Tropical Medicine publications 2018

Musoro JZ, Zwinderman AH, Bosman R, Abu-Hanna A, Geskus RB. 2018. Dynamic prediction of mortality among patients in intensive care using the sequential organ failure assessment (SOFA) score: a joint competing risk survival and longitudinal modeling approach Statistica Neerlandica, 72 (1), pp. 34-47. | Show Abstract | Read more

© 2017 The Authors. Statistica Neerlandica © 2017 VVS. In intensive care units (ICUs), besides routinely collected admission data, a daily monitoring of organ dysfunction using scoring systems such as the sequential organ failure assessment (SOFA) score has become practice. Such updated information is valuable in making accurate predictions of patients' survival. Few prediction models that incorporate this updated information have been reported. We used follow-up data of ICU patients who either died or were discharged at the end of hospital stay, without censored cases. We propose a joint model comprising a linear mixed effects submodel for the development of longitudinal SOFA scores and a proportional subdistribution hazards submodel for death as end point with discharge as competing risk. The two parts are linked by shared latent terms. Because there was no censoring, it was straightforward to fit our joint model using available software. We compared predictive values, based on the Brier score and the area under the receiver operating characteristic curve, from our model with those obtained from an earlier modeling approach by Toma et al. [Journal of Biomedical Informatics 40, 649, (2007)] that relied on patterns discovered in the SOFA scores over a given period of time.

Cravo P, Machado RB, Leite JA, Leda T, Suwanarusk R, Bittencourt N, Albrecht L, Judice C, Lopes SCP, Lacerda MVG et al. 2018. In silico epitope mapping and experimental evaluation of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) as a malaria vaccine candidate. Malar J, 17 (1), pp. 20. | Show Abstract | Read more

BACKGROUND: Technical limitations for culturing the human malaria parasite Plasmodium vivax have impaired the discovery of vaccine candidates, challenging the malaria eradication agenda. The immunogenicity of the M2 domain of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) antigen cloned from the Plasmodium yoelii murine parasite, has been previously demonstrated. RESULTS: Detailed epitope mapping of MAEBL through immunoinformatics identified several MHCI, MHCII and B cell epitopes throughout the peptide, with several of these lying in the M2 domain and being conserved between P. vivax, P. yoelii and Plasmodium falciparum, hinting that the M2-MAEBL is pan-reactive. This hypothesis was tested through functional assays, showing that P. yoelii M2-MAEBL antisera are able to recognize and inhibit erythrocyte invasion from both P. falciparum and P. vivax parasites isolated from Thai patients, in ex vivo assays. Moreover, the sequence of the M2-MAEBL is shown to be highly conserved between P. vivax isolates from the Amazon and Thailand, indicating that the MAEBL antigen may constitute a vaccine candidate outwitting strain-specific immunity. CONCLUSIONS: The MAEBL antigen is promising candidate towards the development of a malaria vaccine.

Adhikari B, Phommasone K, Kommarasy P, Soundala X, Souvanthong P, Pongvongsa T, Henriques G, Newton PN, White NJ, Day NPJ et al. 2018. Why do people participate in mass anti-malarial administration? Findings from a qualitative study in Nong District, Savannakhet Province, Lao PDR (Laos). Malar J, 17 (1), pp. 15. | Show Abstract | Read more

