The risk of morbidity and mortality following recurrent malaria in Papua, Indonesia: a retrospective cohort study

Abstract

Background: An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale, relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia.

Methods: We undertook a retrospective analysis of routinely collected data from malaria patients attending the primary referral hospital in Papua, Indonesia, between April 2004 and December 2013. Multi-state modelling was used to estimate the effect of recurring malaria episodes on re-presentation and admission to hospital and death. The risks of early (≤ 14 days) and late (15 to 365 days) hospital admission and death were estimated separately in our study to distinguish between the direct and indirect effects of malaria recurrence on adverse outcomes.

Results: A total of 68,361 patients were included in the analysis, of whom 37,168 (54.4%) presented initially with P. falciparum, 22,209 (32.5%) with P. vivax, and 8984 (13.1%) with other species. During 12 months of follow-up after each of the first four malaria episodes, 10,868 (15.9%) patients were admitted to hospital and 897 (1.3%) died. The risk of re-presenting to the hospital with malaria increased from 34.7% (95% CI 34.4%, 35.1%) at first episode to 58.6% (57.5%, 59.6%) following the third episode of malaria. After adjusting for co-factors, infection with P. vivax was a significant risk factor for re-presentation (hazard ratio (HR) = 1.48 (95% CI 1.44, 1.51)) and late admission to hospital (HR = 1.17 (1.11, 1.22)). Patients infected with P. falciparum had a greater overall rate of mortality within 14 days (HR = 1.54 (1.25, 1.92)), but after multiple episodes of malaria, there was a trend towards a higher rate of early death in patients infected with P. vivax compared to P. falciparum (HR = 1.91 (0.73, 4.97)).

Conclusions: Compared to patients initially infected with P. falciparum, those infected with P. vivax had significantly more re-presentations to hospital with malaria, and this contributed to a high risk of inpatient admission and death. These findings highlight the importance of radical cure of P. vivax to eliminate the dormant liver stages that trigger relapses.

Keywords: Falciparum; Indonesia; Malaria recurrence; Papua; Plasmodium; Vivax.

Fig. 1

Schematic of the multi-state model. A total of 68,361 patients infected with malaria enter the study at state (1). Two separate models with different terminal states are analysed. In Model (1), the terminal state is first (hospital inpatient) admission and in Model (2) the terminal state is death. The patients start at their first malaria presentation (recorded between 2004 and 2013), and then either re-present with a malaria episode, are admitted to hospital due to any cause, die or are censored 12 months following their previous episode. Thus, at each malaria episode, a patient is at risk of re-presentation to hospital with a malaria infection or admission/death. Note, the re-presentations in Model (1) are those with only outpatient treatment as the terminal state is all-cause (hospital inpatient) admission, whilst in Model (2) each re-presentation can be accompanied with either outpatient or inpatient treatment for malaria; for more information about the multi-state model, see Section A of the Additional file 1. Frequency of re-presentations, admissions and deaths following each episode are shown; the number inside the brackets for an episode is the percentage of patients in the preceding episode who transitioned to the current episode

Fig. 2

Distribution of time to event following an initial malaria infection (episode 1) or re-presentation (episodes 2 to 4). The first and second rows correspond to {1 → 2, 2 → 3, 3 → 4} and {1 → admission, 2 → admission, 3 → admission, 4 → admission}, respectively in Model (1). The third and fourth rows correspond to the same transitions as the above rows but for Model (2) where the terminal state is death. The columns from left to right correspond to the episodes 1 to 4

Fig. 3

Frequency of events stratified by species. The events (re-presentation with any species, admission and death) are stratified by species at each prior episode (i.e., species at episode j for j → j + 1 transition). Top row: frequency of a malaria re-presentation and b hospital admission in Model (1). Bottom row: frequency of c malaria re-presentation and d death in Model (2). Pf—P. falciparum, Pv—P. vivax, Mix—mixed infection, Pm—P. malariae, Po—P. ovale

Fig. 4

Risk of re-presentation to hospital. Cumulative probability of re-presentation for a all patients from episodes 1–3 and b only those infected with P. falciparum (red) and P. vivax (blue) species at each episode; the second to fourth columns correspond to episodes 1–3 and present the risk of re-presentation for the subsequent episode (i.e., transitions 1 → 2, 2 → 3, 3 → 4). Since the results of re-presentation were almost identical in Models (1) and (2), only the results of Model (1) are shown

Fig. 5

Risk factors of re-presentation to hospital. Adjusted hazard ratios (HRs; 95% confidence interval) of the associations between the age, sex, ethnicity and malaria species (Pf—P. falciparum, Pv—P. vivax, Mix—mixed infection), and any re-presentation with malaria. The HRs of re-presentation in Model (2) are not shown for brevity, because the values were very similar to Model (1) estimates. The risk factors were considered to have the same effect across the re-presentation transitions. The patients with P. malariae and P. ovale infections were excluded from the analysis due to rare number of events. The age categories (0, 1], (1, 5] and (5, 15] represent the ages >0 to ≤1 years, >1 to ≤ 5 years and >5 to ≤15 years, respectively

Fig. 6

Risk of all-cause admission to hospital. Cumulative probability of early (top row) and late (bottom row) all-cause admission to hospital a, c for all patients from episodes 1–4 and b, d only for those infected with P. falciparum (red) and P. vivax (blue); the second to fifth columns correspond to episodes 1–4, respectively. Early and late admissions are defined as the first hospital admission (receiving inpatient treatment) within 14 days and between 15 and 365 days of an episode, respectively

Fig. 7

Risk factors of all-cause admission to hospital. Adjusted hazard ratios (HRs; 95% confidence interval) of the associations between the age, sex, ethnicity and malaria species (Pf—P. falciparum, Pv—P. vivax, Mix—mixed infection), and all-cause admission to hospital. The risk factors were considered to have the same effect across the admission transitions. The patients with P. malariae and P. ovale infections were excluded from the analysis due to rare number of events. The red and blue solid circles correspond to estimates of HR for early and late admission, respectively. The age categories (0, 1], (1, 5] and (5, 15] represent the ages >0 to ≤1 years, >1 to ≤ 5 years and >5 to ≤15 years, respectively

Fig. 8

Risk of all-cause death. Cumulative probability of early (top row) and late (bottom row) death a, c for all patients from episodes 1–4 and b, d only for those infected with P. falciparum (red) and P. vivax (blue); the second to fifth columns correspond to episodes 1–4, respectively. Early and late death are defined as the deaths within 14 days and between 15 and 365 days of an episode, respectively

Fig. 9

Risk factors of all-cause death. Adjusted hazard ratios (HRs; 95% confidence interval) of the associations between the age, sex, ethnicity and malaria species (Pf—P. falciparum, Pv—P. vivax, Mix—mixed infection), and death. The risk factors of death were considered to have the same effect across the transitions. The patients with P. malariae and P. ovale infections were excluded from the analysis due to rare number of events. The red and blue solid circles correspond to estimates of HR for early and late death, respectively. The age categories (0, 1], (1, 5] and (5, 15] represent the ages >0 to ≤1 years, >1 to ≤ 5 years and >5 to ≤15 years, respectively