Intended for healthcare professionals

Authors' reply to Dr Anand, Re: Is Mycobacterium tuberculosis infection life long?

Dr. Anand is correct that Mycobacterium tuberculosis infection can lead to progression of disease. In those who don’t progress to disease, the granulomas in the lung, lymph nodes, or both sites become calcified. Several phthisiologists in the early to mid-20th century performed microbiologic studies of these calcified granulomas in people who had died to determine whether they contained viable M. tuberculosis using guinea pig inoculation, a very sensitive method of detecting live M. tuberculosis. The conclusion from these studies was that calcified lesions very rarely contained live bacteria. Canetti reviewed these studies, including his own monumental study (1), in a paper that discusses whether exogenous reinfection or endogenous relapse were responsible for TB in those remotely infected with TB who develop TB years later (2). He says: “It follows that in the very great majority of subjects who have had the usual latent primary infection for more than five years, 'there is not even the possibility of a reactivation of the primary foci'.” [single quotes are Canetti’s].

It is also correct that M. tuberculosis infection is often, though not always, accompanied by immunoreactivity to M. tuberculosis antigens as measured by skin testing, or more recently by interferon-gamma release assays. We digress here to mention that fundamental studies of TB immunoreactivity and preventive treatment of TB infection were conducted by sometimes forgotten women scientists, including Shirly Ferebee and Florence Seibert, who conducted clinical trials and developed the standardized purified protein derivative of tuberculin (“PPD-S”) used in skin testing, respectively (3, 4). Ferebee and others cited in our paper showed that tuberculin reactivity was simply indicative of past infection and that a positive test could persist for many years even after the use of preventive TB therapy. More recently, this has also been shown to be the case with interferon-gamma release assays in people treated for either active TB, or asymptomatic M. tuberculosis infection in recent TB contacts, where the reversion rates are unaffected by effective chemotherapy (5-7). We further show in our paper that a positive test is rarely indicative of persistent infection.

Most people, including us, thought that M. tuberculosis infection was life-long and that only a robust host immune system kept that in check. However, the analyses we present in this paper suggest instead that this concept is invalid in the vast majority of people who have been infected, and that our prior beliefs were incorrect.

1. Canetti G. The tubercle bacillus in the pulmonary lesion of man. Histobacteriology and its bearing on the therapy of pulmonary tuberculosis. New York, NY: Springer; 1955. 249 p.
2. Canetti G. Endogenous reactivation and exogenous reinfection: their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc. 1972;47:116-34.
3. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Advances in Tuberculosis Research. 1970;17:28-106.
4. Seibert FB. The chemistry of the proteins of the acid-fast bacilli. Bacteriol Rev. 1941;5(1):69-95.
5. Adetifa IM, Ota MO, Jeffries DJ, Lugos MD, Hammond AS, Battersby NJ, et al. Interferon-gamma ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial. Am J Respir Crit Care Med. 2013;187(4):439-45.
6. Clifford V, He Y, Zufferey C, Connell T, Curtis N. Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review. Tuberculosis (Edinb). 2015;95(6):639-50.
7. Denkinger CM, Pai M, Patel M, Menzies D. Gamma interferon release assay for monitoring of treatment response for active tuberculosis: an explosion in the spaghetti factory. J Clin Microbiol. 2013;51(2):607-10.

Competing interests: No competing interests

08 November 2019
Paul H Edelstein
physician, microbiologist
Behr, Marcel A.; Ramakrishnan Lalita
Perelman School of Medicine, University of Pennsylvania; Department of Medicine, University of Cambridge
Dept of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA