Study finds some household contacts resistant to TB infection
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A study conducted in eight countries with a middle or high burden of tuberculosis found that at least 10% of household contacts can be classified as resistant to TB infection, including those with high exposure.
“We know from decades of TB household contact studies and public health work that some contacts remain negative on tests for TB infection, even after prolonged exposure,” Davit Baliashvili, a PhD student at the Emory University Rollins School of Public Health, and N. Sarita Shah, MD, an associate professor there, told Healio.
“This intriguing observation raised the question of whether some individuals may be able to resist becoming infected with Mycobacterium tuberculosis (Mtb) or can rapidly clear an infection,” they said. “If we can learn more about who these individuals are and what immunologic or genetic factors allow them to resist infection, we can develop better biomedical prevention and treatment tools, including a TB vaccine.”
Baliashvili and Shah said key challenges in this area of research include defining who is resistant based on the currently “imperfect” tests for TB and measurements of exposure.
“We had a unique opportunity to examine a diverse population of household contacts of drug-resistant TB index cases from 16 sites in eight high- and medium-TB burden countries who had undergone testing for TB infection and interviews about exposure to the index case,” they said.
Baliashvili, Shah and colleagues conducted a longitudinal study of index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant TB and their household contacts in Botswana, Brazil, Haiti, India, Kenya, Peru, South Africa and Thailand.
According to the study, they tested contacts for TB infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. They quantified exposure based on index patients’ infectiousness, index patient and household contact interaction, and age. Additionally, the researchers explored multiple definitions of resistance to TB infection by varying TST negativity cut-offs (0 vs. < 5 mm), classification of missing test results and exposure level.
In total, they evaluated 1,016 contacts from 284 households. Five hundred and seventy-two contacts aged 5 years and older had TST and longitudinal IGRA results available. Overall, 77 (13%) or 71 (12%) contacts were classified as resisters with a less than 5 mm or 0 mm TST threshold, respectively. Among 263 highly exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using the cut-offs, respectively.
According to the researchers, this translated to between 10% and 21% of household contacts being resistant to Mtb despite substantial exposure to an infectious index case across all definitions used in the study. They said the prevalence of resisters did not differ substantially by sex, age, HIV coinfection or comorbid conditions.
“Even though we have long known about individuals who remain uninfected with Mtb despite exposure, we have been hampered in further studying this important population due to limitations in defining a ‘resister phenotype.’ Our study was able to examine several definitions using various tests for TB infection, exposure measures, and follow-up,” Baliashvili and Shah said. “Regardless of which definition we used, we found one in 10 — or up to one in five — contacts could be classified as resisting infection. Developing a common definition can allow research in this population to be conducted with a more uniform approach to unlock potential clues to effectively prevent TB infection.”
Perspective
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In contact investigations of TB, household contacts (HHCs) are the group most likely to be infected by persons with active TB (index patents) and are a priority for preventive therapy. A substantial proportion may be uninfected, based on negative TSTs or IGRAs, raising questions like: Are HHCs truly not infected when others in the same home are infected, and if not, are they somehow resistant to infection (“resisters”)?
Baliashvili and colleagues evaluated the proportion of HHCs who likely were resisters despite prolonged exposure to index patients with MDR-TB. This was a large, multinational longitudinal study of HHCs who were assessed for eligibility into a clinical trial of the safety and efficacy of delamanid vs. isoniazid as preventive therapy. Different definitions of resisters among HHCs were explored, based on cut-offs of TSTs or IGRAs and levels of exposure. Using the most stringent definition (0 mm TST at baseline and negative IGRAs after 1 year) in those with high levels of exposure (index patients who were AFB smear-positive, cavitary disease and proximity in the household), they estimated that at least 10% of HHCs were resisters.
The strengths of the study were a large sample size; heterogeneity, with several countries involved; and prevalence of the resister phenotype consistent with prior studies in India and Uganda. The limitations included the accuracy and potential discordance of TSTs and IGRAs and missing data for many participants. A multivariate analysis did not reveal any clinical or behavioral risk factors associated with the resister phenotype. The authors concluded that resistance to Mtb infection is likely based on genetic and immunologic factors, and that these mechanisms require further study, with implications for new treatments and vaccines.
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