Severe Falciparum and Vivax Malaria on the Thailand-Myanmar Border: A Review of 1503 Cases.

BACKGROUND: The northwestern border of Thailand is an area of low seasonal malaria transmission. Until recent successful malaria elimination activities, malaria was a major cause of disease and death. Historically the incidences of symptomatic Plasmodium falciparum and Plasmodium vivax malaria were approximately similar. METHODS: All malaria cases managed in the Shoklo Malaria Research Unit along the Thailand-Myanmar border between 2000 and 2016 were reviewed. RESULTS: There were 80 841 consultations for symptomatic P. vivax and 94 467 for symptomatic P. falciparum malaria. Overall, 4844 (5.1%) patients with P. falciparum malaria were admitted to field hospitals, of whom 66 died, compared with 278 (0.34%) with P. vivax malaria, of whom 4 died (3 had diagnoses of sepsis, so the contribution of malaria to their fatal outcomes is uncertain). Applying the 2015 World Health Organization severe malaria criteria, 68 of 80 841 P. vivax admissions (0.08%) and 1482 of 94 467 P. falciparum admissions (1.6%) were classified as severe. Overall, patients with P. falciparum malaria were 15 (95% confidence interval, 13.2-16.8) times more likely than those with P. vivax malaria to require hospital admission, 19 (14.6-23.8) times more likely to develop severe malaria, and ≥14 (5.1-38.7) times more likely to die. CONCLUSIONS: In this area, both P. falciparum and P. vivax infections were important causes of hospitalization, but life-threatening P. vivax illness was rare.

Evolution of genetic markers for drug resistance after the introduction of dihydroartemisinin-piperaquine as first-line anti-malarial treatment for uncomplicated falciparum malaria in Indonesia.

BACKGROUND: Dihydroartemisinin-piperaquine has been Indonesia's first-line anti-malarial treatment since 2008. Annual therapeutic efficacy studies (TES) done in the last 12 years showed continued high treatment efficacy in uncomplicated Plasmodium falciparum malaria. Although these studies did not show evidence for artemisinin resistance, a slight increase in Late Treatment Failure was observed over time. It is highlight to explore the evolution of genetic markers for ACT partner drug resistance since adopting DHA-PPQ. METHODS: Dry blood spots were identified from a mass blood survey of uncomplicated falciparum malaria patients (N = 50) in Sumba from 2010 to 2018. Analysis of genotypic profile (N = 51) and a Therapeutic Efficacy Study (TES) from Papua (N = 142) from 2020 to 2021, 42-day follow-up. PCR correction using msp1, msp2, and glurp was used to distinguish recrudescence and reinfection. Parasite DNA from DBSs was used for genotyping molecular markers for antimalaria drug resistance, including in Pfk13, pfcrt, and pfmdr1, as well as gene copy number variation in pfpm2/3 and pfmdr1. RESULTS: The study revealed the absence of SNPs associated with ART resistance and several novel SNPs such as L396F, I526V, M579I and N537S (4.25%). In Sumba, the mutant haplotype SDD of pfmdr1 was found in one-third of the isolates, while only 8.9% in Papua. None of the pfcrt mutations linked to piperaquine resistance were observed, but 71% of isolates had pfcrt I356L. Amplification of the pfpm2/3 genes was in Sumba (17.02%) and Papua (13.7%), while pfmdr1 copy number prevalence was low (3.8%) in both areas. For the TES study, ten recurrences of infection were observed on days 28, 35, and 42. Late parasitological failure (LPF) was observed in 10/117 (8.5%) subjects by microscopy. PCR correction revealed that all nine cases were re-infections and one was confirmed as recrudescence. CONCLUSION: This study revealed that DHA-PPQ is still highly effective against P. falciparum. The genetic architecture of the parasite P. falciparum isolates during 2010-2021 revealed single copy of Pfpm2 and pfmdr1 were highly prevalent. The slight increase in DHA-PPQ LTF alerts researchers to start testing other ACTs as alternatives to DHA-PPQ for baseline data in order to get a chance of achieving malaria elimination wants by 2030.

Drug resistance of Plasmodium falciparum and Plasmodium vivax isolates in Indonesia.

