The “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 Findings
This 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.
The 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.
In this prospective cohort study, Louis Grandjean and colleagues examine the relative fitness of multidrug-resistant versus drug-susceptible tuberculosis for transmission among household contacts in South Lima and Callao, Peru.
Tuberculosis—a contagious bacterial disease that usually infects the lungs—is a global public health problem. Every year, 8.6 million people develop active tuberculosis (tuberculosis disease), and at least 1.3 million people die as a result, mainly in resource-limited countries. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with tuberculosis disease cough or sneeze. Consequently, an individual’s risk of contracting tuberculosis increases with his/her frequency of contact with people who have the disease; people who live in the same household as someone with tuberculosis disease are at particularly high risk. Other risk factors for contracting tuberculosis include living in crowded or insanitary conditions and being immunocompromised because of, for example, infection with HIV. The characteristic symptoms of tuberculosis disease are persistent cough, fever, weight loss, and night sweats. 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.
Why Was This Study Done?
Taking several antibiotics (including rifampicin and isoniazid) daily for six months can cure tuberculosis, but the emergence of multidrug-resistant tuberculosis (MDRTB) is making the disease increasingly hard to treat. How badly MDRTB will affect tuberculosis control efforts is likely to depend on the relative “fitness” of multi-drug resistant and drug-susceptible M. tuberculosis strains. The fitness of a pathogen (infectious organism) is its ability to survive, reproduce, be transmitted, and cause disease in another host. Animal and laboratory studies indicate that drug-resistant M. tuberculosis strains are less fit than drug-susceptible strains, but these studies do not account for the clinical, environmental, and socio-economic variables that influence a patient’s ability to cause tuberculosis disease in a contact, and may not accurately measure the relative fitness of M. tuberculosis strains. In this prospective cohort study, the researchers estimate the fitness of drug-resistant tuberculosis relative to drug-susceptible tuberculosis by comparing the incidence of additional cases of tuberculosis disease in households with an MDRTB index case and the incidence in households with a drug-susceptible tuberculosis index case. A prospective cohort study follows a group of people over time to see whether specific baseline characteristics are associated with specific outcomes. The incidence of a disease is the number of new cases in a population over a given time period.
What Did the Researchers Do and Find?
The researchers enrolled 1,055 household contacts of 213 MDRTB index cases (individuals whose disease was resistant to at least rifampicin and isoniazid) and 2,362 household contacts of 487 drug-susceptible tuberculosis index cases living in South Lima and Callao, Peru. During three years of follow-up, 35 (3.3%) of the household contacts of the MDRTB index cases and 114 (4.8%) of the household contacts of the drug-susceptible tuberculosis index cases developed tuberculosis disease. After adjusting for factors likely to affect the transmission of tuberculosis, such as HIV status, socio-economic status, and sputum smear grade of the index case (higher smear grades are associated with a higher risk of tuberculosis transmission), the hazard ratio for tuberculosis disease for household contacts of MDRTB index cases was half that of the household contacts of drug-susceptible tuberculosis index cases. That is, the household contacts of MDRTB index cases contracted tuberculosis disease half as often as those of drug-susceptible tuberculosis index cases.
What Do These Findings Mean?
These findings indicate that, within households, MDRTB has a relatively low fitness compared to drug-susceptible tuberculosis. That is, at least during the first three years following exposure, individuals with MDRTB are less likely to transmit disease to their household contacts than individuals with drug-susceptible tuberculosis. These findings agree with those of previous animal and laboratory studies and with the findings of molecular epidemiology studies that have used genetic methods to estimate M. tuberculosis fitness within populations. Because the researchers did not genetically compare M. tuberculosis strains isolated from the index cases with strains isolated from the household contacts who developed tuberculosis disease, some of these contacts may have become infected outside the household. Moreover, it may not be possible to extrapolate these findings to the community setting. Nevertheless, the low relative fitness of MDRTB reported here improves our chances of controlling the spread of drug-resistant tuberculosis, with the proviso that the emergence of fitter MDRTB strains over time might yet threaten global tuberculosis control efforts.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001843.
The World Health Organization provides information (in several languages) on tuberculosis and on multidrug-resistant tuberculosis; the Global Tuberculosis Report 2014 provides information about tuberculosis around the world; a supplement to the report entitled Drug-Resistant TB—Surveillance and Response is available
The Stop TB Partnership is working towards tuberculosis elimination and provides personal stories about tuberculosis (in English and Spanish); the Tuberculosis Vaccine Initiative (a not-for-profit organization) also provides personal stories about tuberculosis
The US Centers for Disease Control and Prevention provides information about tuberculosis and about drug-resistant tuberculosis (in English and Spanish)
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)