This article is more than 5 years old. Information may no longer be current.
Person-to-person MDR-TB transmission drives epidemic in China
Click Here to Manage Email Alerts
Recent data from a population-based, observational study in China revealed that patients were more likely to develop multidrug-resistant tuberculosis from person-to-person transmission than from inadequate treatment.
“Inadequate treatment was considered to be the most common way of developing MDR [tuberculosis (TB)]; however, our data show that most of the patients in our study population who had [MDR-TB] had been infected with MDR strains,” Chongguang Yang, PhD, postdoctoral associate of epidemiology of microbial diseases at Yale School of Medicine, and colleagues wrote in the Lancet Infectious Diseases. “We also found that a majority of transmission events occurred in settings such as residential communities or complexes and related public facilities.”
Yang and colleagues performed variable-number-of-tandem-repeat (VNTR) genotyping and whole-genome sequencing on MDR-TB isolates collected from patients in Shanghai, China to establish transmission patterns and risk factors of MDR-TB in the area. Their analysis included data from 324 patients aged 15 years and older who were diagnosed with MDR-TB between Jan. 1, 2009 and Dec. 31, 2012. The researchers used a standardized questionnaire to determine patients’ social characteristics, history of TB exposure and locations where transmission may have occurred.
According to the data, 59% of patients with MDR-TB were treatment-naive. Overall, 32% of the 324 MDR-TB strains were in 38 genomic clusters that differed by 12 single nucleotide polymorphisms or fewer, indicating recent transmission. The researchers combined treatment-naive cases (n = 191) with cases included in genomic clusters (n = 93) and estimated that up to 73% (95% CI, 67.3-77.3) of all MDR-TB cases were likely caused by transmission of MDR strains.
Epidemiological links were identified in 69% of the genomically clustered cases, only four of which were traced to household contacts. The majority (n = 45) of cases were either linked to other cases from the same residential community or neighborhood street, or cases using the same public health facilities such as food markets. Additional analyses of epidemiological data revealed that a delayed diagnosis of at least 2 months (OR = 2.02; 95% CI, 1.08-3.81), and being aged 45 to 64 years (OR = 1.9; 95% CI, 1.04-3.46) and 65 years or older (OR = 2.94; 95% CI, 1.28-6.79) were independently associated with genomic clustering.
For further investigation, Yang and colleagues mapped mutations associated with drug resistance in MDR-TB strains onto putative transmission networks. They found that 87% of clusters accumulated additional drug resistance mutations during transmission.
“Inadequate therapies could accelerate selection of new mutations and increase drug resistance, and these drug-resistant strains could be transmitted to others,” the researchers wrote. “Unfortunately, inadequate treatment of [MDR-TB] is a problem in China, particularly in hospitals. Therefore, treating patients with [MDR-TB] on the basis of results of drug susceptibility testing should become a mandatory policy.”
In their analysis, Yang and colleagues noted that 66% (95% CI, 56-75) of MDR strains in the genomic clusters had compensatory mutations of rifampicin resistance. This is much higher than the proportion of compensatory mutations reported globally (20%) and in high-burden areas (31%), they wrote.
“To our knowledge, we describe the first population-based study combining genomics with detailed epidemiological data to identify transmission pathways of [MDR-TB] in a region over time in China, the country with the second highest number of [MDR-TB] cases in the world,” the researchers wrote. “Our findings suggest that strategies and interventions to halt ongoing transmission of MDR strains should be a priority for [TB] control programs in China and other settings with a high burden of [MDR-TB].”
In a related editorial, Ben J. Marais, PhD, and Vitali Sintchenko, PhD, of the University of Sydney, said that the spread of MDR-TB in China has implications for non-endemic regions, where most TB cases occur among immigrants, migrant workers and international students despite pre-entry disease screening.
“Without adequate strategies to contain the spread of [MDR-TB], the possibility of epidemic replacement (predominance of drug-resistant strains over drug-susceptible strains) should be recognized as a major threat,” they wrote. “The data … offer an important example of how advances in whole-genome sequencing provide a better understanding of [MDR-TB] transmission dynamics, which will be essential to guide better targeted public health responses and contain its epidemic spread.” – by Stephanie Viguers
Disclosure: The researchers report no relevant financial disclosures.
Perspective
Back to Top
Barun Mathema
The study by Yang and colleagues taps into an interesting and important question in the field. This talented group of researchers unleash the power of genomics to make the claim that the majority of MDR-TB strains are not created, but transmitted in this setting.
The implications of this are quite important. If there is a lot of transmission going on, it underscores the importance of case finding, which in TB, is difficult. As the authors correctly point out, they are limited in terms of possibly not having sampled everybody. As such, there can be marginal errors in their estimation, but negligible in terms of the conclusion.
An important aspect of this paper is that, in a way, it is following a trend amongst researchers for implicating transmission as a major driving force in the drug-resistant epidemic. We saw MDR-TB transmission in New York City in the early 1990s, which was shown through molecular techniques. The molecular techniques that investigators here used are far more sophisticated than those used during that epidemic. Now, researchers are using whole-genome sequencing to look at strain relatedness and to develop a metric to assess how related the strains are (ie, clustering).
Although it is a little surprising that the levels MDR-TB attributed to transmission is as high as it is in Shanghai, where there is not much HIV associated TB (like in South Africa), I believe it. The conclusion of the study itself is not surprising. Globally, the prevalence of TB has come down, mortality associated with TB has come down, but the incidence of TB has been stubbornly slow to come down. So, what drives incidence? The culprit likely is transmission, and even more so with MDR-TB. This means we need to double down on investing in efforts to break the chains of transmission. TB is a major problem in China, including in urban centers like Shanghai. This study provides sound evidence for primary transmission of MDR as a key aspect for TB control to tackle. We need to interrupt transmission by getting people on treatment, but also by finding the cases in the community that may be transmitting TB (undiagnosed but infectious).
The next step is now identifying the main drivers of transmission and target interventions. The authors identified diagnostic delay and age as factors, and acknowledged some correlation with location. Use of high-level data (eg, spatial, demographic and genomic) is needed to pinpoint the hotspots of MDR-TB that are driving this kind of epidemiologic pattern.
Click Here to Manage Email Alerts