BACKGROUND: As a part of targeted malaria elimination (TME) in the Greater Mekong Sub-region (GMS), mass drug administration (MDA) with anti-malarials was conducted in four villages in Nong District, Savannakhet Province, Lao PDR (Laos). A high proportion of the target population participated in the MDA, with over 87% agreeing to take the anti-malarial. Drawing on qualitative data collected alongside the MDA, this article explores the factors that led to this high population coverage. METHODS: Qualitative data collection methods included observations, which were recorded in field notes, focus group discussions (FGDs), and semi-structured interviews (SSIs). Data were collected on local context, MDA-related knowledge, attitudes and perceptions. FGDs and SSIs were audio-recorded, transcribed and translated to English. All transcriptions and field notes underwent qualitative content analysis using QSR NVivo. RESULTS: Respondents recognized malaria as a health concern and described the need for a malaria control program. The risk of malaria including asymptomatic infection was explained in terms of participants' work in forest and fields, and poor hygiene. During the MDA rounds, there was an improvement in knowledge on the concept of asymptomatic malaria, the rationale of MDA and the blood test. In all four villages, poverty affected access to healthcare and the provision of free care by TME was highly appreciated. TME was jointly undertaken by research staff and local volunteers. Authorities were involved in all TME activities. Lao Theung communities were cohesive and community members tended to follow each other's behaviour closely including participation in MDA. Factors such as understanding the concept and rationale of the study, free health care, collaboration with the village volunteers, support from authorities and cohesive communities contributed in building trust and high population coverage in MDA. CONCLUSION: Future malaria control programmes can become successful in achieving the high coverage in MDAs drawing from the success of TME in Laos. A high population coverage in TME was a combination of various factors that included the community engagement to promote the concept and rationale of MDA for asymptomatic malaria in addition to their baseline understanding of malaria as a health concern, provision of free primary health care, partnering of the research with local volunteers and authorities, building social relationship with community members and the cohesive nature of the communities boosted the trust and participation in MDA.

Jones C, Talisuna AO, Snow RW, Zurovac D. 2018. "We were being treated like the Queen": understanding trial factors influencing high paediatric malaria treatment adherence in western Kenya. Malar J, 17 (1), pp. 8. | Show Abstract | Read more

BACKGROUND: Adherence to anti-malarial medication is highly variable but frequently suboptimal. Numerous interventions with a variety of methodological approaches have been implemented to address the problem. A recently conducted, randomized, controlled trial in western Kenya evaluated the effects of short message service (SMS) reminders on paediatric adherence to artemether-lumefantrine (AL) and found over 97% adherence rates in both intervention and control arms. The current study was undertaken to explore participants' experiences in the trial and identify the factors contributing to the high adherence rates. METHODS: In July 2016, 5 months after the trial completion, focus group discussions (FGDs) were undertaken with caregivers of children who had been treated in the intervention (n = 2) or control (n = 2) arms and who, post-trial, had received malaria treatment from the same facilities. The FGDs explored similarities and differences in perceptions and experiences of the care they received during and after the trial. RESULTS: Intervention-arm participants reported that SMS messages were effective dosing reminders. Participants from both arms reported that trial instructions to keep empty AL packs for verification during a home visit by a health worker affected their dosing and adherence practices. Differences between trial and post-trial treatment experiences included: administration of the first AL dose by health workers with demonstration of dispersible tablets dilution; advice on what to do if a child vomited; clear instructions on timing of dosing with efforts made to ensure understanding; and, information that dose completion was necessary with explanation provided. Participants reported that after the trial AL was not available at facilities, constraining their ability to adhere to recommended malaria treatment. They emphasized receiving respectful and personal treatment from trial health workers contributing to perceptions of high quality care and enhanced readiness to adhere to dosing instructions. CONCLUSIONS: This study highlights the complex range of factors that influence AL adherence. The results suggest that in addition to standardized definitions and measurement of adherence, and the influence of enrolment procedures, AL adherence trials need to take account of how intervention impact can be influenced by differences in the quality of care received under trial and routine conditions.

