In endemic regions, the age distribution of malaria varies according to the infecting Plasmodium species. We aimed to delineate the pattern of malaria-related hospitalization from birth in Timika, Papua–an area co-endemic for P. falciparum and P. vivax
Between April 2004 and December 2013, infants born at Mitra Masyarakat Hospital, or presenting within the first 7 days of life, were enrolled retrospectively into a cohort study and followed passively using routinely-collected hospital surveillance data. Outcomes were stratified by the presence or absence of Plasmodium parasitemia and included re-presentation to hospital, requirement for hospital admission and death.
Overall, 11,408 infants were enrolled into the cohort. Median follow-up was 4.3 (maximum 9.7) years. In total, 7,847 (68.9%) infants made 90,766 re-presentations to hospital, 18,105 (19.9%) of which were associated with Plasmodium parasitemia. The incidence of re-presentations with malaria during the first year of life was 213 per 1,000 person-years (py) for P. vivax and 79 per 1,000py for P. falciparum (Incidence Rate Ratio (IRR) = 2.69, 95% Confidence Interval (95%CI): 2.48–2.92). After the age of 5 years, the incidence of P. vivax had fallen to 77/1,000py and the incidence of P. falciparum had risen to 95/1,000py (IRR = 0.80, 95%CI: 0.73–0.88). Overall, 79.7% (14,431/18,105) of malaria re-presentations were recurrences rather than initial infections. Malaria accounted for 31.7% (2,126/3,120) of all hospital admissions. The infant mortality rate in this study was 52 deaths per 1,000 live births. Beyond the early neonatal period, 13.4% of deaths were associated with Plasmodium parasitemia.
Citation: Douglas NM, Kenangalem E, Hasanuddin A, Anstey NM, Sugiarto P, Price RN, et al. (2020) Malaria-related hospitalization during childhood in Papua, Indonesia: A retrospective cohort study. PLoS ONE 15(1): e0228018. https://doi.org/10.1371/journal.pone.0228018
Editor: Luzia Helena Carvalho, Instituto Rene Rachou, BRAZIL
Received: October 27, 2019; Accepted: January 5, 2020; Published: January 29, 2020
Copyright: © 2020 Douglas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The study was funded by the Wellcome Trust (Senior Fellowship in Clinical Science to RNP 200909 and Training Fellowship in Tropical Medicine to JRP 099875), the Bill and Melinda Gates Foundation (OPRA, OPP1054404), and the Australian National Health and Medical Research Council (Program grants #1132975 and #1037304; the HOT NORTH initiative #1131932 and a Fellowship to NMA #1135820; and the Australian Centre of Research Excellence on Malaria Elimination, ACREME #1134989). The Timika Research Facility and Papuan Community Health Foundation is supported by the Australian Department of Foreign Affairs and Trade (DFAT). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Malaria is caused by mosquito-borne, protozoan parasites of the genus Plasmodium. The most common species globally are P. falciparum and P. vivax . In malaria endemic regions, the age distribution of symptomatic and/or severe Plasmodium infections is determined primarily by the force of infection and the speed with which immunity develops. For both epidemiological and biological reasons (most notably the ability of Plasmodium vivax to relapse multiple times after a single inoculation), the age distribution frequently differs for P. falciparum and P. vivax malaria [2–7].
Acute malaria in children causes a wide spectrum of clinical manifestations ranging from an uncomplicated febrile illness to severe disease and death. Recurrent episodes of malaria during early life have deleterious effects on health as well as causing substantial social and economic hardship for children and their families [8–11]. Malaria in endemic regions can also exact a large toll on hospital resources with attendant opportunity costs. Determining the pattern of symptomatic Plasmodium infections in non-study settings requires an ability to differentiate malaria from other causes of febrile illness coupled with an ability to link multiple clinical episodes to a single individual.
The aim of this study was to use routinely collected hospital data to delineate the pattern of malaria-related morbidity and mortality from birth in a cohort of children in Timika, Papua. We also aimed to define the proportionate contribution of malaria care to the total hospital workload for these children.
