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Abstract
BackgroundThe “fitness” of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients.Methods and FindingsThis 3-y (2010–2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases.A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow-up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34–0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting.ConclusionsThe low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult.
Highlights
Natural selection of an infectious pathogen occurs as a consequence of differential reproductive success at the level of the gene or the organism during its interaction with the environment
A total of 306 multidrug-resistant tuberculosis (MDRTB) index patients were identified for interview from the regional reference laboratories
A total of 657 drug-susceptible tuberculosis index patients were identified as matched controls for the MDRTB index patients, of whom 170 could not be recruited: 147 patients (86%) could not be located either at the health post or at home as an erroneous address had been provided or they had abandoned treatment at the health post after leaving a diagnostic specimen, 20 patients (12%) chose not to consent to enter the study, and three patients (2%) died prior to interview
Summary
Natural selection of an infectious pathogen occurs as a consequence of differential reproductive success at the level of the gene or the organism during its interaction with the environment. The “fitness” of Mycobacterium tuberculosis is defined as the ability of the organism to survive in the host, reproduce, be transmitted, and cause disease in another host [1,2]. Population-level molecular epidemiological studies support this finding These studies estimate tuberculosis fitness by measuring the proportion of strains that are genetically clustered and attributable to recent transmission [8,9,10]. Laboratory competitive fitness assays have demonstrated a variable fitness cost in drug-resistant M. tuberculosis bacilli, with most strains demonstrating a fitness cost and some demonstrating superior fitness [11,12,13] Studies of this kind do not account for the myriad of potential clinical, environmental, and socio-economic confounding variables that influence the ability of a patient to transmit the pathogen and cause tuberculosis disease in a contact. Diagnostic tests for the disease include sputum smear microscopy (microscopic analysis of mucus coughed up from the lungs), the growth of M. tuberculosis from sputum samples, and chest X-rays
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