Malaria.

Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service disruption. In 2021, there were an estimated 247 million malaria cases and 619 000 deaths in 84 endemic countries. Plasmodium falciparum strains partly resistant to artemisinins are entrenched in the Greater Mekong region and have emerged in Africa, while Anopheles mosquito vectors continue to evolve physiological and behavioural resistance to insecticides. Elimination of Plasmodium vivax malaria is hindered by impractical and potentially toxic antirelapse regimens. Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay of patient management. Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can improve survival in severe malaria. Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. Improved surveillance, better access to effective treatment, more labour-efficient vector control, continued drug development, targeted mass drug administration, and sustained political commitment are required to achieve targets for malaria reduction by the end of this decade.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

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

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.

High Risk of Plasmodium vivax Malaria Following Splenectomy in Papua, Indonesia.

Background: Splenectomy increases the risk of severe and fatal infections; however, the risk of Plasmodium vivax malaria is unknown. We quantified the Plasmodium species-specific risks of malaria and other outcomes following splenectomy in patients attending a hospital in Papua, Indonesia. Methods: Records of all patients attending Mitra-Masyarakat Hospital 2004-2013 were reviewed, identifying those who underwent splenectomy. Subsequent risks of specific clinical outcomes within 12 months for splenectomized patients were compared to nonsplenectomized patients from their first recorded hospital admission. In addition, patients splenectomized for trauma 2015-2016 were followed prospectively for 14 months. Results: Of the 10774 patients hospitalized during 2004-2013, 67 underwent splenectomy. Compared to nonsplenectomized inpatients, patients undergoing splenectomy had a 5-fold higher rate of malaria presentation within 12 months (adjusted hazard ratio [AHR] = 5.0 [95% confidence interval (CI): 3.4-7.3], P < .001). The AHR was 7.8 (95% CI: 5.0-12.3) for P. vivax and 3.0 (95% CI: 1.7-5.4) for P. falciparum (both P < .001). Splenectomized patients had greater risk of being hospitalized for any cause (AHR = 1.8 [95% CI: 1.0-3.0], P = .037) and diarrheal (AHR = 3.5 [95% CI: 1.3-9.6], P = .016). In the 14-month prospective cohort, 12 episodes of P. vivax and 6 episodes of P. falciparum were observed in 11 splenectomised patients. Conclusions: Splenectomy is associated with a high risk of malaria, greater for P. vivax than P. falciparum. Eradication of P. vivax hypnozoites using primaquine (radical cure) and subsequent malaria prophylaxis is warranted following splenectomy in malaria-endemic areas.

Performance of the Access Bio/CareStart rapid diagnostic test for the detection of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.

BACKGROUND: To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994). METHODS AND FINDINGS: Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90-0.99) and a specificity of 0.95 (95% CI 0.92-0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94-1.00), with an LR+ and an LR- of 18.23 (95% CI 13.04-25.48) and 0.05 (95% CI 0.02-0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings. CONCLUSIONS: The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR- render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings.

Malaria morbidity and mortality following introduction of a universal policy of artemisinin-based treatment for malaria in Papua, Indonesia: A longitudinal surveillance study.

BACKGROUND: Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species. METHODS AND FINDINGS: A prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013. In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species. Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria. The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre-policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of -12.9% (95% confidence interval [CI] -13.5% to -12.2%). There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = -0.21% [95% CI -0.34 to -0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = -0.05% [95% CI -0.20 to 0.09]). Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital. After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48-0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71-0.73]). The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy. CONCLUSIONS: In this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality. The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria. In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria.

The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. METHODS: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. RESULTS: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. CONCLUSIONS: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. TRIAL REGISTRATION: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

Safety of primaquine in infants with Plasmodium vivax malaria in Papua, Indonesia.

