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.

Low-Quality Housing Is Associated With Increased Risk of Malaria Infection: A National Population-Based Study From the Low Transmission Setting of Swaziland.

BACKGROUND: Low-quality housing may confer risk of malaria infection, but evidence in low transmission settings is limited. METHODS: To examine the relationship between individual level housing quality and locally acquired infection in children and adults, a population-based cross-sectional analysis was performed using existing surveillance data from the low transmission setting of Swaziland. From 2012 to 2015, cases were identified through standard diagnostics in health facilities and by loop-mediated isothermal amplification in active surveillance, with uninfected subjects being household members and neighbors. Housing was visually assessed in a home visit and then classified as low, high, or medium quality, based on housing components being traditional, modern, or both, respectively. RESULTS: Overall, 11426 individuals were included in the study: 10960 uninfected and 466 infected (301 symptomatic and 165 asymptomatic). Six percent resided in low-quality houses, 26% in medium-quality houses, and 68% in high-quality houses. In adjusted models, low- and medium-quality construction was associated with increased risk of malaria compared with high-quality construction (adjusted odds ratio [AOR], 2.11 and 95% confidence interval [CI], 1.26-3.53 for low vs high; AOR, 1.56 and 95% CI, 1.15-2.11 for medium vs high). The relationship was independent of vector control, which also conferred a protective effect (AOR, 0.67; 95% CI, .50-.90) for sleeping under an insecticide-treated bed net or a sprayed structure compared with neither. CONCLUSIONS: Our study adds to the limited literature on housing quality and malaria risk from low transmission settings. Housing improvements may offer an attractive and sustainable additional strategy to support countries in malaria elimination.

Limitations of Rapid Diagnostic Testing in Patients with Suspected Malaria: A Diagnostic Accuracy Evaluation from Swaziland, a Low-Endemicity Country Aiming for Malaria Elimination.

Background: The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Methods: Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. Results: From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively. After exclusion of samples with parasite densities <100/µL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. Conclusions: In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.