An analysis challenges the longstanding notion that tuberculous infection is a life-long infection that could strike at any time and cause tuberculosis (TB). Based on a review of clinical studies, researchers from the Perelman School of Medicine at the University of Pennsylvania and colleagues show that people who test positive with immunologic TB skin or blood tests rarely develop TB. They suggest it’s because the infecting organism, Mycobacterium tuberculosis, is likely dead, wiped out naturally by people’s immune systems. Despite that, these people retain an immunological memory to the disease, which the authors say likely explains why standard TB tests show a positive result, since those tests look for an immune response and not live bacteria.
The findings upend commonly held beliefs, as well as approaches to care and research around the world, for the 2bn people who test positive for TB and are thought to be persistently infected and at risk for active disease.
“The National Institutes of Health and other non-profit organisations spend millions of dollars on studies of the latent state because of the assumption that TB infection is life-long, held in check by the immune system. However, based on our analysis, we believe that it is rarely life-long, and in 90 percent or more of infected people, there is no possibility of TB development even with severe immuno-suppression,” said co-author Dr Paul H Edelstein, an emeritus professor of pathology and laboratory medicine at Penn.
Additional co-authors on the study include Dr Marcel A Behr, a professor of medicine at McGill University, and Dr Lalita Ramakrishnan, a professor of immunology and infectious diseases at the University of Cambridge.
In their review, the team pointed to several previous studies to demonstrate the natural history of TB immuno-reactivity in people given preventive treatment, and of active TB in immuno-reactive people with various forms of severe immuno-suppression, like patients with HIV and those who have received an organ transplant. One study showed that treatment of people with TB immuno-reactivity for one year lowered the incidence of active TB by 60 to 70 percent over the next nine years. Yet, those treated remained skin test positive for TB up to nine years later, showing TB immuno-reactivity can outlast elimination of infection by at least nine years.
In another study of patients co-infected with HIV and TB – who are at a higher risk for active TB – researchers showed that between 89% and 97.5% of those with positive TB immunoreactivity tests remained free of TB from their remote infection over a five-year period. And in a third study of stem cell transplant patients, none of the 29 participants from the US cohort with TB immunoreactivity developed TB after a total of 89 person-years of observation, the authors wrote.
“TB immunoreactivity is not a marker for the presence of continued TB infection,” Edelstein’s team wrote. “Rather, it serves as a sign of having been infected with TB at some point.”
The researchers believe future resources should focus on developing tests that can better identify infected people who are not symptomatic. Currently, there are no specific tests for these patients. They also believe that detecting and treating people with active TB should be a high priority, as well as providing TB preventive therapy for those around them.
“We need to put more effort into controlling active TB and to determine how to detect the 10% of people who actually do have lifelong infection,” Edelstein said. The authors note that a test to identify that patient group should reduce the cost and morbidity of treatment 10-fold while maintaining the effectiveness of the intervention. The authors say they hope this analysis will lead to further discussion in the field, as well as future research on the mechanisms of how to clear the pathogen from a host.
Objective: To measure the association between phenotypic drug resistance and the risk of tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis.
Setting: 106 district health centers in Lima, Peru between September 2009 and September 2012.
Design: Prospective cohort study.
Participants: 10 160 household contacts of 3339 index patients with tuberculosis were classified on the basis of the drug resistance profile of the patient: 6189 were exposed to drug susceptible strains of Mycobacterium tuberculosis, 1659 to strains resistant to isoniazid or rifampicin, and 1541 to strains that were multidrug resistant (resistant to isoniazid and rifampicin).
Main outcome measures: Tuberculosis infection (positive tuberculin skin test) and the incidence of active disease (diagnosed by positive sputum smear or chest radiograph) after 12 months of follow-up.
Results: Household contacts exposed to patients with multidrug resistant tuberculosis had an 8% (95% confidence interval 4% to 13%) higher risk of infection by the end of follow-up compared with household contacts of patients with drug sensitive tuberculosis. The relative hazard of incident tuberculosis disease did not differ among household contacts exposed to multidrug resistant tuberculosis and those exposed to drug sensitive tuberculosis (adjusted hazard ratio 1.28, 95% confidence interval 0.9 to 1.83).
Conclusion: Household contacts of patients with multidrug resistant tuberculosis were at higher risk of tuberculosis infection than contacts exposed to drug sensitive tuberculosis. The risk of developing tuberculosis disease did not differ among contacts in both groups. The evidence invites guideline producers to take action by targeting drug resistant and drug sensitive tuberculosis, such as early detection and effective treatment of infection and disease.
Mercedes C Becerra, Chuan-Chin Huang, Leonid Lecca, Jaime Bayona, Carmen Contreras, Roger Calderon, Rosa Yataco, Jerome Galea, Zibiao Zhang, Sidney Atwood, Ted Cohen, Carole D Mitnick, Paul Farmer, Megan Murray