James Andrew Watson

Dengue-associated liver injury is common, prognostically significant, and associated with high mortality at severe thresholds. Oxidative stress is a key, potentially modifiable mechanism. N-acetylcysteine has strong biological plausibility and supportive preclinical data, but clinical evidence remains limited, underscoring the need for well-designed randomized trials to inform practice and policy.

Background: Serum or plasma concentrations of creatinine and urea are the usual laboratory parameters measured to assess kidney function and disease severity in patients with suspected severe malaria. Creatinine is preferred for estimation of the glomerular filtration rate, but the current threshold for defining severe malaria ( > 265 umol/L) is based on adult values and does not reflect the large difference between children and adults in normal values resulting from differences in muscle mass. We reevaluated these thresholds and their prognostic significance in severe malaria using individual patient data from large prospective studies. Methods: We pooled individual patient data from studies of severe malaria. Patients were included in the primary analysis population if their age (if missing, imputed from weight or height), coma status on admission, and either an admission serum or plasma creatinine or urea measurement (blood urea nitrogen, BUN), were all recorded. The primary outcome was mortality by day 28. The secondary outcome was the admission plasma Pf HRP2 concentration (a measure of parasite biomass). Bayesian penalised spline regression models were used to characterise the age-specific relationships (interaction with age) between the outcome and the absolute creatinine, the creatinine fold change relative to the age/weight predicted baseline, and the absolute urea. The models adjusted for coma status and calendar year, with nested random additive effects by study site and study. We estimated threshold plasma or serum creatinine and urea concentrations associated with > 5% mortality with probability > 0.9. Results: We pooled individual patient data from 22,663 patients recruited into 14 studies of severe malaria of whom 16,441 were included in the primary analysis population. The majority (84%; 13,793/16,441) were children under 15 years of age. Current thresholds for renal impairment were associated with mortalities substantially greater than 5%, especially in children. A creatinine increase of more than three times the age/weight predicted baseline value was associated with 0.9 probability of mortality >5%. A urea of 10 mmol/L had approximately similar prognostic value. A urea > 10 mmol/L was 3.5 times more common in adults than children. In children < 15 years of age urea was a better prognostic indicator of death than creatinine and, unlike creatinine, correlated with the plasma Pf HRP2 concentration. Interpretation: Admission serum or plasma creatinine > 3 times the age/weight expected baseline value (KDIGO stage 3) can be used to define severe malaria. In children urea is a better predictor of the true infection biomass and a better prognostic indicator for death. We recommend the following as defining criteria for severe malaria; either the simple urea (BUN) threshold of 10 mmol/L for both children and adults, or a > 3 times fold change in creatinine from predicted baseline.

Background: Seasonal malaria chemoprevention (SMC) using monthly sulfadoxine-pyrimethamine-amodiaquine (SPAQ) is being deployed in East Africa, where antimalarial drug-resistance levels are high. Dihydroartemisinin-piperaquine (DP) is a potential alternative. Methods: A prospective 28-day pharmacometric assessment of SMC was conducted in Karamoja, northern Uganda. In 2 villages children received SPAQ and in a third were randomized to DP versus no SMC. The primary outcome was malaria infection defined by capillary blood sample quantitative PCR (qPCR) positivity on day 28, or presentation with fever and slide or rapid test positivity after day 2. Results: Baseline qPCR malaria parasitemia prevalence among 1250 enrolled children was 46% (575/1250); Plasmodium falciparum 85%, other malarias (mainly Plasmodium ovale) 25%. Breakthrough parasitemias occurred in 7% (33/496) of DP, 31% (158/504) of SPAQ, and 39% (98/250) of no drug recipients. Clinical malaria (all P falciparum) developed in 17% of no drug (42/250; 1 severe), 8% of SPAQ (38/504; 2 severe), and 2% of DP (13/496) recipients. Adjusted protective efficacies against all malaria parasitemia, P falciparum parasitemia, and clinical malaria for SPAQ were 56% (95% CI, 35%–70%), 46% (11%–68%), and 60% (27%–78%) and for DP were 84% (77%–89%), 86% (75%–92%), and 86% (74%–92%), respectively. Some asymptomatic P falciparum infections were not cleared by SPAQ. All 260 P falciparum isolates genotyped were PfCRT K76 (haplotype CVMNK, marker of 4-aminoquinoline susceptibility); most were quintuple Pfdhfr/dhps mutants (ie, relatively sulfadoxine-pyrimethamine resistant). The chemoprevention drug exposure–response relationship was strong for desethylamodiaquine, but weak for sulfadoxine. Conclusions: SPAQ SMC had low clinical and parasitological chemopreventive efficacy in northern Uganda, whereas DP was effective. Clinical Trials Registration: NCT05323721.

