.06-1.02), hospitalisation (RR: 0.38-1.26) or increases access to prompt treatment (RR: 1.00-2.39) because the certainty of this evidence is very low.

Conclusion: Proactive case detection may provide promising benefits for child health, but evidence is insufficient to draw conclusions. More research is needed on proactive case detection with rigorous study designs that use standardised outcomes and measurement methods, and report more detail on complex intervention design and implementation.

Prospero Registration Number: CRD42017074621.
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http://dx.doi.org/10.1136/bmjgh-2019-001799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936477PMC
December 2019

Impact of Plasmodium falciparum malaria and intermittent preventive treatment of malaria in pregnancy on the risk of malaria in infants: a systematic review.

Malar J 2019 Sep 3;18(1):304. Epub 2019 Sep 3.

London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: Studies of the association between malaria in pregnancy (MiP) and malaria during infancy have provided mixed results. A systematic review was conducted to evaluate available evidence on the impact of Plasmodium falciparum malaria infection during pregnancy, and intermittent preventive treatment of malaria during pregnancy (IPTp), on the risk of clinical malaria or parasitaemia during infancy.

Methods: MEDLINE, EMBASE, Global Health, and Malaria in Pregnancy Library databases were searched from inception to 22 May 2018 for articles published in English that reported on associations between MiP and malaria risk in infancy. Search terms included malaria, Plasmodium falciparum, pregnancy, placenta, maternal, prenatal, foetal, newborn, infant, child or offspring or preschool. Randomized controlled trials and prospective cohort studies, which followed infants for at least 6 months, were included if any of the following outcomes were reported: incidence of clinical malaria, prevalence of parasitaemia, and time to first episode of parasitaemia or clinical malaria. Substantial heterogeneity between studies precluded meta-analysis. Thus, a narrative synthesis of included studies was conducted.

Results: The search yielded 14 published studies, 10 prospective cohort studies and four randomized trials; all were conducted in sub-Saharan Africa. Infants born to mothers with parasitaemia during pregnancy were at higher risk of malaria in three of four studies that assessed this association. Placental malaria detected by microscopy or histology was associated with a higher risk of malaria during infancy in nine of 12 studies, but only one study adjusted for malaria transmission intensity. No statistically significant associations between the use of IPTp or different IPTp regimens and the risk of malaria during infancy were identified.

Conclusion: Evidence of an association between MiP and IPTp and risk of malaria in infancy is limited and of variable quality. Most studies did not adequately adjust for malaria transmission intensity shared by mothers and their infants. Further research is needed to confirm or exclude an association between MiP and malaria in infancy. Randomized trials evaluating highly effective interventions aimed at preventing MiP, such as IPTp with dihydroartemisinin-piperaquine, may help to establish a causal association between MiP and malaria in infancy.
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http://dx.doi.org/10.1186/s12936-019-2943-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724246PMC
September 2019

Consequences of restricting antimalarial drugs to rapid diagnostic test-positive febrile children in south-west Nigeria.

Trop Med Int Health 2019 11 3;24(11):1291-1300. Epub 2019 Oct 3.

London School of Tropical Medicine and Hygiene, London, UK.

Objectives: To investigate the consequence of restricting antimalarial treatment to febrile children that test positive to a malaria rapid diagnostic test (MRDT) only in an area of intense malaria transmission.

Methods: Febrile children aged 3-59 months were screened with an MRDT at health facilities in south-west Nigeria. MRDT-positive children received artesunate-amodiaquine (ASAQ), while MRDT-negative children were treated based on the clinical diagnosis of non-malaria febrile illness. The primary endpoint was the risk of developing microscopy-positive malaria within 28 days post-treatment.

Results: 309 (60.5%) of 511 children were MRDT-positive while 202 (39.5%) were MRDT-negative at enrolment. 18.5% (50/275) of MRDT-positive children and 7.6% (14/184) of MRDT-negative children developed microscopy-positive malaria by day 28 post-treatment (ρ = 0.001). The risk of developing clinical malaria by day 28 post-treatment was higher among the MRDT-positive group than the MRDT-negative group (adjusted OR 2.74; 95% CI, 1.4, 5.4). A higher proportion of children who were MRDT-positive at enrolment were anaemic on day 28 compared with the MRDT-negative group (12.6% vs. 3.1%; ρ = 0.001). Children in the MRDT-negative group made more unscheduled visits because of febrile illness than those in MRDT-positive group (23.2% vs. 12.0%; ρ = 0.001).

Conclusion: Restricting ACT treatment to MRDT-positive febrile children only did not result in significant adverse outcomes. However, the risk of re-infection within 28 days was significantly higher among MRDT-positive children despite ASAQ treatment. A longer-acting ACT may be needed as the first-line drug of choice for treating uncomplicated malaria in high-transmission settings to prevent frequent re-infections.
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http://dx.doi.org/10.1111/tmi.13304DOI Listing
November 2019

Effectiveness of intermittent screening and treatment for the control of malaria in pregnancy: a cluster randomised trial in India.

BMJ Glob Health 2019 29;4(4):e001399. Epub 2019 Jul 29.

Department of Disease Control, London School of Hygiene & Tropical Medicine Faculty of Infectious and Tropical Diseases, London, UK.

Background: The control of malaria in pregnancy (MiP) in India relies on testing women who present with symptoms or signs suggestive of malaria. We hypothesised that intermittent screening and treatment for malaria at each antenatal care visit (ISTp) would improve on this approach and reduce the adverse effects of MiP.

Methods: A cluster randomised controlled trial comparing ISTp versus passive case detection (PCD) was conducted in Jharkhand state. Pregnant women of all parities with a gestational age of 18-28 weeks were enrolled. Women in the ISTp group were screened with a rapid diagnostic test (RDT) for malaria at each antenatal clinic visit and those in the PCD group were screened only if they had symptoms or signs suggestive of malaria. All RDT positive women were treated with artesunate/sulfadoxine-pyrimethamine. The primary endpoint was placental malaria, determined by placental histology, and the key secondary endpoints were birth weight, gestational age, vital status of the newborn baby and maternal anaemia.

Results: Between April 2012 and September 2015, 6868 women were enrolled; 3300 in 46 ISTp clusters and 3568 in 41 PCD clusters. In the ISTp arm, 4.9% of women were tested malaria positive and 0.6% in the PCD arm. There was no difference in the prevalence of placental malaria in the ISTp (87/1454, 6.0%) and PCD (65/1560, 4.2%) groups (6.0% vs 4.2%; OR 1.34, 95% CI 0.78 to 2.29, p=0.29) or in any of the secondary endpoints.

Conclusion: ISTp detected more infections than PCD, but monthly ISTp with the current generation of RDT is unlikely to reduce placental malaria or impact on pregnancy outcomes. ISTp trials with more sensitive point-of-care diagnostic tests are needed.
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http://dx.doi.org/10.1136/bmjgh-2019-001399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666812PMC
July 2019
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