Materials and methods
This was a retrospective cohort study of children who were either born at Mitra Masyarakat Hospital (RSMM) in Timika, Papua between April 2004 and December 2013 or whose first presentation to hospital during this accrual period occurred within the first 7 days of life. Follow-up information for these children was obtained passively from routinely-collected hospital data via unique hospital identification number linkage, as described previously [12,13].
Timika is situated in the lowlands of southcentral Papua, Indonesia. The population in 2004 was 120,457 growing to 196,401 in 2013 . The main ethnic groups in the region are Highland and Lowland Papuans and Indonesians from elsewhere in the country. Until late 2009, RSMM was the only referral hospital in the district. After that date, a second public hospital opened (RSUD). RSMM has 110 inpatient beds, a high care unit and a 24-hour emergency department. Both the outpatients and the emergency departments are open every day and together attend to approximately 100,000 patient presentations per year. Healthcare at RSMM is provided at a small cost to non-Papuan Indonesians (3–5 USD for outpatient malaria treatment), but is free of charge to Papuans from one of the 7 largest local tribes, who make up 93% of attendees. As such the hospital is the preferred source of medical care for inpatient, outpatient and antenatal encounters . A community household survey of treatment seeking behavior in 2005, estimated that more than 80% of children under 5 who had died in the preceding year had done so at the RSMM hospital . Malaria transmission in Timika is perennial with minimal seasonal variation. The main mosquito vectors are Anopheles punctulatus, An. koliensis and An. farauti complex. The point prevalence of microscopic parasitemia in 2005 was 7.5% for P. falciparum and 6.4% for P. vivax with an estimated incidence of malaria overall of 876 episodes per 1,000 people per year . In 2013 the point prevalence was 5.2% for P. falciparum and 5.7% for P. vivax . Malaria diagnostics and treatment can be sought at RSMM (and, since January 2010, at RSUD), one of the 12 government-funded community public health clinics, one of 10 clinics administered by the malaria control arm of the PT Freeport Indonesia mining corporation, or at a range of unregulated private sector facilities such as shops and pharmacies. Vector control activities in the region were fairly consistent between 2002 and 2013 and involved twice-yearly indoor residual spraying and distribution of insecticide-treated bednets–covering approximately 10–20% of households .
Hospital data collection and procedures
Data for every patient presentation to RSMM are collected routinely and entered into an electronic Q-pro® database by hospital administrators. Information recorded includes patient identifiers (with a unique hospital number assigned at the point of first presentation to hospital), demographic details such as age, sex and ethnicity, clinical information including hospital department, diagnoses assigned by the attending physician (using the International Classification of Diseases 10 coding system) and vital status at the end of the clinical episode.
Hospital protocol dictates that a blood sample is taken for Giemsa staining and thick film examination for any patient presenting to outpatients with fever or history of fever and all patients who are severely ill, regardless of presumed diagnosis. Microscopy in early neonates was not routine during the study period and only requested if there was clinical concern. If parasitemia is too high to count on a thick film, the hospital microscopists will also read a thin film.
Prior to April 2006, treatment of uncomplicated malaria at RSMM generally consisted of oral quinine for P. falciparum infections and oral quinine plus low-dose primaquine (3.5mg/kg total dose) for P. vivax and P. ovale infections. The treatment of severe malaria during this era was IV quinine. In April 2006, treatment policy was changed to dihydroartemisinin-piperaquine for uncomplicated malaria due to any Plasmodium species with the addition of high dose primaquine (7mg/kg total dose) for P. vivax and P. ovale infections. At the same time, treatment of severe malaria was also changed to intravenous artesunate .