This review article aims to investigate the genotypic profiles of Plasmodium falciparum and Plasmodium vivax isolates collected across a wide geographic region and their association with resistance to anti-malarial drugs used in Indonesia. A systematic review was conducted between 1991 and date. Search engines, such as PubMed, Science Direct, and Google Scholar, were used for articles published in English and Indonesian to search the literature. Of the 471 initially identified studies, 61 were selected for 4316 P. falciparum and 1950 P. vivax individual infections. The studies included 23 molecular studies and 38 therapeutic efficacy studies. K76T was the most common pfcrt mutation. K76N (2.1%) was associated with the haplotype CVMNN. By following dihydroartemisinin-piperaquine (DHA-PPQ) therapy, the mutant pfmdr1 alleles 86Y and 1034C were selected. Low prevalence of haplotype N86Y/Y184/D1246Y pfmdr1 reduces susceptibility to AS-AQ. SNP mutation pvmdr1 Y976F reached 96.1% in Papua and East Nusa Tenggara. Polymorphism analysis in the pfdhfr gene revealed 94/111 (84.7%) double mutants S108N/C59R or S108T/A16V in Central Java. The predominant pfdhfr haplotypes (based on alleles 16, 51, 59,108, 164) found in Indonesia were ANCNI, ANCSI, ANRNI, and ANRNL. Some isolates carried A437G (35.3%) or A437G/K540E SNPs (26.5%) in pfdhps. Two novel pfdhps mutant alleles, I588F/G and K540T, were associated with six pfdhps haplotypes. The highest prevalence of pvdhfr quadruple mutation (F57L/S58R/T61M/S117T) (61.8%) was detected in Papua. In pvdhps, the only polymorphism before and after 2008 was 383G mutation with 19% prevalence. There were no mutations in the pfk13 gene reported with validated and candidate or associated k13 mutation. An increased copy number of pfpm2, associated with piperaquine resistance, was found only in cases of reinfection. Meanwhile, mutation of pvk12 and pvpm4 I165V is unlikely associated with ART and PPQ drug resistance. DHA-PPQ is still effective in treating uncomplicated falciparum and vivax malaria. Serious consideration should be given to interrupt local malaria transmission and dynamic patterns of resistance to anti-malarial drugs to modify chemotherapeutic policy treatment strategies. The presence of several changes in pfk13 in the parasite population is of concern and highlights the importance of further evaluation of parasitic ART susceptibility in Indonesia.

Associations Between Restrictive Fluid Management and Renal Function and Tissue Perfusion in Adults With Severe Falciparum Malaria: A Prospective Observational Study.

BACKGROUND: Liberal fluid resuscitation has proved harmful in adults with severe malaria, but the level of restriction has not been defined. METHODS: In a prospective observational study in adults with severe falciparum malaria, restrictive fluid management was provided at the discretion of the treating physician. The relationships between the volume of fluid and changes in renal function or tissue perfusion were evaluated. RESULTS: A total of 154 patients were studied, 41 (26.6%) of whom died. Median total fluid intake during the first 6 and 24 hours from enrollment was 3.3 (interquartile range [IQR], 1.8-5.1) mL/kg per hour and 2.2 (IQR, 1.6-3.2) mL/kg per hour, respectively. Total fluid intake at 6 hours was not correlated with changes in plasma creatinine at 24 hours (n = 116; rs = 0.16; P = .089) or lactate at 6 hours (n = 94; rs = -0.05; P = .660). Development of hypotensive shock or pulmonary edema within 24 hours after enrollment were not related to the volume of fluid administration. CONCLUSIONS: Restrictive fluid management did not worsen kidney function and tissue perfusion in adult patients with severe falciparum malaria. We suggest crystalloid administration of 2-3 mL/kg per hour during the first 24 hours without bolus therapy, unless the patient is hypotensive.

Prevalence and diversity of human rotavirus among Thai adults.