BACKGROUND: Primaquine (PQ) prevents relapses of vivax malaria but may induce severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. Data on the safety of primaquine in infants are limited. METHODS: A retrospective, hospital-based cohort study of infants aged 1-12 months with vivax malaria was carried out in Timika, Papua province, Indonesia. Risks of admission, death and severe haematological outcomes within 30 days of first presentation were compared between infants who did and did not receive primaquine. Infants were not tested routinely for G6PD deficiency as per local guidelines. RESULTS: Between 2004 and 2013, 4078 infants presented to the hospital for the first time with vivax malaria, of whom 3681 (90.3%) had data available for analysis. In total 1228 (33.4%) infants were aged between 1 and 6 months and 2453 (66.6%) between 6 and 12 months of age. Thirty-three (0.9%) patients received low-dose primaquine (LDP), 174 (4.7%) received high-dose primaquine (HDP), 3432 (93.2%) received no primaquine (NPQ) and 42 patients received either a single dose or an unknown dose of primaquine. The risk of the Hb concentration falling by > 25% to less than 5 g/dL was similar in the LDP or HDP groups (4.3%, 1/23) versus the NPQ group (3.5%, 16/461). Three infants (1.4%) died following receipt of PQ, all of whom had major comorbidities. Seventeen patients (0.5%) died in the NPQ group. None of the infants had documented massive haemolysis or renal impairment. CONCLUSIONS: Severe clinical outcomes amongst infants treated with primaquine in Papua were rare. The risks of using primaquine in infancy must be weighed against the risks of recurrent vivax malaria in early life.

Early and late mortality after malaria in young children in Papua, Indonesia.

BACKGROUND: In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown. METHODS: Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital. Analysis was primarily by Kaplan Meier and Cox regression methods. RESULTS: In total 15,716 children presenting with malaria between April 2004 and December 2013 were included in the analysis; 6184 (39.3%) with Plasmodium falciparum, 7499 (47.7%) with P. vivax, 203 (1.3%) with P. malariae, 3 with P. ovale and 1827 (11.6%) with mixed infections. Within 1 year, 48.4% (7620/15,716) of children represented a total of 16,957 times with malaria (range 1 to 11 episodes), with the incidence of malaria being greater in patients initially presenting with P. vivax infection (1334 [95%CI 1307-1361] per 1000 patient years) compared to those with P. falciparum infection (920 [896-944]). In total 266 (1.7%) children died within 1 year of their initial presentation, 129 (48.5%) within 30 days and 137 (51.5%) between 31 and 365 days. There was no significant difference in the mortality risk in patients infected with P. vivax versus P. falciparum either before 30 days (Hazard Ratio (HR) 1.02 [0.69,1.49]) or between 31 and 365 days (HR = 1.30 [0.90,1.88]). Children who died had a greater incidence of malaria, 2280 [95%CI 1946-2671] per 1000 patient years preceding their death, compared to 1141 [95%CI 1124-1158] per 1000 patient years in those surviving. CONCLUSIONS: Children under-5 years old with P. vivax malaria, are at significant risk of multiple representations with malaria and of dying within 1 year of their initial presentation. Preventing recurrent malaria must be a public health priority in this vulnerable population.

Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study.

BACKGROUND: Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia. METHODS AND FINDINGS: Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%-50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4-24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up. CONCLUSIONS: Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.

Plasmodium vivax infection: a major determinant of severe anaemia in infancy.