Outcomes and data analysis
Patients aged less than 7 days old at their first appearance in the hospital dataset were selected and followed passively until the 31st of December 2013 by means of unique hospital identification number linkage. Outcomes of interest were: subsequent re-presentation to hospital (defined as any new attendance at the hospital after study entry), admission for inpatient care, total bed occupancy (assuming 0.5 days of occupancy for outpatient and emergency department visits) and death during the hospital encounter with delineation of the absolute and proportionate contributions of P. falciparum, P. vivax and mixed Plasmodium species infections to these outcomes. Patients with no further documented re-presentation to hospital were assumed to have remained in the hospital catchment area and therefore to have been at risk of re-presentation until the 31st of December 2013. For the purposes of graphical presentation, actuarial life tables were used to determine the number of patients at risk of the outcomes of interest in each 6-month period from birth. Kaplan-Meier survival analysis was used to estimate the cumulative risk of the outcomes of interest and incidence rates were given per 1,000 person-years for the two age brackets <1 year and ≥5 years. The effect of previous hospital presentation on the risk of a further representation was explored using Kaplan-Meier survival analysis and univariable and multivariable Cox regression models for each Plasmodium species. Covariables in the multivariable Cox models included: age, sex, ethnicity (Highland Papuan, Lowland Papuan, non-Papuan) and the year of birth. The proportional hazards assumption was assessed for each variable by comparing visually observed versus predicted survival curves. When the proportional hazards assumption was violated, Cox models were either stratified or omitted altogether. Allowance was made in all Cox models for within-patient correlation by using the Huber-White sandwich estimator to calculate robust standard errors. All analyses and graphing were done in STATA® version 15.1 (College Station, Tx).
Ethics approval and consent to participate
Ethical approval for this study was obtained from the Health Research Ethics Committees of the University of Gadjah Mada, Indonesia (KE/FK/544/EC) and Menzies School of Health Research, Darwin, Australia (HREC 10.1397). Data were anonymized prior to access for this study. The ethics committees waived the requirement for informed consent and therefore individual patient consent for participation was not sought.
Between April 2004 and December 2013, 11,408 neonates were enrolled into the cohort, of whom 52.4% (n = 5,974) were male. In total 48.9% (5,559) were Highland Papuan, 20.1% (2,290) were lowland Papuan and 31.0% (3,526) were non-Papuan. Of these patients, 11,307 (99.1%) either did not have a malaria diagnostic test or were negative for Plasmodium parasitemia at the point of entry to the study and 101 (0.90%) had congenital malaria. The median duration of follow-up from the time of entry to the study until the 31st of December 2013 was 4.3 years and the maximum follow-up was 9.7 years.
Total hospital usage
Overall 7,847 (68.8%) patients re-presented 90,766 times to hospital during follow-up. By 5 years of age the cumulative risk of at least one re-presentation was 70.7% (95% Confidence Interval (95%CI) 69.8–71.6%) with a median number of 9 presentations (maximum = 134) (Fig 1). In total 93.6% (7,343/7,847) of first re-presentations occurred within the first 12 months of life (cumulative risk = 65.5%, 95%CI 64.7–66.4%).
Overall 19.9% (18,105/90,766) of representations were attributable to malaria with a cumulative risk of at least one malaria re-presentation by 5 years of 38.1% (95%CI 37.1–39.1%); Fig 2. Of the malaria-related re-presentations, 5,462 (30.2%) were due to P. falciparum, 9,556 (52.8%) to P. vivax, 6 (0.0%) to P. ovale, 200 (1.1%) to P. malariae and 2,881 (15.9%) to mixed species infection.
Total number of re-presentations divided by number of patients at risk (left) and proportion of all re-presentations by age stratified by Plasmodium species (middle). Proportion of malaria re-presentations due to the different Plasmodium species stratified by the number of previous re-presentations due to the same species (right). Abbreviations: Pv; Plasmodium vivax, Pf; Plasmodium falciparum, Mix; mixed Plasmodium species infection.
In the first year of life, the incidence of malaria was 335 events per 1,000 person-years (py). The incidence of P. vivax infections (213/1,000py) was significantly higher than that of P. falciparum infections (79/1,000py; Incidence Rate Ratio (IRR) = 2.69, 95%CI: 2.48–2.92). After the age of 5 years the overall incidence of malaria declined to 225 events per 1,000py (IRR = 0.67, 95%CI: 0.64–0.71)) with a reduction in the incidence of P. vivax to 77 per 1,000py (IRR = 0.35, 95%CI: 0.33–0.38), but an increase in P. falciparum to 95/1,000py (IRR = 1.19, 95%CI: 1.09–1.31). Within the first year of life, 49.9% (1,699/3,402) of malaria-related presentations were first episodes whereas after the age of 5 years, only 6.0% (137/2,292) of presentations were first episodes. The corresponding Plasmodium species specific proportions due to first episodes were 75.3% and 15.9% for P. falciparum and 55.9% and 16.4% for P. vivax. Overall, 79.7% (14,431/18,105) of the presentations with malaria were recurrences rather than initial infections.
