The effect of new Mycobacterium tuberculosis infection on the sensitivity of prognostic TB signatures

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcriptomic signature (RISK11) for predicting incident TB in a high transmission setting. RISK11 is able to predict TB disease progression but optimal prognostic performance was limited to a 6-month horizon.METHODS: Using a mathematical model, we estimated how subsequent Mycobacterium tuberculosis (MTB) infection may have contributed to the decline in sensitivity of RISK11. We calculated the effect at different RISK11 thresholds (60% and 26%) and for different assumptions about the risk of MTB infection.RESULTS: Modelled sensitivity over 15 months, excluding new infection, was 28.7% (95% CI 12.3–74.1) compared to 25.0% (95% CI 12.7–45.9) observed in the trial. Modelled sensitivity exceeded the minimum criteria (>75%) over a 9-month horizon at the 60% threshold and over 12 months at the 26% threshold.CONCLUSIONS: The effect of new infection on prognostic signature performance is likely to be small. Signatures such as RISK11 may be most useful in individuals, such as household contacts, where probable time of infection is known.

Malaria vector dynamics and utilization of insecticide-treated nets in low-transmission setting in Southwest Ethiopia: implications for residual transmission

Background Understanding the behaviour of local malaria vectors is essential as effectiveness of the commonly used vector-targeted malaria control tools heavily relies on behaviour of the major malaria vectors. This study was conducted to determine species composition, biting behaviour, host preference and infectivity of anopheline mosquitoes, and assess utilization of insecticide-treated nets (ITNs) in a low transmission setting in Southwest Ethiopia. Methods Adult anopheline mosquitoes were collected using human landing catches (HLCs), Centers for Disease Control and Prevention (CDC) light traps (LTs) and Pyrethrum Spray Catches (PSCs) from June 2016 to May 2018 in Kishe, Jimma Zone, Southwest Ethiopia. The anopheline mosquitoes were morphologically identified. Moreover, sub-sample of An. gambiae s.l. was identified to species using polymerase chain reaction (PCR). Circum-sporozoite proteins (CSPs) and blood meal sources of the anopheline mosquitoes were tested using enzyme-linked immunosorbent assay (ELISA). In addition, a cross-sectional survey was conducted to assess ITN utilization by the inhabitants. Results A total of 3659 anopheline mosquitoes comprising An. coustani complex (84.4%), An. gambiae s.l. (11.3%), and An. pharoensis and An. squamosus comprising less than 5% were collected. The anopheline mosquitoes showed marked outdoor (67%) and early evening (63%) biting behaviour. An. coustani complex and An. gambiae s.l. were predominantly zoophilic and anthropophilic, respectively. None of the sampled anopheline were CSP-positive. Most of the households (97.8%) owned at least one ITN, with modest usage by the inhabitants (73.4%). ITN usage was significantly higher among under-five children (AOR = 7.9, 95% CI: 4.41–14.03), household heads and spouses (AOR = 4.8, 95% CI: 3.0–7.59), those with sufficient access to ITNs (AOR = 1.8, 95% CI: 1.39–2.35), and who were not utilizing alternative mosquito repellents (AOR = 2.2, 95% CI: 1.58–2.99). Conclusion The anopheline mosquito species exhibited predominantly outdoor and early evening biting activity. Household ITN coverage was high with slight gap in usage. Vector control interventions should target outdoor and early biting vectors to further suppress the local mosquito population. Moreover, sensitization of the community on consistent use of ITNs is required.

Both co-infection and superinfection drive complex Anaplasma marginale strain structure in a natural transmission setting

Vector-borne pathogens commonly establish multi-strain infections, also called complex infections. How complex infections are established, either prior to or after the development of an adaptive immune response, termed co-infection or superinfection, respectively, has broad implications for the maintenance of genetic diversity, pathogen phenotype, epidemiology, and disease control strategies. Anaplasma marginale , a genetically diverse, obligate, intracellular tick-borne bacterial pathogen of cattle commonly establishes complex infections, particularly in regions with high transmission rates. Both co-infection and superinfection can be established experimentally, however it is unknown how complex infections develop in a natural transmission setting. To address this question, we introduced naïve animals into a herd in southern Ghana with high infection prevalence and high transmission pressure and tracked strain acquisition of A. marginale through time using multi-locus sequence typing. As expected, genetic diversity among strains was high and 97% of animals in the herd harboured multiple strains. All the introduced, naïve animals became infected, and three to four strains were typically detected in an individual animal prior to seroconversion, while one to two new strains were detected in an individual animal following seroconversion. On average, the number of strains acquired via superinfection was 16% less than those acquired via co-infection. Thus, while complex infections develop via both co-infection and superinfection, co-infection predominates in this setting. These findings have broad implications for the development of control strategies in high transmission settings.

