Abstract
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.
Background
Malaria remains a major cause of anaemia in malaria endemic countries, with a complex pathogenesis attributable to red cell destruction and haematopoietic suppression [1] that can be compounded by malnutrition, helminth carriage and inherited blood disorders [2]. Artemisinin-based combination therapy (ACT) is the first-line antimalarial treatment for uncomplicated malaria in almost all endemic countries [3], achieving high cure rates, rapid parasite clearance and reduced ongoing transmission of the parasite [4, 5]. However, artemisinin derivatives can suppress reticulocytosis and contribute to haemolysis; their use has been associated with delayed-onset anaemia [6, 7]. The haematological recovery and adverse consequences of the artemisinin derivatives, following the treatment of falciparum malaria, may vary between different ACTs [8].
To assess the comparative benefits of different antimalarial treatment regimens, it is critical to quantify the haematological impact attributable to P. falciparum infection and the clinical and demographic factors that underlie this. The aim of this study was to determine the pattern of haematological recovery following uncomplicated falciparum malaria and define the risk factors for moderately severe haematological outcomes at baseline and during early follow-up.
Methods
The WWARN repository and study selection
Haemoglobin concentrations are often not reported in antimalarial trial publications, even if these data are collected. Since a review of published literature would not provide sufficiently comprehensive information, the focus of this individual patient data meta-analysis was on studies identified in the WWARN repository. The WWARN repository contains data from 451 antimalarial efficacy studies in which patients were enrolled from locations in 69 countries, with a diverse range of P. falciparum transmission intensities. Data in the repository have been standardised and collated using methodology described previously in the WWARN Clinical Module Data Management and Statistical Analysis Plan [9].
The WWARN repository was searched in August 2015 for all antimalarial efficacy studies of uncomplicated P. falciparum malaria in non-pregnant patients that followed subjects prospectively for a minimum of 28 days and reported haemoglobin concentration (or haematocrit) at least at baseline (day 0). Investigators of the identified studies were invited to participate in this study group and information was made available on the WWARN website [10]. Uncomplicated P. falciparum malaria was defined as microscopy-proven falciparum malaria without features of severe malaria [11]. Patients were excluded if they had severe malaria.
Outcomes of interest
The primary outcome of the analysis was the risk of moderately severe anaemia (Hb < 7 g/dL) on day 7 after initiation of treatment. Secondary outcomes included the mean fall in haemoglobin at day of nadir and day 7, the timing of nadir haemoglobin, risk of moderately severe anaemia at days 0 and 3, and the risk of a large reduction in haemoglobin from baseline, defined as a fractional fall in Hb of ≥ 25% on day 3 or 7.
Statistical methods
All statistical analyses were done using R (Version 3.2.5, The R Foundation for Statistical Computing) or Stata MP 15, based on an a priori statistical plan shared with data contributors [10].
Haematocrit measurements were converted to haemoglobin concentrations using the following formula: Haemoglobin = (Haematocrit − 5.62)/2.60 [12]. The timing of sampling was defined as day 0 if occurring on the day of enrolment / first day of treatment, with sequential numbering thereafter. Data were stratified by region (Africa, Asia and South America). Univariable and multivariable mixed effects logistic regression models were used to model risk of (i) moderately severe anaemia on day 0, 3 or 7 and (ii) large reduction in haemoglobin on day 3 or 7. Study site (sites within countries) was included as a random intercept in these models.
Changes in mean haemoglobin over time were examined, after stratifying by region, using linear mixed effects models. Fractional polynomial terms for time were fitted as random effects for patients to capture the nonlinear associations and random intercepts for patients and study site. All available haemoglobin measurements were included in these analyses. Additional analyses of mean haemoglobin over time within each region were undertaken, stratified by age group (< 5 years and ≥ 5 years).
For all regression models, independent risk factors were identified following the strategy recommended by Collet [13]. Covariates examined included the following: age in years (categorised as < 1 year, 1 to 4 years, 5 to 11 years and ≥ 12 years), sex, fever (temperature > 37.5 °C) on enrolment, baseline parasitaemia (after log transformation), mixed Plasmodium species infection, underweight (defined as weight-for-age Z-score <−2 for children younger than 5 years) [14], high parasitaemia (defined as > 100,000 parasites/μL [15]), presence of gametocytaemia on enrolment, transmission intensity, treatment (artemisinin-based therapy versus non-artemisinin-based therapy) and parasite clearance (early clearance on day 1 or day 2 versus delayed parasite clearance on day 3 or later). Red cell indices were not available. Malaria transmission intensity was defined based on estimates of P. falciparum prevalence rate (PfPR) according to enrolment year and location [16], assuming low transmission for study sites with a PfPR < 0.15, moderate transmission if PfPR 0.15 to < 0.40 and high transmission if PfPR ≥ 0.40. Fractional polynomials were used to define the nonlinear relationships between outcome and continuous covariates.
Ethics
All data included in this analysis were obtained in accordance with ethical approvals from the countries of origin. The data are fully anonymised and cannot be traced back to individuals. This analysis did not require separate ethical approval according to the guidelines of the Oxford Central University Research Ethics Committee.
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