Previous presentation to hospital with malaria was a major risk factor for further re-presentation with malaria (Hazard Ratio (HR) = 4.8, 95%CI 4.5–5.0, p<0.001) and this was still apparent after controlling for confounding factors (Adjusted Hazard Ratio (AHR) = 3.0, 95%CI 2.8–3.2, p<0.001; Table 1). This finding was similar for P. vivax monoinfections (AHR = 3.2, 95%CI 2.9–3.4, p<0.001) and P. falciparum monoinfections (AHR = 2.8, 95%CI 2.6–3.1, p<0.001; Fig 3 and Table 1). Conversely, prior presentation with a nonmalarial illness was not associated with a substantially increased risk of a further nonmalarial re-presentation: the 5-year cumulative risk of re-presentation being 80.6% (95%CI: 79.6–81.6%) versus 69.6% (95%CI: 68.7–70.4%) respectively (violation of proportional hazards precluded Cox regression). Highland Papuans were at significantly greater risk of re-presentation with malaria than both Lowland Papuans and non-Papuans (Table 1).
Abbreviations: prev; previous, Pv; Plasmodium vivax, Pf; Plasmodium falciparum, mix; mixed Plasmodium species infection, 95%CI; 95% confidence interval.
Overall, 3,120 children had 6,710 admissions to hospital during follow-up. The 5-year cumulative risk of at least one admission was 31.1% (95%CI: 30.2–32.1%), with 48.6% (1,517/3,120) of these patients being admitted more than once (median = 2, maximum = 20). Malaria due to any Plasmodium species was present in 2,126 (31.7%) of the children admitted (Fig 4). Within the first year of life, malaria was present in 22.6% (675/2,990) of inpatients whereas after the age of 5 years, the proportion with malaria had risen to 43.9% (133/303) of admissions. The incidence of malaria admissions was 67/1,000py in children under one year of age and 14/1,000py after the age of 5 years (IRR = 4.80, 95%CI: 4.00–5.79). The incidence of P. vivax-related admissions decreased from 34/1,000py in infants under one year to 3/1,000py (IRR = 11.0, 95%CI: 7.62–16.5) whereas there was a smaller reduction in the incidence of P. falciparum admissions from 23/1,000py to 8/1,000py (IRR = 2.87, 95%CI: 2.21–3.75).
Total number of admissions divided by number of patients at risk (left) and proportion of all admissions by age from birth stratified by Plasmodium species (middle). Proportion of malaria admissions due to the different Plasmodium species stratified by the number of previous admissions due to the same species (right). Abbreviations: Pv; Plasmodium vivax, Pf; Plasmodium falciparum, Mix; mixed Plasmodium species infection.
Overall, 11.9% (353/2,967) of children presenting for the first time with a P. vivax monoinfection required admission to hospital whereas 20.9% (458/2,187) of initial P. falciparum presentations resulted in admission. Inpatient care of the children in this cohort resulted in 26,604 days of bed occupancy, of which 6,586 days (24.8%) were in patients with malaria: 4,149 days (15.6%) in patients admitted for the first time with malaria and 2,437 days (9.2%) in patients admitted for the second or subsequent time with malaria. The proportion of patients being admitted for the second or subsequent time with the same species was higher with P. vivax in the first 18 months, but higher with P. falciparum thereafter (Fig 4).
In total 667 children in the cohort died at the hospital of whom 480 (72.0%) were less than 7 days old (early neonatal deaths), 481 (72.1%) were less than 28 days old (neonatal mortality rate = 42 deaths per 1,000 live births) and 589 (88.3%) were less than one year old (infant mortality rate = 52 deaths per 1,000 live births) (Fig 5). The cumulative risk of death by one year was 5.3% (95%CI 4.9–5.7%) and by 5 years this had risen to 6.1% (95%CI 5.7–6.6%). Overall 4.3% (29/667) of the patients had a diagnosis of malaria at the time of death: 14 (48.3%) due to P. falciparum, 10 (34.5%) due to P. vivax and 4 (13.8%) due to mixed species infection. Beyond the early neonatal period, 13.4% (25/187) of deaths were associated with Plasmodium parasitemia. The cumulative risk of a malaria related death was 0.1% (95%CI 0.07–0.21) by one year and 0.3% (95%CI 0.20–0.44) by 5 years.