Fellmeth G, Plugge EH, Carrara V, Fazel M, Oo MM, Phichitphadungtham Y, Pimanpanarak M, Wai NK, Mu O, Charunwatthana P et al. 2018. Migrant perinatal depression study: a prospective cohort study of perinatal depression on the Thai-Myanmar border. BMJ Open, 8 (1), pp. e017129. | Show Abstract | Read more

PURPOSE: Perinatal depression is a significant contributor to maternal morbidity. Migrant women in resource-poor settings may be at increased risk, yet little research has been conducted in low-income and middle-income settings. This prospective cohort study of migrant women on the Thai-Myanmar border aims to establish prevalence of perinatal depression, identify risk factors for perinatal depression and examine associations with infant outcomes. PARTICIPANTS: Participating women are labour migrants and refugees living on the Thai-Myanmar border. A total of 568 women were recruited in their first trimester of pregnancy and are being followed up to 1-year postpartum. FINDINGS TO DATE: At baseline, women in our study had a median age of 25 years, the predominant ethnicity was Sgaw Karen (48.9%), agriculture was the main employment sector (39.2%) and educational attainment was low with a median of 4 years of education. In the first trimester of pregnancy, a quarter (25.8%; 95% CI 22.3 to 29.5) of all women were depressed as diagnosed by the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. FUTURE PLANS: Follow-up is ongoing and expected to continue until January 2018. The prevalence of depression at later stages of pregnancy and during the first postpartum year will be identified, and associations between depression status and demographic, social, migration-related, medical, obstetric and infant factors will be quantified. TRIAL REGISTRATION NUMBER: NCT02790905.

Janet S, Carrara VI, Simpson JA, Thin NWW, Say WW, Paw NTM, Chotivanich K, Turner C, Crawley J, McGready R. 2018. Early neonatal mortality and neurological outcomes of neonatal resuscitation in a resource-limited setting on the Thailand-Myanmar border: A descriptive study. PLoS One, 13 (1), pp. e0190419. | Show Abstract | Read more

BACKGROUND: Of the 4 million neonatal deaths worldwide yearly, 98% occur in low and middle-income countries. Effective resuscitation reduces mortality and morbidity but long-term outcomes in resource-limited settings are poorly described. This study reports on newborn neurological outcomes following resuscitation at birth in a resource-limited setting where intensive newborn care including intubation is unavailable. METHODS: Retrospective analysis of births records from 2008 to 2015 at Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border. FINDINGS: From 21,225 newbonrs delivered, 15,073 (71%) met the inclusion criteria (liveborn, singleton, ≥28 weeks' gestation, delivered in SMRU). Neonatal resuscitation was performed in 460 (3%; 422 basic, 38 advanced) cases. Overall early neonatal mortality was 6.6 deaths per 1000 live births (95% CI 5.40-8.06). Newborns receiving basic and advanced resuscitation presented an adjusted rate for death of 1.30 (95%CI 0.66-2.55; p = 0.442), and 6.32 (95%CI 3.01-13.26; p<0.001) respectively, compared to newborns given routine care. Main factors related to increased need for resuscitation were breech delivery, meconium, and fetal distress (p<0.001). Neurodevelopmental follow-up to one year was performed in 1,608 (10.5%) of the 15,073 newborns; median neurodevelopmental scores of non-resuscitated newborns and those receiving basic resuscitation were similar (64 (n = 1565) versus 63 (n = 41); p = 0.732), while advanced resuscitation scores were significantly lower (56 (n = 5); p = 0.017). INTERPRETATIONS: Newborns requiring basic resuscitation at birth have normal neuro-developmental outcomes at one year of age compared to low-risk newborns. Identification of risk factors (e.g., breech delivery) associated with increased need for neonatal resuscitation may facilitate allocation of staff to high-risk deliveries. This work endorses the use of basic resuscitation in low-resource settings, and supports on-going staff training to maintain bag-and-mask ventilation skills.

