Intermittent screening and treatment for malaria complementary to routine immunisation in the first year of life in Papua, Indonesia: a cluster randomised superiority trial

In malaria endemic areas, the susceptibility of infants to malaria increases as maternal antibodies wane after birth, rendering infants at risk of severe disease and dying [1‐4]. In Timika, Papua (Indonesia), Plasmodium falciparum and P. vivax are highly prevalent and a third of hospitalised infants are diagnosed with malaria, often associated with severe anaemia and respiratory distress in the first year of life [2]. Infants and children under-5 years of age are also more prone to repeated episodes of P. vivax malaria than older children and adults. If undetected and inadequately treated, recurrent parasitaemia leads to a cumulative risk of severe anaemia and death [5‐7].

In infancy, the signs and symptoms of malaria are not specific, leading to a delay in diagnosis and treatment [2]. Early diagnosis and prompt effective treatment can prevent the adverse outcomes [8] but is logistically challenging to implement, particularly in places where resources are limited and access to healthcare is poor.

In areas of high transmission of P. falciparum in Africa, the implementation of intermittent preventive treatment in infancy (IPTi) with curative dose of sulfadoxine-pyrimethamine (SP) has been shown to be an effective malaria control strategy [9, 10]. However, in co-endemic regions in Asia and the Pacific, the evidence of benefit is weaker with only one study demonstrating the effectiveness of IPTi with SP and amodiaquine in reducing malaria in the first year of life [11]. In areas where SP resistance is high, monthly dihydroartemisinin-piperaquine (DHP) has been proposed as an alternative regimen for IPTi [12].

DHP has been the first-line treatment for uncomplicated malaria in Indonesia since 2006, and its use as monthly IPT during pregnancy has been shown to be effective in reducing the risk of maternal malaria [13]. However, its applicability to infants in such settings requires additional evidence on its feasibility and acceptability [14]. Due to concerns of administering antimalarial drugs without testing in infants and pregnant women living in an area of high malaria transmission, intermittent screening and treatment (IST) may provide an alternative strategy to IPT [13, 15‐17]. However, to date, no studies have examined the effectiveness of intermittent screening and treatment in the first year of life. We undertook a cluster randomised controlled trial to evaluate whether ISTi was more effective than passive case detection (PCDi) in reducing the incidence of clinical malaria in the first year of life and prevalence of parasitaemia at 12 months of age infants living in an area of high malaria transmission.

The study was conducted over 33 months with the first recruitment on 7 May 2014, the last patient enrolled on 6 April 2016 and the last follow-up visit on 23 February 2017. A total of 757 infants (755 singletons and 1 set of twins) were enrolled into the study (Fig. 1). Infant characteristics are presented in Table 1. A greater number of infants in ISTi arms were from maternal IST group (47.1%) compared to those in PCDi arms (32.7%) (Table 2), whereas more infants in PCDi arms were from maternal IPTp-DHP group compared to those in ISTi arms (35.4% and 22.0% respectively). In addition, higher proportion of infants in PCDi arms had mothers with anaemia and severe anaemia (25.6% and 3.2% respectively) compared to those in ISTi arms (18.6% and 1% respectively). At delivery, 18.6% (128/686) of women had parasitaemia (peripheral or placental) with a prevalence of maternal parasitaemia of 17.5% (50/285) in the ISTi arm and 19.5% (78/401) in the PCDi arms (Additional file 1: p 14).

During the first 12 months of life, the total incidence of peripheral parasitaemia was 132 episodes of which 17 (12.8%) were in symptomatic infants. At 6 months, 1.0% (7/668) of infants had peripheral patent parasitaemia detected by RDT or microscopy (Additional file 1: p 2 and Table 3). At 12 months, peripheral parasitaemia, detected by any method, was present in 14.2% (90/633) of infants, of whom 88.9% (80/90) were asymptomatic and 78.9% (71/90) submicroscopic (qPCR positive but negative by microscopy or RDT); Table 3. There were no significant differences in the distributions of species of infection between the intervention arm. The geometric mean parasite density in infants with microscopically detected parasitaemia ranged from 13.1 to 94.2 parasites/μL for P. falciparum and from 34.2 to 85.0 parasites/μL for P. vivax.

Our study highlights that in this area of high malaria transmission, the incidence of clinical malaria in the first year of life, in infants born of mothers offered protection from malaria during pregnancy, was low (incidence rate of 24 and 19 episodes per 1000 children-years for ISTi and PCDi respectively). Although there were a higher number of clinical malaria episodes in the ISTi clusters, the overall benefit of ISTi compared to PCDi arms in reducing clinical malaria was inconclusive. Overall 12.9% of the 132 detected episodes of parasitaemia were associated with symptomatic illness. By 12 months, 14% of infants had detectable peripheral parasitaemia, but almost 80% of these infections were submicroscopic.