Rotavirus infections have become one of the most common causes of infectious gastroenteritis in children. Although rotavirus infections have been intensively studied in infants and young children, the study in adults has been limited. As such, this study assessed the prevalence of rotaviruses and performed the molecular characterization of rotaviruses circulating in Thai adults experiencing acute gastroenteritis between January 2018 and December 2018. Group A human rotaviruses were detected in 100 feces samples by rapid immunochromatography. The peak incidence of infection occurred in February and began to decline in the summer months. From January 2018 to December 2018, there were 1344 acute gastroenteritis adult cases in the Hospital for Tropical Diseases, Bangkok, Thailand. Among these, 310 cases were rotavirus-suspected cases. Only 100 samples tested positive for rotavirus via an immunochromatography test. Twentynine out of the 100 rotavirus-positive samples were further characterized by real-time polymerase chain reaction. The G3[P8] strain was identified as the most prevalent (31.0%) followed by G1P[8], G8P[8] and G9P[8], and G2P[8], which accounted for 20.8%, 17.2%, and 13.8%, respectively. Because of the detection of rare rotavirus genotypes, such as G8, the surveillance of rotavirus epidemiology is crucial in monitoring new emergences of rotavirus strains, leading to a better understanding of the effects of strain variation for further vaccine development.

Prevalence and determinants of perinatal depression among labour migrant and refugee women on the Thai-Myanmar border: a cohort study.

BACKGROUND: Perinatal depression is a significant contributor to maternal morbidity and mortality globally. Migrant women, particularly those living in low- and middle-income settings, represent a particularly vulnerable group due to stressors experienced before, during and after migration. The vast majority of global migration flows occurring within and between low- and middle-income regions, yet existing evidence focuses predominantly on migrants in high-income destinations. This study aimed to redress this significant gap in the evidence by determining the prevalence and determinants of perinatal depression among migrant women on the Thai-Myanmar border. METHODS: A cohort of labour migrant and refugee women was followed-up from the first trimester of pregnancy to one month post-partum. Depression status was assessed in the first, second and third trimesters of pregnancy and at one month post-partum using the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. Women diagnosed with depression had immediate access to care. Data on potential demographic, social and clinical associated factors was collected using a questionnaire. Prevalence and incidence of any depressive disorder and moderate-severe depressive disorder was calculated. Univariable and multivariable logistic regression using complete case analysis was used to estimate odds ratios (OR) of association between exposure variables and depression status. RESULTS: Five hundred sixty-eight women participated. Period prevalence (from first trimester of pregnancy to one month post-partum) of moderate-severe perinatal depression was 18.5% (95% CI 15.4-21.9%). Overall, 15.4% (95% CI 11.8-19.6%) of women developed new-onset moderate-severe depression during the study period. Forty-two participants received treatment for depression. Risk factors were interpersonal violence (OR 4.5; 95% CI 1.9-11.1); history of trauma (OR 2.4; 95% CI 1.4-4.3); self-reported history of depression (OR 2.3; 95% CI 1.2-4.2); labour migrant status (OR 2.1; 95% CI 1.1-4.0); low social support (OR 2.1; 95% CI 1.1-3.7); and maternal age (OR 1.1 per year; 95% CI 1.0-1.1). Limitations of the study include that culturally specific manifestations of depression may have been missed. CONCLUSIONS: Perinatal depression represents a significant burden among migrant women on the Thai-Myanmar border. Programmes to address the determinants along with early case identification and effective treatment and referral systems are key to addressing perinatal depression in this low-resource setting.

Nutrition in transition: historical cohort analysis summarising trends in under- and over-nutrition among pregnant women in a marginalised population along the Thailand-Myanmar border from 1986 to 2016.

The objective of the present study is to summarise trends in under- and over-nutrition in pregnant women on the Thailand-Myanmar border. Refugees contributed data from 1986 to 2016 and migrants from 1999 to 2016 for weight at first antenatal consultation. BMI and gestational weight gain (GWG) data were available during 2004-2016 when height was routinely measured. Risk factors for low and high BMI were analysed for <18·5 kg/m2 or ≥23 kg/m2, respectively. A total of 48 062 pregnancies over 30 years were available for weight analysis and 14 646 pregnancies over 13 years (2004-2016) had BMI measured in first trimester (<14 weeks' gestational age). Mean weight at first antenatal consultation in any trimester increased over the 30-year period by 2·0 to 5·2 kg for all women. First trimester BMI has been increasing on average by 0·5 kg/m2 for refugees and 0·6 kg/m2 for migrants, every 5 years. The proportion of women with low BMI in the first trimester decreased from 16·7 to 12·7 % for refugees and 23·1 to 20·2 % for migrants, whereas high BMI increased markedly from 16·9 to 33·2 % for refugees and 12·3 to 28·4 % for migrants. Multivariate analysis demonstrated low BMI as positively associated with being Burman, Muslim, primigravid, having malaria during pregnancy and smoking, and negatively associated with refugee as opposed to migrant status. High BMI was positively associated with being Muslim and literate, and negatively associated with age, primigravida, malaria, anaemia and smoking. Mean GWG was 10·0 (sd 3·4), 9·5 (sd 3·6) and 8·3 (sd 4·3) kg, for low, normal and high WHO BMI categories for Asians, respectively.

Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.

Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration: NCT01641289.

Living with severe perinatal depression: a qualitative study of the experiences of labour migrant and refugee women on the Thai-Myanmar border.

BACKGROUND: Perinatal depression is an important contributor to maternal morbidity and mortality worldwide. Migrant women, particularly those resettling within low- and middle-income settings, are at increased risk of perinatal depression due to multiple stressors experienced before, during and after migration. Evidence on migrant perinatal mental health to date has focused largely on women in high-income destination countries, leaving the voices of displaced women in low-income settings unheard. This study addresses the current evidence gap by exploring the experiences of migrant women living on the Thai-Myanmar border. METHODS: In-depth interviews were conducted with pregnant and post-partum labour migrant and refugee women on the Thai-Myanmar border who had been diagnosed with severe depression. An interview guide covering women's current and past life experiences, social support and the impact of depression on social and occupational functioning was used as a prompt. Thematic analysis was used to identify themes emerging from women's narratives. RESULTS: Eleven pregnant and post-partum women with severe perinatal depression took part. Participating women provided extensive insight into the many difficult aspects of their lives that they perceived as contributing to their depression status. Predominant themes emerging from women's narratives included difficult relationships with partners, challenging life situations, mechanisms for coping with depression and impressions of mental health care. CONCLUSIONS: Labour migrant and refugee women with severe perinatal depression face a wide range of chronic stressors at the individual, household and community levels that are likely to have both short- and long-term negative effects on their mental well-being and day-to-day functioning. Participating women responded positively to the mental health support they received, and findings provide important insights into how services might further support their needs.

Adolescents' perceptions and experiences of pregnancy in refugee and migrant communities on the Thailand-Myanmar border: a qualitative study.

BACKGROUND: Adolescent pregnancy remains a global health concern, contributing to 11% of all births worldwide and 23% of the overall burden of disease in girls aged 15-19 years. Premature motherhood can create a negative cycle of adverse health, economic and social outcomes for young women, their babies and families. Refugee and migrant adolescent girls might be particularly at risk due to poverty, poor education and health infrastructure, early marriage, limited access to contraception and traditional beliefs. This study aims to explore adolescents' perceptions and experiences of pregnancy in refugee and migrant communities on the Thailand-Myanmar border. METHODS: In June 2016 qualitative data were collected in one refugee camp and one migrant clinic along the Thailand-Myanmar border by conducting 20 individual interviews with pregnant refugee and migrant adolescents and 4 focus group discussions with husbands, adolescent boys and non-pregnant girls and antenatal clinic staff. Inductive thematic analysis was used to identify codes and themes emerging from the data. RESULTS: Study participants perceived adolescent pregnancy as a premature life event that could jeopardise their future. Important themes were premarital sex, forced marriage, lack of contraception, school dropout, fear of childbirth, financial insecurity, support structures and domestic violence. Supportive relationships with mothers, husbands and friends could turn this largely negative experience into a more positive one. The main underlying reasons for adolescent pregnancy were associated with traditional views and stigma on sexual and reproductive health issues, resulting in a knowledge gap on contraception and life skills necessary to negotiate sexual and reproductive choices, in particular for unmarried adolescents. CONCLUSIONS: Adolescents perceive pregnancy as a challenging life event that can be addressed by developing comprehensive adolescent-friendly sexual and reproductive health services and education in refugee and migrant communities on the Thailand-Myanmar border. Creating a more tolerant and less stigmatising environment in these communities and their governing bodies will help to achieve this goal.

Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

BACKGROUND: Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD "normal" by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. METHODS AND FINDINGS: In a cohort study nested within a randomised clinical trial that compared different treatment regimens for P. vivax malaria, patients with a normal standard NADPH fluorescent spot test result (≳30%-40% of normal G6PD activity) were randomised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants. Between 21 February 2012 and 04 July 2014, 241 female participants were enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 d) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 d) dose (2/16 [13%]; p = 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-d regimen): -20.4% (95% CI -26.0% to -14.8%) (nadir on day 5) compared with the standard high (14 d) dose: -13.1% (95% CI -17.6% to -8.6%) (nadir day 6). Two heterozygotes taking the higher (7 d) primaquine dose required blood transfusion. In wild-type participants, mean haematocrit reductions were clinically insignificant and similar with both doses: -5.8 (95% CI -7.2% to -4.4%) (nadir day 3) compared with -5.5% (95% CI -7.4% to -3.7%) (nadir day 4), respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype and that the heterozygote groups were small. CONCLUSION: Higher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640574.

Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study.

BACKGROUND: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown. METHODS: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined. RESULTS: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 µM; 95% CI, 6.2-12.3 µM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 µM; 95% CI, 4.0-6.6 µM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis. CONCLUSIONS: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.

Sequestration and Red Cell Deformability as Determinants of Hyperlactatemia in Falciparum Malaria.

BACKGROUND: Hyperlactatemia is a strong predictor of mortality in severe falciparum malaria. Sequestered parasitized erythrocytes and reduced uninfected red blood cell deformability (RCD) compromise microcirculatory flow, leading to anaerobic glycolysis. METHODS: In a cohort of patients with falciparum malaria hospitalized in Chittagong, Bangladesh, bulk RCD was measured using a laser diffraction technique, and parasite biomass was estimated from plasma concentrations of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). A multiple linear regression model was constructed to examine their associations with plasma lactate concentrations. RESULTS: A total of 286 patients with falciparum malaria were studied, of whom 224 had severe malaria, and 70 died. Hyperlactatemia (lactate level, ≥ 4 mmol/L) was present in 111 cases. RCD at shear stresses of 1.7 Pa and 30 Pa was reduced significantly in patients who died, compared with survivors, individuals with uncomplicated malaria, or healthy individuals (P < .05, for all comparisons). Multiple linear regression analysis showed that the plasma PfHRP2 level, parasitemia level, total bilirubin level, and RCD at a shear stress of 1.7 Pa were each independently correlated with plasma lactate concentrations (n = 278; R(2) = 0.35). CONCLUSIONS: Sequestration of parasitized red blood cells and reduced RCD both contribute to decreased microcirculatory flow in severe disease.

The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis.

BACKGROUND: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined. METHODS: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course. RESULTS: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study. CONCLUSIONS: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.

Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study.

BACKGROUND: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. METHODS: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. RESULTS: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). CONCLUSIONS: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

The role of previously unmeasured organic acids in the pathogenesis of severe malaria.

INTRODUCTION: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria. METHODS: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death. RESULTS: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and ß-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81). CONCLUSIONS: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Pregnant migrant and refugee women's perceptions of mental illness on the Thai-Myanmar border: a qualitative study.

BACKGROUND: Mental illness is a significant contributor to the global burden of disease, with prevalence highest in low- and middle-income countries. Rates are high in women of childbearing age, especially during pregnancy and the first year post-partum. Migrant and refugee populations are at risk of developing mental illness due to the multiple stressors associated with migration. The Thai-Myanmar border area is home to large populations of migrants and refugees as a result of long-standing conflict, poverty and unemployment in Myanmar. This study aims to explore perceptions of mental illness among pregnant migrants and refugees and antenatal clinic staff living and working along the Thai-Myanmar border. METHODS: Thirteen focus group discussions were conducted with pregnant migrants, pregnant refugees and antenatal clinic staff. Focus groups were held in one large refugee camp and two migrant health clinics along the Thai-Myanmar border. Thematic analysis was used to identify and code themes emerging from the data. RESULTS: A total of 92 pregnant women and 24 antenatal clinic staff participated. Discussions centered around five main themes: symptoms of mental illness; causes of mental illness; suicide; mental illness during pregnancy and the post-partum period; and managing mental illness. Symptoms of mental illness included emotional disturbances, somatic symptoms and socially inappropriate behavior. The main causes were described as current economic and family-related difficulties. Suicide was frequently attributed to shame. Mental illness was thought to be more common during and following pregnancy due to a lack of family support and worries about the future. Talking to family and friends, medication and hospitalization were suggested as means of helping those suffering from mental illness. CONCLUSIONS: Mental illness was recognized as a concept by the majority of participants and there was a general willingness to discuss various aspects of it. More formal and systematic training including the development of assessment tools in the local languages would enable better ascertainment and treatment of mental illness in this population.

