Inferring person-to-person networks of Plasmodium falciparum transmission: are analyses of routine surveillance data up to the task?

BACKGROUND: Inference of person-to-person transmission networks using surveillance data is increasingly used to estimate spatiotemporal patterns of pathogen transmission. Several data types can be used to inform transmission network inferences, yet the sensitivity of those inferences to different data types is not routinely evaluated. METHODS: The influence of different combinations of spatial, temporal, and travel-history data on transmission network inferences for Plasmodium falciparum malaria were evaluated. RESULTS: The information content of these data types may be limited for inferring person-to-person transmission networks and may lead to an overestimate of transmission. Only when outbreaks were temporally focal or travel histories were accurate was the algorithm able to accurately estimate the reproduction number under control, Rc. Applying this approach to data from Eswatini indicated that inferences of Rc and spatiotemporal patterns therein depend upon the choice of data types and assumptions about travel-history data. CONCLUSIONS: These results suggest that transmission network inferences made with routine malaria surveillance data should be interpreted with caution.

Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial.

INTRODUCTION: To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective. METHODS: We conducted a pragmatic cluster randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin-piperaquine (DP) or RACD involving RDTs and artemether-lumefantrine. Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence. RESULTS: From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.95 (95% CI 0.55 to 1.65) for all malaria and 0.82 (95% CI 0.40 to 1.71) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage. CONCLUSION: In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed. TRIAL REGISTRATION NUMBER: NCT02315690.

Active Case Finding for Malaria: A 3-Year National Evaluation of Optimal Approaches to Detect Infections and Hotspots Through Reactive Case Detection in the Low-transmission Setting of Eswatini.

BACKGROUND: Reactive case detection (RACD) is a widely practiced malaria elimination intervention whereby close contacts of index cases receive malaria testing to inform treatment and other interventions. However, the optimal diagnostic and operational approaches for this resource-intensive strategy are not clear. METHODS: We conducted a 3-year prospective national evaluation of RACD in Eswatini, a malaria elimination setting. Loop-mediated isothermal amplification (LAMP) was compared to traditional rapid diagnostic testing (RDT) for the improved detection of infections and for hotspots (RACD events yielding ≥1 additional infection). The potential for index case-, RACD-, and individual-level factors to improve efficiencies was also evaluated. RESULTS: Among 377 RACD events, 10 890 participants residing within 500 m of index cases were tested. Compared to RDT, LAMP provided a 3-fold and 2.3-fold higher yield to detect infections (1.7% vs 0.6%) and hotspots (29.7% vs 12.7%), respectively. Hotspot detection improved with ≥80% target population coverage and response times within 7 days. Proximity to the index case was associated with a dose-dependent increased infection risk (up to 4-fold). Individual-, index case-, and other RACD-level factors were considered but the simple approach of restricting RACD to a 200-m radius maximized yield and efficiency. CONCLUSIONS: We present the first large-scale national evaluation of optimal RACD approaches from a malaria elimination setting. To inform delivery of antimalarial drugs or other interventions, RACD, when conducted, should utilize more sensitive diagnostics and clear context-specific operational parameters. Future studies of RACD's impact on transmission may still be needed.

High Genetic Diversity of Plasmodium falciparum in the Low-Transmission Setting of the Kingdom of Eswatini.

BACKGROUND: To better understand transmission dynamics, we characterized Plasmodium falciparum genetic diversity in Eswatini, where transmission is low and sustained by importation. METHODS: Twenty-six P. falciparum microsatellites were genotyped in 66% of confirmed cases (2014-2016; N = 582). Population and within-host diversity were used to characterize differences between imported and locally acquired infections. Logistic regression was used to assess the added value of diversity metrics to classify imported and local infections beyond epidemiology data alone. RESULTS: Parasite population in Eswatini was highly diverse (expected heterozygosity [HE] = 0.75) and complex: 67% polyclonal infections, mean multiplicity of infection (MOI) 2.2, and mean within-host infection fixation index (FWS) 0.84. Imported cases had comparable diversity to local cases but exhibited higher MOI (2.4 vs 2.0; P = .004) and lower mean FWS (0.82 vs 0.85; P = .03). Addition of MOI and FWS to multivariate analyses did not increase discrimination between imported and local infections. CONCLUSIONS: In contrast to the common perception that P. falciparum diversity declines with decreasing transmission intensity, Eswatini isolates exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission. Estimates of malaria transmission intensity from genetic data need to consider the effect of importation, especially as countries near elimination.

Development of a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine and artemether-lumefantrine to treat Plasmodium falciparum infections in Swaziland: a pilot study.

BACKGROUND: Countries remain reluctant to adopt the 2012 World Health Organization recommendation for single low-dose (0.25 mg/kg) primaquine (SLD PQ) for Plasmodium falciparum transmission-blocking due to concerns over drug-related haemolysis risk, especially among glucose-6-phosphate dehydrogenase-deficient (G6PDd) people, without evidence demonstrating that it can be safely deployed in their settings. Pharmacovigilance methods provide a systematic way of collecting safety data and supporting the rollout of SLD PQ. METHODS: The Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT), comprising: (1) a standardized form to support the surveillance of possible adverse events following SLD PQ treatment; (2) a patient information card to enhance awareness of known adverse drug reactions of SLD PQ use; and (3) a database compiling recorded information, was developed and piloted. Data on patient characteristics, malaria diagnosis and treatment are collected. Blood samples are taken to measure haemoglobin (Hb) and test for G6PD deficiency. Active follow-up includes a repeat Hb measurement and adverse event monitoring on or near day 7. A 13-month prospective pilot study in two hospital facilities in Swaziland alongside the introduction of SLD PQ generated preliminary evidence on the feasibility and acceptability of PROMPT. RESULTS: PROMPT was well received by nurses as a simple, pragmatic approach to active surveillance of SLD PQ safety data. Of the 102 patients enrolled and administered SLD PQ, none were G6PDd. 93 (91.2 %) returned on or near day 7 for follow-up. Four (4.6 %) patients had falls in Hb ≥25 % from baseline, none of whom presented with signs or symptoms of anaemia. No patient's Hb fell below 7 g/dL and none required a blood transfusion. Of the 11 (11 %) patients who reported an adverse event over the study period, three were considered serious and included two deaths and one hospitalization; none were causally related to SLD PQ. Four non-serious adverse events were considered definitely, probably, or possibly related to SLD PQ. CONCLUSION: Improved pharmacovigilance to monitor and promote the safety of the WHO recommendation is needed. The successful application of PROMPT demonstrates its potential as an important tool to rapidly generate locally acquired safety data and support pharmacovigilance in resource-limited settings.