Community transmission of multidrug-resistant tuberculosis is associated with activity space overlap in Lima, Peru.

BACKGROUND: Transmission of multidrug-resistant tuberculosis (MDRTB) requires spatial proximity between infectious cases and susceptible persons. We assess activity space overlap among MDRTB cases and community controls to identify potential areas of transmission. METHODS: We enrolled 35 MDRTB cases and 64 TB-free community controls in Lima, Peru. Cases were whole genome sequenced and strain clustering was used as a proxy for transmission. GPS data were gathered from participants over seven days. Kernel density estimation methods were used to construct activity spaces from GPS locations and the utilization distribution overlap index (UDOI) was used to quantify activity space overlap. RESULTS: Activity spaces of controls (median = 35.6 km2, IQR = 25.1-54) were larger than cases (median = 21.3 km2, IQR = 17.9-48.6) (P = 0.02). Activity space overlap was greatest among genetically clustered cases (mean UDOI = 0.63, sd = 0.67) and lowest between cases and controls (mean UDOI = 0.13, sd = 0.28). UDOI was positively associated with genetic similarity of MDRTB strains between case pairs (P < 0.001). The odds of two cases being genetically clustered increased by 22% per 0.10 increase in UDOI (OR = 1.22, CI = 1.09-1.36, P < 0.001). CONCLUSIONS: Activity space overlap is associated with MDRTB clustering. MDRTB transmission may be occurring in small, overlapping activity spaces in community settings. GPS studies may be useful in identifying new areas of MDRTB transmission.

Ongoing challenges to understanding multidrug- and rifampicin-resistant tuberculosis in children versus adults.

Previous analyses suggest that children with tuberculosis (TB) are no more or no less likely to have multidrug (MDR)- or rifampicin-resistant (RR)-TB than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted.We used data from population-representative surveys and surveillance collected between 2000 and 2018 to compare the odds ratio of MDR/RR-TB among children (aged <15 years) with TB, compared to the odds of MDR/RR-TB among adults (aged ≥15 years) with TB.In most settings (45 out of 55 countries), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings, such as former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in Western Europe in general, and the United Kingdom, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. 16 countries had sufficient data to compare over time between 2000-2011 and 2012-2018, with evidence for decreases in the odds ratio in children compared to adults in Germany, Kazakhstan and the United States of America.Our results support findings that in most settings a child with TB is as likely as an adult with TB to have MDR/RR-TB. However, setting-specific heterogeneity requires further investigation. Furthermore, the odds ratio for MDR/RR-TB in children compared to adults is generally either stable or decreasing. There are important gaps in detection, recording and reporting of drug resistance among paediatric TB cases, limiting our understanding of transmission risks and measures needed to combat the global TB epidemic.

A Case-Control Study to Identify Community Venues Associated with Genetically-clustered, Multidrug-resistant Tuberculosis Disease in Lima, Peru.

BACKGROUND: The majority of tuberculosis transmission occurs in community settings. Our primary aim in this study was to assess the association between exposure to community venues and multidrug-resistant (MDR) tuberculosis. Our secondary aim was to describe the social networks of MDR tuberculosis cases and controls. METHODS: We recruited laboratory-confirmed MDR tuberculosis cases and community controls that were matched on age and sex. Whole-genome sequencing was used to identify genetically clustered cases. Venue tracing interviews (nonblinded) were conducted to enumerate community venues frequented by participants. Logistic regression was used to assess the association between MDR tuberculosis and person-time spent in community venues. A location-based social network was constructed, with respondents connected if they reported frequenting the same venue, and an exponential random graph model (ERGM) was fitted to model the network. RESULTS: We enrolled 59 cases and 65 controls. Participants reported 729 unique venues. The mean number of venues reported was similar in both groups (P = .92). Person-time in healthcare venues (adjusted odds ratio [aOR] = 1.67, P = .01), schools (aOR = 1.53, P < .01), and transportation venues (aOR = 1.25, P = .03) was associated with MDR tuberculosis. Healthcare venues, markets, cinemas, and transportation venues were commonly shared among clustered cases. The ERGM indicated significant community segregation between cases and controls. Case networks were more densely connected. CONCLUSIONS: Exposure to healthcare venues, schools, and transportation venues was associated with MDR tuberculosis. Intervention across the segregated network of case venues may be necessary to effectively stem transmission.

The relative fitness of drug-resistant Mycobacterium tuberculosis: a modelling study of household transmission in Peru.

The relative fitness of drug-resistant versus susceptible bacteria in an environment dictates resistance prevalence. Estimates for the relative fitness of resistant Mycobacterium tuberculosis (Mtb) strains are highly heterogeneous and mostly derived from in vitro experiments. Measuring fitness in the field allows us to determine how the environment influences the spread of resistance. We designed a household structured, stochastic mathematical model to estimate the fitness costs associated with multidrug resistance (MDR) carriage in Mtb in Lima, Peru during 2010-2013. By fitting the model to data from a large prospective cohort study of TB disease in household contacts, we estimated the fitness, relative to susceptible strains with a fitness of 1, of MDR-Mtb to be 0.32 (95% credible interval: 0.15-0.62) or 0.38 (0.24-0.61), if only transmission or progression to disease, respectively, was affected. The relative fitness of MDR-Mtb increased to 0.56 (0.42-0.72) when the fitness cost influenced both transmission and progression to disease equally. We found the average relative fitness of MDR-Mtb circulating within households in Lima, Peru during 2010-2013 to be significantly lower than concurrent susceptible Mtb If these fitness levels do not change, then existing TB control programmes are likely to keep MDR-TB prevalence at current levels in Lima, Peru.