The annual parasite incidence in the study area is approximately 250–400 cases per 1000 population, and thus the incidence of malaria in the infants enrolled was significantly lower than expected. Malaria in early life can result from vertical transmission (that may manifest months after birth), development of immune tolerance to malaria antigen in utero (increased susceptibility to malaria) or sporozoite inoculation by infected mosquitos in early life [24‐27]. The low number of infected infants in our study may reflect the low (4%) prevalence of microscopic parasitaemia at delivery in mothers who had been carefully monitored during pregnancy with greater awareness in the need to protect their infants from malaria. Mothers participating in the maternal intervention study were also provided with LLIN. Although further infant studies could help clarify the potential benefits of ISTi in high risk children independent of any maternal interventions, a combined approach is warranted to improve maternal-infant health and the key question to address is the degree to which resources are focused pre or post natal.

Despite the low risk of infant malaria, almost 30% of participants were anaemic (Hb < 10 g/dl) by the time they were 12 months old. Although greater number of infants in PCDi arms had mothers with anaemia and severe anaemia, the risk of anaemia was similar between infants in ISTi and PCDi arms at 6 months (23.7% and 28.6% respectively, p = 0.280) and at 12 months (28.1% and 30.2% respectively, p = 0.810) suggesting minimal effect of maternal anaemia status in these infants. As well as malaria, nutritional deficiencies including iron are major causes of anaemia in early life [28] and associated with long-term developmental and cognitive impairment [29]. Anaemia in infancy occurs physiologically 8-12 weeks after birth with Hb falling to 9 g/dl, before increasing to 11–12 g/dl by 12–24 months of age providing that there are no other contributory causes of anaemia [30].

Among paediatric populations, test and treat strategies have been shown to have benefit in reducing malaria infections in school children and have been suggested as an alternative to IPT in moderate to highly malaria endemic areas [17]. Our study suggests that in an area with a high incidence of malaria, such a strategy during infancy offered no apparent benefit in reducing malaria. A key factor undermining ISTi in our study was that the very low level of peripheral parasitaemia, with 80% of detected cases being below the level of microscopic detection and in those with microscopic detectable infection, 95% of infections had a parasitaemia less than 85.0 parasites/μL. Since current point-of-care RDTs have a threshold of detection of > 100 parasites/μL, they are unlikely to detect the majority of infected infants [31].

In an area coendemic for malaria in Papua New Guinea, where the incidence of malaria was 1700 per 1000 children-years, intermittent preventive treatment with SP and amodiaquine without testing (IPTi) reduced the risk of clinical malaria by 29% and the risk of anaemia by 25% [11]. However, the risk of clinical malaria in our study was 60 fold lower, and in this setting, IPTi is less likely to offer significant clinical benefit disease or be cost effective. Whilst the prevalence of parasitaemia was almost 15% at 12 months, most infections were submicroscopic and asymptomatic. Although the clinical consequences of such low level parasitaemia are unclear, those with subclinical infection were more likely to be anaemic compared to uninfected infants (41% vs 27%), suggesting that interventions to reduce low level infection have potential to prevent anaemia as well as ongoing transmission.

In areas of high malaria endemicity in Africa, maternal and infant malaria intervention strategies are often combined to optimise impact. However, our study in a coendemic high transmission area suggests that the benefits of effective malaria control activities provided during antenatal care may have protected the babies in the first year of life [10, 32‐34], potentially accounting for a 10 fold reduction in malaria.

Our study has a number of limitations. First, the study population may have been biased to individuals with a more positive attitude towards malaria, since mothers were attending antenatal care in village health posts, bringing their babies for immunisation and contact with the clinic staff. Additionally, children in the ISTi intervention arm were tested for malaria at 2, 3, 4, 6 and 9 months, increasing the likelihood of detecting a clinical malaria episode compared with the passive detection in the PCDi arm. These potential biases may have reduced the observed effect impact of ISTi. Second, infants in the ISTi arm were more likely to have come from the maternal IST group whereas infants in the PCDi arm were more likely to have been in the maternal IPTp-DHP group. This may have contributed to the reduction in the observed benefit of ISTi since maternal IPTp-DHP was associated with a significant reduction in the risk of malaria during pregnancy compared to maternal IST [13]. Third, the predicted incidence that was used for our sample size calculations was too high and thus our study was underpowered. True incidence data of malaria in the first year of life in this region are scarce, so our estimate was based on experience working in the local hospital where infants can have 2–5 recurrent episodes of malaria within 1 year of their first presentation with malaria. Lastly, almost 20% of patients had incomplete follow-up, with the majority of this attrition bias attributable to migration from the study area, potentially confounding our estimates of ISTi efficacy.

In an area of high malaria transmission, where P. falciparum and P. vivax are coendemic, there was no clear benefit to infants receiving ISTi compared to current passive case detection, although this may have reflected reduced power of the study associated with concomitant interventions to reduce maternal malaria. Robust malaria control strategies during pregnancy may provide protection of infants from malaria but not from anaemia. In early life the clinical consequences of submicroscopic asymptomatic infections need to be explored, to inform complementary interventions for mothers and infants at high risk of malaria.