BACKGROUND: Most malarious countries outside of Africa are co-endemic for Plasmodium falciparum and Plasmodium vivax. The comparative burden of anaemia in the community caused by these two species is incompletely characterized. METHODS: A three-stage, cross-sectional, community survey was used to determine the proportion of moderate or severe anaemia (haemoglobin <7 g/dL) attributable to patent P. vivax, P. falciparum and mixed parasitaemia in Papua, Indonesia. Adjusted population-attributable fractions were calculated from multivariable logistic regression models. Eight hundred and twenty-five households were surveyed with a total of 5255 occupants, 3890 (74 %) of whom were present and provided a blood sample. Plasmodium falciparum parasitaemia was present in 8.1 % (n = 315) of participants, P. vivax in 6.4 % (n = 250) and mixed infections in 1.9 % (n = 72). Overall, P. falciparum was associated with a mean reduction in haemoglobin of 1.16 g/dL compared to those without patent parasitaemia [95 % confidence interval (95 % CI) 0.91, 1.41 g/dL]. The corresponding values for P. vivax and mixed infections were 0.66 g/dL (95 % CI 0.35, 0.96) and 1.25 g/dL (0.71, 1.80), respectively. Overall, 16.7 % (95 % CI 8.52, 24.2 %) of haemoglobin concentrations <7 g/dL in the community were estimated to be attributable to patent parasitaemia. The fractions for infants and 1-5 years old were 34.4 % (95 % CI -3.30, 58.3 %) and 23.2 % (95 % CI 3.34, 39.0 %), respectively. Plasmodium vivax was associated with a greater than threefold higher attributable fraction of anaemia in infants compared with P. falciparum [27.6 % (95 % CI -3.20, 49.2 %) versus 7.94 % (-5.87, 20.0 %)]. CONCLUSION: Despite comparatively low-level endemicity, malaria is associated with a significant proportion of all cases of community anaemia in southern Papua. Contrary to its benign reputation, P. vivax is an important and preventable risk factor for anaemia during infancy-a probable consequence of relapsing disease prior to the development of immunity.

Severe malarial thrombocytopenia: a risk factor for mortality in Papua, Indonesia.

BACKGROUND: The significance of thrombocytopenia to the morbidity and mortality of malaria is poorly defined. We compared the platelet counts and clinical correlates of patients with and those without malaria in southern Papua, Indonesia. METHODS: Data were collated on patients presenting to a referral hospital between April 2004 and December 2012. RESULTS: Platelet measurements were available in 215 479 patients (23.4%), 66 421 (30.8%) of whom had clinical malaria. Patients with Plasmodium falciparum monoinfection had the lowest platelet counts and greatest risk of severe thrombocytopenia (platelet count, <50,000 platelets/µL), compared with those without malaria (adjusted odds ratio [OR], 6.03; 95% confidence interval [CI], 5.77-6.30]). The corresponding risks were 5.4 (95% CI, 5.02-5.80) for mixed infections, 3.73 (95% CI, 3.51-3.97) for Plasmodium vivax infection, and 2.16 (95% CI, 1.78-2.63) for Plasmodium malariae infection (P<.001). In total, 1.3% of patients (2701 of 215 479) died. Patients with severe malarial anemia alone (hemoglobin level, <5 g/dL) had an adjusted OR for death of 4.93 (95% CI, 3.79-6.42), those with severe malarial thrombocytopenia alone had an adjusted OR of 2.77 (95% CI, 2.20-3.48), and those with both risk factors had an adjusted OR of 13.76 (95% CI, 10.22-18.54; P<.001). CONCLUSIONS: Severe thrombocytopenia identifies both children and adults at increased risk of death from falciparum or vivax malaria, particularly in those with concurrent severe anemia.

Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia.

BACKGROUND: Plasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known. METHODS: To define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital. RESULTS: Between January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections. CONCLUSIONS: Although uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection.

Gametocyte dynamics and the role of drugs in reducing the transmission potential of Plasmodium vivax.