Total number of deaths divided by number of patients at risk (left) and proportion of all deaths by age from birth and Plasmodium species (middle). Proportion of malaria deaths due to the different Plasmodium species stratified by the number of previous malaria episodes (right). Abbreviations: Pv; Plasmodium vivax, Pf; Plasmodium falciparum, Mix; mixed Plasmodium species infection, Mal; malaria.
We present a large, retrospective, hospital-based birth cohort study in southern Papua, Indonesia. Over 70% of the children in the study re-presented to the hospital during a median of 4.3 years of follow-up and almost 40% re-presented with malaria. Malaria accounted for about 20% of all hospital re-presentations, 32% of hospital admissions and 25% of total inpatient bed occupancy. The incidence of P. vivax-related hospital presentations decreased significantly between infancy and 5 years of age whereas the incidence of P. falciparum increased. Prior malaria, whether due to P. vivax or P. falciparum, was a strong risk factor for a further presentation with malaria. Indeed 80% of all malaria-related presentations made by the children in this study were recurrences rather than initial infections. Despite the major contribution of malaria to the total hospital workload, direct mortality associated with malaria was dwarfed by the high early neonatal mortality in this cohort (approximately 1 in 24 live births). While patent parasitemia was only present in 4.3% of all children who died in hospital, this rose to 13.4% among those who died after day seven.
Given that a single episode of malaria, regardless of species, identifies a child as being at significant risk for future re-presentation with malaria, the first episode of malaria represents a particularly important opportunity to intervene to prevent morbidity and mortality from multiple recurrences and substantially reduce hospital workload. Some of the increased risk of recurrence will be attributable to P. vivax relapses, preventable, in those who are eligible, by using radically curative courses of primaquine [19–21]. Unsupervised primaquine has previously been shown to be relatively ineffective for preventing re-presentation to hospital with vivax malaria in this region, likely due to poor medication adherence . Supervision of therapy and/or primaquine regimens that encourage better adherence compared with the existing 14-day course would be highly desirable. Our finding that P. falciparum infection also increases the risk of malaria recurrence suggests that at least part of the increased risk may be due to epidemiological risk factors such as socio-economic status, proximity to mosquito breeding areas and local vector control activity. Geolocating patients presenting for the first time with malaria may be an effective strategy to target transmission hotspots through vector control, distribution of insecticide treated bednets and/or mass drug administration. Current vector control strategies in the region are targeted at village, rather than individual, level. A third explanation for the increased risk of re-presentation in those with prior malaria is simply that an initial malaria presentation identified a subset of patients who were more likely to seek treatment for any condition at RSMM than the remaining children–potentially due to proximity or specific health care preferences. Given that previous nonmalaria-related presentations had relatively little bearing on the risk of a future re-presentation, this is unlikely to have been the sole explanation.
Ideally, testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be undertaken prior to prescription of primaquine for radical cure of P. vivax infection to minimise the risk of drug-induced hemolysis. One of the barriers to primaquine use is the cost of such testing . Our results suggest that the number of G6PD tests required at a facility such as RSMM would be much lower than the total number of P. vivax presentations might suggest. Nearly 85% of presentations with vivax malaria by the age of 5 years are recurrences as opposed to first episodes and G6PD status need only be assessed once.