Hong Chau TT, Minh Chau NN, Hoang Le NT, Chung The H, Voong Vinh P, Nguyen To NT, Ngoc NM, Tuan HM, Chau Ngoc TL, Kolader M-E et al. 2018. A Double-blind, Randomized, Placebo-controlled Trial of Lactobacillus acidophilus for the Treatment of Acute Watery Diarrhea in Vietnamese Children. Pediatr Infect Dis J, 37 (1), pp. 35-42. | Show Abstract | Read more

BACKGROUND: Probiotics are the most frequently prescribed treatment for children hospitalized with diarrhea in Vietnam. We were uncertain of the benefits of probiotics for the treatment of acute watery diarrhea in Vietnamese children. METHODS: We conducted a double-blind, placebo-controlled, randomized trial of children hospitalized with acute watery diarrhea in Vietnam. Children meeting the inclusion criteria (acute watery diarrhea) were randomized to receive either 2 daily oral doses of 2 × 10 CFUs of a local probiotic containing Lactobacillus acidophilus or placebo for 5 days as an adjunct to standard of care. The primary end point was time from the first dose of study medication to the start of the first 24-hour period without diarrhea. Secondary outcomes included the total duration of diarrhea and hospitalization, daily stool frequency, treatment failure, daily fecal concentrations of rotavirus and norovirus, and Lactobacillus colonization. RESULTS: One hundred and fifty children were randomized into each study group. The median time from the first dose of study medication to the start of the first 24-hour diarrhea-free period was 43 hours (interquartile range, 15-66 hours) in the placebo group and 35 hours (interquartile range, 20-68 hours) in the probiotic group (acceleration factor 1.09 [95% confidence interval, 0.78-1.51]; P = 0.62). There was also no evidence that probiotic treatment was efficacious in any of the predefined subgroups nor significantly associated with any secondary end point. CONCLUSIONS: This was a large double-blind, placebo-controlled trial in which the probiotic underwent longitudinal quality control. We found under these conditions that L. acidophilus was not beneficial in treating children with acute watery diarrhea.

Agweyu A, Lilford RJ, English M, Clinical Information Network Author Group. 2018. Appropriateness of clinical severity classification of new WHO childhood pneumonia guidance: a multi-hospital, retrospective, cohort study. Lancet Glob Health, 6 (1), pp. e74-e83. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Management of pneumonia in many low-income and middle-income countries is based on WHO guidelines that classify children according to clinical signs that define thresholds of risk. We aimed to establish whether some children categorised as eligible for outpatient treatment might have a risk of death warranting their treatment in hospital. METHODS: We did a retrospective cohort study of children aged 2-59 months admitted to one of 14 hospitals in Kenya with pneumonia between March 1, 2014, and Feb 29, 2016, before revised WHO pneumonia guidelines were adopted in the country. We modelled associations with inpatient mortality using logistic regression and calculated absolute risks of mortality for presenting clinical features among children who would, as part of revised WHO pneumonia guidelines, be eligible for outpatient treatment (non-severe pneumonia). FINDINGS: We assessed 16 162 children who were admitted to hospital in this period. 832 (5%) of 16 031 children died. Among groups defined according to new WHO guidelines, 321 (3%) of 11 788 patients with non-severe pneumonia died compared with 488 (14%) of 3434 patients with severe pneumonia. Three characteristics were strongly associated with death of children retrospectively classified as having non-severe pneumonia: severe pallor (adjusted risk ratio 5·9, 95% CI 5·1-6·8), mild to moderate pallor (3·4, 3·0-3·8), and weight-for-age Z score (WAZ) less than -3 SD (3·8, 3·4-4·3). Additional factors that were independently associated with death were: WAZ less than -2 to -3 SD, age younger than 12 months, lower chest wall indrawing, respiratory rate of 70 breaths per min or more, female sex, admission to hospital in a malaria endemic region, moderate dehydration, and an axillary temperature of 39°C or more. INTERPRETATION: In settings of high mortality, WAZ less than -3 SD or any degree of pallor among children with non-severe pneumonia was associated with a clinically important risk of death. Our data suggest that admission to hospital should not be denied to children with these signs and we urge clinicians to consider these risk factors in addition to WHO criteria in their decision making. FUNDING: Wellcome Trust.