BACKGROUND: Designing interventions that will reduce transmission of vivax malaria requires knowledge of Plasmodium vivax gametocyte dynamics. METHODS: We analyzed data from a randomized controlled trial in northwestern Thailand and 2 trials in Papua, Indonesia, to identify and compare risk factors for vivax gametocytemia at enrollment and following treatment. RESULTS: A total of 492 patients with P. vivax infections from Thailand and 476 patients (162 with concurrent falciparum parasitemia) from Indonesia were evaluable. Also, 84.3% (415/492) and 66.6% (209/314) of patients with monoinfection were gametocytemic at enrollment, respectively. The ratio of gametocytemia to asexual parasitemia did not differ between acute and recurrent infections (P = .48 in Thailand, P = .08 in Indonesia). High asexual parasitemia was associated with an increased risk of gametocytemia during follow-up in both locations. In Thailand, the cumulative incidence of gametocytemia between day 7 and day 42 following dihydroartemisinin + piperaquine (DHA + PIP) was 6.92% vs 29.1% following chloroquine (P < .001). In Indonesia, the incidence of gametocytemia was 33.6% following artesunate + amodiaquine (AS + AQ), 7.42% following artemether + lumefantrine, and 6.80% following DHA + PIP (P < .001 for DHA + PIP vs AS + AQ). CONCLUSIONS: P. vivax gametocyte carriage mirrors asexual-stage infection. Prevention of relapses, particularly in those with high asexual parasitemia, is likely the most important strategy for interrupting P. vivax transmission.

Single-Dose Rifampicin Leprosy Chemoprophylaxis for Household Contacts in Kiribati: An Audit of a Combined Retrospective and Prospective Approach.

Kiribati is a Pacific Island nation with a widely dispersed population and one of the highest rates of leprosy worldwide. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) of leprosy contacts has reduced new case detection rates in controlled trials. In 2018, an SDR-PEP programme was introduced in Kiribati that included screening and chemoprophylaxis of household contacts of leprosy cases retrospectively (2010-2017) and prospectively (2018-2022). We conducted a retrospective audit to determine the comprehensiveness, timeliness and feasibility of the SDR-PEP programme. Overall, 13,641 household contacts were identified (9791 in the retrospective and 3850 in the prospective cohort). In the retrospective cohort, 1044 (11%) contacts were absent, 403 (4%) were ineligible for SDR, and 42 new cases were detected (0.4%) Overall, SDR coverage was 84.7%. In the prospective cohort, 164 (4%) contacts were absent, 251 (7%) were ineligible for SDR, and 23 new cases were diagnosed (0.6%). Overall, SDR coverage was 88.1%. Across both cohorts, there were 23 SDR refusals. The median time to SDR administration was 220 days (IQR 162-468) and 120 days (IQR 36-283) for the retrospective and prospective cohorts, respectively. SDR was readily accepted in both cohorts. The new case detection rate (0.5%) is consistent with that in other studies. Overall SDR coverage in both the retrospective and prospective phases met programmatic expectations.

Major burden of severe anemia from non-falciparum malaria species in Southern Papua: a hospital-based surveillance study.

BACKGROUND: The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. METHODS AND FINDINGS: Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81-9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16-9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44-9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49-9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99-3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00-2.23), 1.87 (95% CI 1.74-2.01), and 2.18 (95% CI 1.76-2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%-13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%-16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17-6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses. CONCLUSIONS: In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.

Primaquine-induced Severe Hemolysis in the Absence of Concomitant Malaria: Effects on G6PD Activity and Renal Function.

Primaquine prevents relapses of Plasmodium vivax malaria but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The clinical and laboratory features of this outcome are usually confounded by the clinical and hemolytic effects of concomitant malaria. We describe a case of severe hemolysis occurring after a total dose of 2.04 mg/kg of primaquine used for prophylaxis in a young, G6PD-deficient (Kaiping variant), Australian man without malaria. During acute hemolysis, he had markedly elevated urinary beta-2-microglobulin, suggestive of renal tubular injury (a well-recognized complication of primaquine-induced hemolysis). He also had albuminuria and significantly increased excretion of glycocalyx metabolites, suggestive of glomerular glycocalyx degradation and injury. We show that regularly dosed paracetamol given for its putative renoprotective effect is safe in the context of severe oxidative hemolysis. Acute drug-induced hemolysis transiently increases G6PD activity. Cases such as this improve our understanding of primaquine-induced hemolysis and ultimately will help facilitate widespread safe and effective use of this critically important drug.