Impact of asymptomatic Plasmodium falciparum infection on the risk of subsequent symptomatic malaria in a longitudinal cohort in Kenya

Background:Asymptomatic Plasmodium falciparum infections are common in sub-Saharan Africa, but their effect on subsequent symptomaticity is incompletely understood.Methods:In a 29-month cohort of 268 people in Western Kenya, we investigated the association between asymptomatic P. falciparum and subsequent symptomatic malaria with frailty Cox models.Results:Compared to being uninfected, asymptomatic infections were associated with an increased 1-month likelihood of symptomatic malaria [adjusted Hazard Ratio (aHR):2.61, 95%CI:2.05-3.33], and this association was modified by sex, with females [aHR:3.71, 95%CI:2.62-5.24] at higher risk for symptomaticity than males [aHR:1.76, 95%CI:1.24-2.50]. This increased symptomatic malaria risk was observed for asymptomatic infections of all densities and in people of all ages. Long-term risk was attenuated but still present in children under 5 [29-month aHR:1.38, 95%CI:1.05-1.81].Conclusions:In this high-transmission setting, asymptomatic P. falciparum can be quickly followed by symptoms and may be targeted to reduce the incidence of symptomatic illness.Funding:This work was supported by the National Institute of Allergy and Infectious Diseases (R21AI126024 to WPO, R01AI146849 to WPO and SMT).

Susceptibility of zero community transmission regimes to new variants of SARS-CoV-2: a modelling study of Queensland

Objectives: To assess the risk of sustained community transmission of SARS-CoV-2/COVID-19 in Queensland (Australia) in the presence of high-transmission variants of the virus. Design: We used an agent-based model Covasim and the demographics, policies, and interventions implemented in the state. Using the calibrated model, we simulated possible epidemic trajectories that could eventuate due to leakage of infected cases with high-transmission variants, during a period of zero community transmission. Setting: Model calibration covered the first-wave period from early March 2020 to May 2020. Predicted epidemic trajectories were simulated from early February 2021 to late March 2021. Participants: None (simulation study). Main outcomes: A calibrated model of COVID-19 epidemiology in Queensland; the conditions that could lead to an outbreak; and how likely that situation is to occur. Results: Simulations showed that one infected agent with the ancestral (A.2.2) variant has a 14% chance of crossing a threshold of sustained community transmission (i.e., > 5 infections per day, more than 3 days in a row), assuming no change in the prevailing preventative and counteracting policies. However, one agent carrying a more infectious variant (e.g., B.1.1.7) has a 43% chance of crossing the same threshold; a threefold increase. Doubling the average number of daily tests results in a decrease of this probability from 43% to 23%. Conclusions: The introduction of even a small number of people infected with high-transmission variants dramatically increases the probability of sustained community transmission in Queensland.

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

IntroductionTo reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practiced, but the rapid diagnostic tests (RDTs) used miss low-density infections. Presumptive treatment near index cases (reactive focal mass drug administration (rfMDA)) may be safe and more effective.MethodsWe conducted a 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 (AL). 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.ResultsFrom Sept 2015–Aug 2017, 220 index cases from 47 clusters triggered 49 RACD events and 68 rfMDA events. RACD and rfMDA were delivered to 1696 and 1932 individuals, respectively. Index case and target population intervention coverages for both arms were 75.6%–81.4% and adherence to DP was 98.7%. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73–2.59) and 1.97 (1.57–2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00–1.67) and 0.97 (0.71–1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio (aIRR) for rfMDA versus RACD was 0.93 (95% CI 0.54–1.60) for all malaria and 0.77 (95% CI 0.38–1.56) for locally acquired malaria. No serious adverse events occurred.ConclusionIn a very low-endemic, real-world setting, this trial is the first to evaluate rfMDA using DP. rfMDA was safe and resulted in lower cumulative incidence compared to RACD, but we were unable to confirm its effectiveness, potentially due to insufficient power. To assess impact of interventions in very low-endemic settings, multi-site, adaptive trials and use of complementary interventions may be needed.What is already known?Reactive case detection (RACD), or malaria testing and treatment in the vicinity of passively detected malaria cases, is a standard of care intervention used in low and very low transmission settings aiming for malaria elimination.Despite the use of RACD, progress toward malaria elimination has stalled in many countries and new strategies are needed.Reactive focal mass drug administration (rfMDA) is a transmission reducing strategy that has been shown to be effective in a low transmission setting, but there are no trial data from a very low transmission setting.What are the new findings?In a pragmatic, cluster-randomised controlled trial of rfMDA using dihydroartemisinin-piperaquine compared to RACD, we found that rfMDA was safe.rfMDA resulted in lower cumulative incidence, but we were unable to confirm its effectiveness compared to RACD, potentially due to insufficient power (we expected 63 total clusters would have incident cases, but observed 47).What do the new findings imply?When implemented in a real-world, very low transmission setting, rMDA was safe but evidence regarding its effectiveness to reduce transmission was weak.The challenge to show a statistically significant impact of a targeted community-based intervention in a very low transmission setting highlights the need for such trials to be multi-site, adaptive, and consider use of complementary interventions.