Thapa SS, Basnyat B. 2018. Common Bite-Bizarre Rash. Wilderness Environ Med, | Read more

Carrington LB, Tran BCN, Le NTH, Luong TTH, Nguyen TT, Nguyen PT, Nguyen CVV, Nguyen HTC, Vu TT, Vo LT et al. 2018. Field- and clinically derived estimates of Wolbachia-mediated blocking of dengue virus transmission potential in Aedes aegypti mosquitoes. Proc Natl Acad Sci U S A, 115 (2), pp. 361-366. | Show Abstract | Read more

The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel-infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-born arboviruses.

Nguon C, Dysoley L, Davoeung C, Sovann Y, Sanann N, Sareth M, Kunthea P, Vuth S, Sovann K, Kol K et al. 2018. Art and theatre for health in rural Cambodia. Glob Bioeth, 29 (1), pp. 16-21. | Show Abstract | Read more

This article describes our experience using art and theatre to engage rural communities in western Cambodia to understand malaria and support malaria control and elimination. The project was a pilot science-arts initiative to supplement existing engagement activities conducted by local authorities. In 2016, the project was conducted in 20 villages, involved 300 community members and was attended by more than 8000 people. Key health messages were to use insecticide-treated bed-nets and repellents, febrile people should attend village malaria workers, and to raise awareness about the risk of forest-acquired malaria. Building on the experience and lessons learnt in the year prior, the 2017 project which was conducted in 15 villages involved 600 community members and attracted more than 12,000 people. In addition to the malaria theme, upon discussion with local health authorities, secondary theme (infant vaccination) was added to the 2017 project. We learnt the following lessons from our experience in Cambodia: involving local people including children from the beginning of the project and throughout the process is important; messages should be kept simple; it is necessary to take into consideration practical issues such as location and timing of the activities; and that the project should offer something unique to communities.

Otten C, Brilli M, Vollmer W, Viollier PH, Salje J. 2018. Peptidoglycan in obligate intracellular bacteria. Mol Microbiol, 107 (2), pp. 142-163. | Show Abstract | Read more

Peptidoglycan is the predominant stress-bearing structure in the cell envelope of most bacteria, and also a potent stimulator of the eukaryotic immune system. Obligate intracellular bacteria replicate exclusively within the interior of living cells, an osmotically protected niche. Under these conditions peptidoglycan is not necessarily needed to maintain the integrity of the bacterial cell. Moreover, the presence of peptidoglycan puts bacteria at risk of detection and destruction by host peptidoglycan recognition factors and downstream effectors. This has resulted in a selective pressure and opportunity to reduce the levels of peptidoglycan. In this review we have analysed the occurrence of genes involved in peptidoglycan metabolism across the major obligate intracellular bacterial species. From this comparative analysis, we have identified a group of predicted 'peptidoglycan-intermediate' organisms that includes the Chlamydiae, Orientia tsutsugamushi, Wolbachia and Anaplasma marginale. This grouping is likely to reflect biological differences in their infection cycle compared with peptidoglycan-negative obligate intracellular bacteria such as Ehrlichia and Anaplasma phagocytophilum, as well as obligate intracellular bacteria with classical peptidoglycan such as Coxiella, Buchnera and members of the Rickettsia genus. The signature gene set of the peptidoglycan-intermediate group reveals insights into minimal enzymatic requirements for building a peptidoglycan-like sacculus and/or division septum.

