XDR-TB: Person-to-Person Transmission Fueling Epidemic

Norra MacReady

January 20, 2017

Person-to-person transmission of extensively drug-resistant (XDR) tuberculosis, not the development of new resistance, may be the engine driving the spread of disease in South Africa, according to the results of a new study published in the January 19 issue of the New England Journal of Medicine.

"Inadequate treatment of [multidrug-resistant] tuberculosis accounted for, at most, 31% of cases of XDR tuberculosis," the authors write. In contrast, transmission was a confirmed or possible factor in more than 90% of the cases analyzed, the study authors report.

The results point to a "complex web of interconnectedness" among cases in community settings such as schools, churches, and businesses, as well as homes and healthcare settings, they write.

"These findings provide insight as to why this epidemic continues despite interventions to improve [tuberculosis] treatment over the past decade," senior author Neel R. Gandhi, MD, said in a press release. "Public health and research efforts must focus more intensely on identifying and implementing additional or new interventions that halt transmission in hospitals and community settings."

The incidence of XDR tuberculosis, defined as tuberculosis that is resistant to at least four first-line and second-line tuberculosis drugs, is growing worldwide. South Africa has one of the highest burdens of the disease, and the epidemic there has continued "unabated" since the organism was first described in 2006, the authors report. "In the past decade, the number of cases of XDR tuberculosis has increased by a factor of 10, to more than 1500 cases in 2012."

Inadequate drug therapy for tuberculosis, leading to acquired resistance, has traditionally been considered the major cause of drug-resistant disease, although transmitted resistance, or direct infection from someone with a resistant strain, has also been described.

It has been unclear, however, what proportion of cases is a result of transmitted resistance, the study authors explain. In addition, "data from geographic areas where HIV infection is highly prevalent are lacking."

Therefore, Dr Gandhi, from the Emory University Rollins School of Public Health and School of Medicine, Atlanta, Georgia, and colleagues conducted a prospective study of residents of KwaZulu-Natal Province, South Africa, who received a culture-confirmed diagnosis of XDR tuberculosis between 2011 and 2014. Using specially structured social network questionnaires, the patients identified contacts at work and at home, including people who had also been diagnosed with tuberculosis. The participants also listed community locations where they spent at least 2 hours per week, and individual contacts at those sites.

The researchers reviewed the patients' medical records for any previous treatment with antituberculosis medication (even for nontuberculosis indications), as well as the results of any previous drug susceptibility testing. HIV testing was offered to anyone whose HIV status was unknown.

Study participants with a history of treatment for MDR tuberculosis before their XDR tuberculosis diagnosis or of treatment with second-line antituberculosis drugs for nontuberculosis indications for at least 10 days were assumed to have the acquired form of XDR tuberculosis, Dr Ghandi and colleagues write. "Participants who did not meet any of these criteria were classified as having XDR tuberculosis that developed because of transmitted resistance."

Of 521 patients screened, 404 agreed to participate in the study. They had a median age of 34 years (interquartile range, 28 - 43 years), 234 (58%) were female, and 311 (77%) had HIV infection. Of the patients with HIV, 236 (76%) were receiving antiretroviral therapy.

A total of 124 patients (31%) had a history of treatment for MDR tuberculosis, putting them in the acquired-resistance category. Person-to-person transmission was the presumed cause in the remaining 280 cases (69%).

In a genetic analysis of Mycobacterium tuberculosis isolates from 386 participants (96%), 323 (84%) had a genotype matching that of an isolate obtained from another member of the cohort. The matching isolates could be further grouped into 31 clusters of patients. All in all, 61% of the participants who had not been treated for MDR tuberculosis had isolates that were part of a genotypic cluster; "this percentage is a minimum estimate of the proportion of participants with XDR tuberculosis that developed through transmission," the authors write.

Another 8% of participants who had no history of treatment for MDR tuberculosis did not match any of the genotypic clusters, and an additional 23% of those who had been treated for MDR tuberculosis also had isolates that could be clustered with at least one other study participant. "XDR tuberculosis may have developed because of transmission in both these groups of participants as well," the authors suggest.

These findings provide "insight as to why the epidemic continues, at least in this community, as efforts to control tuberculosis to date have not sufficiently addressed the interruption of transmission," they add.

Epidemiologic Links

Epidemiologic links were found among 30% of the study participants, suggesting that further characterization of domestic, occupational, and social networks is necessary for developing interventions that can stop the epidemic. "Early identification of patients with drug-resistant tuberculosis, screening of household contacts, and universal drug-susceptibility testing for all patients who are suspected of having tuberculosis are recommended," the authors state.

They also note that of 2901 contacts named by the participants, 2301 (79%) were household members, 376 (13%) were workplace contacts, and 224 (8%) were from other community settings such as churches, beauty salons, and prisons. Those contacts represent a potential reservoir of latent cases, which could further complicate efforts to control the disease's spread.

This epidemic "is increasingly recognized as a threat to global health," given its high associated mortality and the lack of effective treatment or preventive options, the authors conclude. "As the global tuberculosis community mobilizes around the goal of no new tuberculosis infections, the age-old approach of turning off the tap by stopping transmission is all the more critical for halting epidemics of drug-resistant tuberculosis."

Several study authors received grant support from the National Institutes of Health. No other relevant financial conflicts of interest were disclosed.

N Engl J Med. 2017;376:243-253. Full text

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