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Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.

BackgroundLong lasting insecticide-treated bednets (LLINs) are the most widely used tool for preventing malaria. There has been a plateau in progress in the highest burden African countries since 2015, leading to questions about the effectiveness of LLINs. In this study, remote LLIN use monitors were deployed in a cohort in Eastern Uganda to explore how LLIN use interacts with mosquito exposure.MethodsThe SmartNet study included 20 households from May to October 2019. SmartNet devices recorded, every 15 min, whether an LLIN was unfurled or folded up. Unannounced visits were used to assess SmartNet accuracy. Risk factors associated with poor LLIN use were assessed using generalized linear equations. Female Anopheles exposure was estimated by combining hourly probabilities of exposure from human landing catches and measures of density from biweekly CDC light traps in participants rooms. Mosquito exposure averted by LLINs was quantified using SmartNet measurements and age-related differences were estimated using generalized linear equations, adjusting for relevant covariates and household clustering.Results96 individuals contributed 5,640 SmartNet observation nights. In 126 unannounced visits, SmartNet had an area under the curve of 0.869 in classifying whether the LLIN was up or down. The rate of non-use was 13.5% of nights (95% CI: 12.6–14.3%). Compared to children under 5, non-use was 1.8 times higher (95% CI: 1.6–2.1; p < 0.001) in children 5–15 years and 2.6 times higher (95% CI: 2.2–3.1; p < 0.001) in participants aged 15– 30 years. LLIN use averted 50.3% of female Anopheles mosquito exposure (95% CI: 40.0–60.0%), with decreasing point estimates of efficacy across age groups: from 61.7% (95% CI: 42.6–80.7%) in children under 5 years to 48.0% (95% CI: 29.1–66.8%) in adults over 30.ConclusionsObjective monitors are accurate and can feasibly be deployed to obtain data about LLIN use. LLINs provided protection from only 50% of female Anopheles mosquito exposure in this cohort and protection was dependent upon age. In assessing the role of LLINs in malaria prevention it is crucial to consider the dynamics between mosquito exposure and LLIN use behaviors.

Background The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. Methods Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. Results Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. Conclusions Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.

Additional file 2: List L1. List of included studies. Table S1. Summary of characteristics of included studies.

Additional file 3: Table S2. Baseline characteristics of patients in the analysis of haematological response. Table S3. Association between haemoglobin change and baseline value. Table S4. Bi-variable analysis of factors associated with drop in haemoglobin on Day 7. Table S5. Bi-variable analysis of factors associated with anaemia on Day 7. Table S6. Univariable analysis of recovery from anaemia. Table S7. Haemoglobin measurements in patients with severe anaemia at any time. Table S8. Baseline characteristics of patients included in the analysis of adverse events. Table S9. Listing of Serious Adverse Events reported in any study. Table S10. Baseline characteristics of patients included in the analysis of haemoglobinuria. Table S11. Univariable analysis for haemoglobinuria. Table S12. Multivariable model of change in haemoglobin on Day 7 in sub-Saharan Africa. Fig. S1. Map of study sites. Fig. S2. Haemoglobin in G6PD deficient patients not included in the Day 7 analysis. Fig. S3. Relationship between haemoglobin at baseline and Day 7 as absolute change. Fig. S4. Relationship between haemoglobin at baseline and Day 7 as fractional change Fig. S5. Relationship between baseline parasitaemia and haematological endpoints. Fig. S6. Dose response relationship for haematological endpoints. Fig. S7. Time to recovery by day when anaemia was first recorded. Fig. S8. Meta-analysis of odds of haemoglobinuria after PQ administration. Fig. S9. Distribution of parasitaemia (observed) used in the simulation study. Figure S10- Predicted risk of severe anaemia (Hb

Additional file 4: Table S13. Risk of bias assessment. Table S14. Individual participant data not available. Fig. S12. Sensitivity analysis for the main haematological results.