Peto TJ, Tripura R, Davoeung C, Nguon C, Nou S, Heng C, Kunthea P, Adhikari B, Lim R, James N et al. 2018. Reflections on a Community Engagement Strategy for Mass Antimalarial Drug Administration in Cambodia. Am J Trop Med Hyg, 98 (1), pp. 100-104. | Show Abstract | Read more

Mass drug administration (MDA) to interrupt malaria transmission requires the participation of entire communities. As part of a clinical trial in western Cambodia, four villages received MDA in 2015-2016. Before approaching study communities, a collaboration was established with the local health authorities, village leaders, and village malaria workers. Formative research guided the development of engagement strategies. In each village, a team of volunteers was formed to explain MDA to their neighbors and provide support during implementation. Public mobilization events featuring drama and music were used to introduce MDA. Villages comprised groups with different levels of understanding and interests; therefore, multiple tailored engagement strategies were required. The main challenges were explaining malaria transmission, managing perceptions of drug side effects, and reaching mobile populations. It was important that local leaders took a central role in community engagement. Coverage during each round of MDA averaged 84%, which met the target for the trial.

Inzaule SC, Hamers RL, Calis J, Boerma R, Sigaloff K, Zeh C, Mugyenyi P, Akanmu S, Rinke De Wit TF. 2018. When prevention of mother-To-child HIV transmission fails: Preventing pretreatment drug resistance in African children AIDS, 32 (2), pp. 143-147. | Read more

Chu TTT, Sinha A, Malleret B, Suwanarusk R, Park JE, Naidu R, Das R, Dutta B, Ong ST, Verma NK et al. 2018. Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol, 180 (1), pp. 118-133. | Show Abstract | Read more

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.

Karkey A, Thwaites GE, Baker S. 2018. The evolution of antimicrobial resistance in Salmonella Typhi. Curr Opin Gastroenterol, 34 (1), pp. 25-30. | Citations: 1 (Scopus) | Show Abstract | Read more

PURPOSE OF REVIEW: Increasing antimicrobial resistance in Salmonella Typhi is a serious public health concern, especially in industrializing countries. Here we review recent clinical and laboratory data concerning the evolution of antimicrobial resistance, with particular reference to the emergence resistance against fluoroquinolones, third generation cephalosporins, and azithromycin. RECENT FINDINGS: The last 40 years have witnessed the sequential emergence of resistance to all first-line antimicrobials used in the treatment of S. Typhi infections. Multidrug resistance (MDR), defined by resistance to chloramphenicol, amoxicillin, and co-trimoxazole, emerged in the 1990s, followed rapidly by reduced susceptibility to fluoroquinolones. In the current decade, high-level fluoroquinolone resistance has emerged in south Asia and threatens to spread worldwide. Increasing reliance is now being placed on the activity of third generation cephalosporins and azithromycin, but resistance against these agents is developing. Carbapenems and tigecycline may be alternatives, although clinical data are sparse, and in some settings reversion to chloramphenicol and co-trimoxazole susceptibility is occurring. Therefore, older drugs may yet have a role in the treatment of S. Typhi infections. SUMMARY: Good surveillance, improved diagnostics, more prudent use of antimicrobials, and effective vaccines will all be critical to reducing the burden of disease caused by S. Typhi.

Andrews KA, Wesche D, McCarthy J, Möhrle JJ, Tarning J, Phillips L, Kern S, Grasela T. 2018. Model-Informed Drug Development for Malaria Therapeutics. Annu Rev Pharmacol Toxicol, 58 (1), pp. 567-582. | Show Abstract | Read more

Malaria is a critical public health problem resulting in substantial morbidity and mortality, particularly in developing countries. Owing to the development of resistance toward current therapies, novel approaches to accelerate the development efforts of new malaria therapeutics are urgently needed. There have been significant advancements in the development of in vitro and in vivo experiments that generate data used to inform decisions about the potential merit of new compounds. A comprehensive disease-drug model capable of integrating discrete data from different preclinical and clinical components would be a valuable tool across all stages of drug development. This could have an enormous impact on the otherwise slow and resource-intensive process of traditional clinical drug development.

Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, Wilkes CS, Patel K, Chandna A, Price RN et al. 2018. Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW. Clin Infect Dis, 66 (2), pp. 229-236. | Show Abstract | Read more

Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria. Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration: NCT02001012.

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