Challenges in tackling tuberculosis on the Thai-Myanmar border: findings from a qualitative study with health professionals.

BACKGROUND: Myanmar and Thailand belong to the top 22 high burden countries for tuberculosis (TB). Health care organizations play an essential role in addressing TB control in the two bridging border jurisdictions, Tak province, Thailand and Myawaddy district, Kayin state, Myanmar. However, health professionals face difficulties in TB control effort due to the nature of fluid population movements, resource constraints and ambiguous mechanisms to implement collaboration along the border. The purpose of this study is to identify the challenges to TB control among Myanmar migrants faced by stakeholders, focusing on the area of collaboration and interaction along the border. METHOD: The study conducted in-depth interviews with health policy makers and health care providers responsible for developing and implementing policies and TB programs in Tak province, Thailand and Myawaddy district, Kayin state, Myanmar. The participants included members of government organizations, United Nations agencies, community based organizations, and international NGO. One or two key stakeholders from each organization were approached to participate in the study. We gathered baseline information to identify TB policies and programs available on websites, brochures, and publications. Observations including field notes were made on site. The data transcriptions were coded for qualitative data analysis. Coding also developed categories that led to key themes. RESULTS: A total of 31 respondents (18 in Thailand and 13 in Myanmar) participated in the study. The main theme reported by participants was challenges in limited corroboration and coordination among stakeholders. Unstructured information sharing and lack of communication hindered the stakeholders from engaging in TB control. The respondents stressed that referral mechanisms across the border need to be strengthened. Other challenges were associated with increasing loss to follow up and subsequent MDR cases, constraints of service delivery, shortage of human resources, limited staff capacities within organizations and poor socioeconomic status of patients. CONCLUSIONS: Health professionals face many challenges in effectively addressing TB control. Addressing the insufficient coordination and collaboration by strengthening bi-national collaborative mechanisms among health care organizations is an essential step in reducing the burden of disease. Additional support and resources from governmental and non-governmental agencies will be required to address the challenges.

Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia.

BACKGROUND: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. METHODS: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. RESULTS: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). CONCLUSIONS: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

Pharmacokinetic interactions between primaquine and chloroquine.

Chloroquine combined with primaquine has been the standard radical curative regimen for Plasmodium vivax and Plasmodium ovale malaria for over half a century. In an open-label crossover pharmacokinetic study, 16 healthy volunteers (4 males and 12 females) aged 20 to 47 years were randomized into two groups of three sequential hospital admissions to receive a single oral dose of 30 mg (base) primaquine, 600 mg (base) chloroquine, and the two drugs together. The coadministration of the two drugs did not affect chloroquine or desethylchloroquine pharmacokinetics but increased plasma primaquine concentrations significantly (P ≤ 0.005); the geometric mean (90% confidence interval [CI]) increases were 63% (47 to 81%) in maximum concentration and 24% (13 to 35%) in total exposure. There were also corresponding increases in plasma carboxyprimaquine concentrations (P ≤ 0.020). There were no significant electrocardiographic changes following primaquine administration, but there was slight corrected QT (QTc) (Fridericia) interval lengthening following chloroquine administration (median [range] = 6.32 [-1.45 to 12.3] ms; P < 0.001), which was not affected by the addition of primaquine (5.58 [1.74 to 11.4] ms; P = 0.642). This pharmacokinetic interaction may explain previous observations of synergy in preventing P. vivax relapse. This trial was registered at ClinicalTrials.gov under reference number NCT01218932.