Although presentation to hospital with malaria was dominated by recurrent infections rather than primary infections, requirement for admission to hospital (presumably reflecting severe disease or an inability to take oral medication) occurred mainly in patients presenting for the first time with malaria. The risk was almost twice as high in children presenting with falciparum malaria, a likely reflection of poor immunity and susceptibility to pathogenic processes. We have previously hypothesized that morbidity (particularly severe anemia) caused by vivax malaria tends to result from the cumulative effects of repeated infections rather than a single infection [23,24]. Approximately a fifth of admissions in patients with vivax malaria were in children who had previously presented to hospital with vivax malaria, a slightly lower proportion than for falciparum malaria. This suggests that: 1) initial vivax infections can cause sufficiently severe manifestations to warrant admission to hospital, 2) admission in those with vivax malaria is mostly due to concomitant morbidities or 3) a significant proportion of preceding, less-complicated, episodes of vivax malaria are managed in the primary care system outside the hospital. As shown previously, the incidence of P. vivax infection was heavily skewed towards children under the age of one year whereas P. falciparum infections predominated after the age of 5 years . This likely reflects more rapid acquisition of immunity to P. vivax due to greater parasite exposure resulting from multiple relapses .
Perhaps the most striking finding in this study was the very high infant mortality rate of 52 deaths per 1,000 births, largely attributable to early neonatal deaths. In 2017 the mean infant mortality rate globally was 29 deaths per 1,000 live births, rising to 51 deaths per 1,000 live births in Africa . Anecdotally, approximately 90% of the babies in this study were delivered in hospital electively to women with pregnancies not deemed to be high risk. The remaining 10% of mothers had high risk pregnancies and had been referred to hospital to deliver. The risk of neonatal mortality after delivery in the latter group of women would almost certainly have been higher than in the community and therefore the estimates of childhood mortality will have been somewhat inflated. Regardless, infant mortality in this region remains very high.
Our study has some notable strengths. Due to the lengthy accrual period, relatively large local population and the hospital’s busy obstetric unit, our study included a large number of children and therefore our risk estimates are relatively precise. The hospital’s strict policy regarding blood film assessment ensured that the vast majority of patients with patent parasitemia presenting to the hospital will have been captured. RSMM was the only public tertiary referral centre in the district until late 2009 and therefore a very high proportion of all pediatric inpatient admissions and deaths in hospitalized patients will have been ascertained. Beyond 2009, some admissions and deaths may have occurred at the other public hospital even though birth occurred at RSMM.
Our study has some important limitations. Patients presenting with malaria to community health care facilities (or, after December 2009, to the other public hospital in the region) and those who migrated out of the catchment area prior to the study conclusion will not have been captured. Any ascertainment bias will have underestimated the risk of re-presentation and the true burden of symptomatic malaria in our cohort. This bias was likely to have been particularly important for non-Papuan patients who were required to pay a small amount for health care at RSMM. Our survival analyses of the risk of further re-presentation to hospital only included a relatively limited number of covariables. Data on household income and bednet usage were not available and may have influenced the risk of malaria recurrence. Attribution of events to malaria was based on the presence or absence of patent parasitemia. Some individuals may have had symptomatic subpatent parasitemia while others may have had patent parasitemia that was incidental to other comorbidities. Moreover, previous episodes of malaria may have caused morbidity that contributed to nonmalarial re-presentations. Congenital malaria was frequent in the early years of the study , prior to ACT policy change, but microscopy at birth was not routine during this time. While the proportion of early neonatal deaths with parasitemia is likely to be small, a direct contribution from malaria cannot be excluded in this period. Malaria is also well recognised as a significant indirect cause of mortality [28,29], and the indirect contribution to early neonatal mortality (for example by causing preterm birth and low birth weight ) and post-neonatal mortality could not be measured. Finally, follow-up of the children in this study ended on the 31st of December 2013. Population growth, variations in treatment seeking behaviour and changes in the epidemiology of malaria in the region will have altered the pattern of malaria presentations at RSMM in the last 5 years.
Malaria is a very common cause of representation to hospital during childhood in southcentral Papua, resulting in significant morbidity, mortality and hospital workload. Malaria tends to be recurrent after the initial presentation making the first occurrence a particularly important opportunity to implement preventive measures through optimal antimalarial treatment and geospatially targeted vector control activities. Despite malaria being directly associated with nearly one in seven deaths after the neonatal period, early neonatal causes of mortality predominate in this setting and warrant prospective investigation and intervention.
We would like to thank the staff of Rumah Sakit Mitra Masyarakat. We are grateful to Lembaga Pengembangan Masyarakat Amungme Kamoro, the Mimika District Health Office and the PT Freeport Indonesia Public Health Malaria Control Department for their ongoing support.
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