Is Mycobacterium tuberculosis infection life long?BMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l5770 (Published 24 October 2019) Cite this as: BMJ 2019;367:l5770
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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
I hope the authors will forgive me if I am wrong. My memory (I am aged 87) tells me that in my youth, if one developed a primary complex in the lung, it could either proceed to a spreading infection, or it could "heal" - a healed primary complex with calcification which remained radiologically demonstrable all life long.
You developed a tuberculin reactivity which was demonstrable by Mantoux test or Heaf test.
The reactivity was supposedly long lasting though temporarily depressed by viral infections eg, Measles, Chickenpox.
It was also believed that the bacillus lurked harmlessly unless a severe immune depression led it to blood borne spread, leading for example to Miliary tuberculosis.
Could the authors or anyone else be kind enough to debunk these “myths”.
(worked in cardiothoracic surgery in the 1960s, in England).
Competing interests: No competing interests
This elegantly argued article (Behr et al 2019) follows on from the article by Behr et al (2018), which concludes that TB has a much shorter incubation time than previously thought. These thought-provoking articles dovetail well and support the conclusions suggested.
There is much other work not cited (no doubt in the interest of brevity and to drive the point home clearly) which provides support for their argument. For example, the multiple papers which show that recent transmission is high, even in developed countries with low incidence. Estimates ranging from 80-96% for recent transmission have been published. This data fits well with the estimates of 0.6%-11.3% reactivation suggested by Behr et al. Even for drug-resistant cases, most appear to be from primary transmission (Kendall et al 2015). In apparently “latent with reactivation” cases, many have been shown to be the result of reinfection or may be from underlying drug resistant strains not cured by the regimen used in the primary infection. The recent large prophylaxis study done in miners in South Africa for example (Churchyard et al 2014), showed that after cessation of INH administration, incidence quickly returned to that seen prior to treatment, confirming the importance of transmission as the driving force of the TB epidemic.
In many high prevalence HIV and TB settings, there are numerous adults who have been living with HIV for years, are TST positive, but have never had TB (Rangaka et al 2007). This too supports the idea that these persons are either innately highly resistant to TB, or were infected by TB perhaps prior to HIV infection and eradicated the TB infection. Both are likely scenarios. It should be noted that Behr et al suggest that their estimates of reactivation are calculated conservatively, erring rather on the side of generosity and that the likely proportion of reactivation is lower than what they estimate.
There are very important consequences of this paper. As a research community, we need to re-evaluate the huge investment made in trying to understand persistence or latency, given the high priorities of cure and eradiation. Indeed, as the authors point out, we need far better diagnostics to identify real cases for reactivation disease. We also need a careful rethink of wide-scale prophylaxis. In essence, we think this paper provides good news for eradication, because although it is correct that we cannot eradicate until reactivation cases are dealt with, it suggests that these are few and far between. Therefore by concentrating resources, both research and service, on recent infection, we should be able to achieve more in TB control in a shorter time than we thought possible.
1. Behr, MA, Edelstein, PH, Ramakrishnan, L (2019) Is Mycobacterium tuberculosis infection life long? BMJ 2019; 367: 15770 doi: 10.1136/bmj15770 ( published 24 October 2019)
2. Behr, MA, Edelstein, PH, Ramakrishnan, L ( 2018) Revisiting the timetable of tuberculosis. BMJ 2018; 362:k2738
3. Kendall EA, Fofana MO, Dowdy DW. Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. The Lancet Respiratory medicine 2015; 3(12): 963-72
4. Churchyard, GJ, Fielding, KL, Lewis, JJ, Coetzee, L, Corbett, EL, Godfrey-Faussett P, Hayes, RJ, Chaisson, RE, Grant, AD for the Thibela TB Study Team. A Trial of Mass Isoniazid Preventive Therapy for Tuberculosis Control. N Engl J Med 2014; 370:301-310 DOI: 10.1056/NEJMoa1214289
5. Rangaka,M, Wilkinson, KA, Seldon,R, Van Cutsem, G, Meintjes, GA, Morroni, C, Mouton,P, Diwakar, L, Connell, TG( 2007) Gary Maartens1,5, and Robert J. Wilkinson1,2,6 Effect of HIV-1 Infection on T-Cell–based and Skin Test Detection of Tuberculosis Infection. Am J Respir Crit Care Med Vol 175. pp 514–520.
Competing interests: No competing interests