Distinguishing treatment failure (recrudescence) from reinfection in uncomplicated falciparum malaria is essential for characterising antimalarial treatment efficacy in malaria endemic areas. Classification of recrudescence versus reinfection is usually based on a comparison of parasite allelic calls derived from PCR amplification and electrophoresis of individual polymorphic markers in the acute and recurrent blood samples. Match-counting methods (e.g., 3/3 or 2/3 matching alleles) have usually been applied, but these do not account for multiple comparisons per-marker when infections are polyclonal. We show that when infections are polyclonal, as is common in high transmission settings, currently used match-counting and model-based methods may have unacceptably high false-discovery rates leading to overestimation of treatment failure. We develop the software PfRecur which provides analytical Bayesian posterior probabilities of treatment failure in recurrent falciparum malaria. We use data from a recent study in Angola to demonstrate the potential utility of our model in resolving complex polyclonal P. falciparum infections, thereby providing more accurate estimation of treatment failure rates.

Dengue, caused by any one of four distinct virus serotypes, is the most rapidly spreading mosquito-borne viral disease worldwide. It is a primary arboviral infection with increasing global incidence, driven by climate change, urbanisation, and the expanding range of Aedes mosquito vectors. Despite growing research interest, outcome and measurement instrument heterogeneity in dengue clinical trials remains high, limiting comparability and evidence synthesis. This project aimed to develop a globally relevant Core Outcome Measurement Set (COMS) for use in dengue clinical trials through international consensus.This consensus study followed COMET and COS-STAD guidelines and was conducted in two phases. Phase I focused on developing a core outcome set (COS) through six steps: (1) a systematic literature review; (2) qualitative interviews with people with lived experience of dengue; (3) review by the management group and steering committee; (4) a two-round modified Delphi survey and structured online consensus meetings to finalise the COS for ‘hospitalised’ and ‘early’ stages of dengue. Input from critical care experts informed recommendations for the ‘ICU/HDU’ COS. Phase II involved: (5) targeted review of outcome measurement instruments; and (6) a hybrid international consensus workshop to finalise the COMS.The agreed COMS for ‘hospitalised’ dengue included seven outcomes; the ‘early’ COS includes these plus four more. For critical care trials, use of existing ICU-specific COS was recommended. Unified definitions were developed for nine clinician-reported outcomes.The DEN-CORE COMS provides a consensus-based framework for harmonising outcome selection and measurement in dengue trials, improving comparability and supporting policy and clinical decision-making.

Primaquine is the only widely available drug to prevent relapses of Plasmodium vivax malaria. Primaquine is underused because of concerns over oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing ‘slow burn’ hemolysis were safe in G6PD-deficient Thai and Burmese male volunteers. We developed and calibrated a within-host model of primaquine hemolysis in G6PD deficiency, using detailed serial hemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique time points). We estimate that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that 5 mg/kg primaquine total dose can be administered safely to G6PD-deficient individuals over 14 days with expected hemoglobin drops of 18 to 43% (2.7 to 6.5 g/dL drop from a baseline of 15 g/dL). CLINICAL TRIALS: This study is registered with the Thai Clinical Trials Registry (TCTR) as TCTR20170830002 a nd TCTR20220317004 .