First problem is how to even know if TB (tuberculosis) can be immediately cleared. A somewhat mythic phenomenon, it’s only support comes from careful case contact studies, i.e., accurately identify individuals who undoubtedly came in close contact with an active TB patient and assess their prognosis. Closer and longer the exposure to person with heavy TB disease, greater their likelihood of getting TB infected. Heavy TB disease means excreting copious numbers of MTB (Mycobacterium tuberculosis) in Sputum (phlegm from the lower airways). Among such close contacts, MTB’s immediate clearance or early clearance (EC) is surmised to have occurred in those who develop neither markers of infection nor signs of disease.

How To Assess TB Exposure?

Currently, there are two standard tests to assess MTB exposure: the >100 year old TST (tuberculin skin test, Mantoux test) and the ~15 year old IGRA (Interferon gamma release assay).

  • In TST, a complex MTB antigen mix is injected into the dermis and reaction size measured 48 to 72 hours later.
  • IGRA assesses white blood cell capacity to release interferon-gamma, a cytokine, in response to specific MTB antigens.

Historically, some case contacts of heavily infected active TB patients developed signs of neither TB infection, i.e., neither positive TST (see table below from 1) nor IGRA, nor disease. Problem is neither test is a foolproof marker of TB infection. In fact, TST is both poorly specific and sensitive. Thus, in such situations likelihood of TB exposure is surmised by strong circumstantial evidence.

However, there is one extraordinary example where TB exposure was proven. The tragic case of Lübeck, Germany. In 1930, children in this Northern German town were scheduled for the BCG vaccine. In a ghastly oversight, BCG and virulent TB strains were accidentally cultured in the same incubator. Those early vaccine days lacked rigorously controlled means of vaccine production in labs set aside solely for this purpose. Thus, instead of getting vaccinated with BCG, 252 infants got vaccinated with TB-contaminated BCG (2, 3, 4). Given by the oral route, 75 died within the 1st year and another 135 got infected but recovered. Remarkably, ~44 never showed signs of infection and remained healthy, suggesting they likely managed EC of TB.

How Is TB’s Early Clearance (EC) Possible?

  • Since time duration involved in EC is maybe mere days, even hours, and since both TST and IGRA require the involvement of the Adaptive immune system, EC likely precludes conventional T- and B-cell dominated adaptive immune responses. Rather, EC may be the sole purview of the Innate immune system. Since, unlike adaptive immune responses, innate immunity entails Germline encoded responses, genetic differences in the strength and quality of the anti-TB innate immune responses could thus play a role in EC. TST response for example is highly hereditary.
    • A genome-wide linkage study showed a single locus accounted for 65% of TST variability in a Colombian population (5).
    • Two loci were involved in TST responsiveness in a South African population (6). One loci, TST1, is associated with TST unresponsiveness while the other, TST2, is associated with response strength.
    • TST responsiveness is also linked to cytokine gene polymorphisms (7, 8). Again, not surprising since early cytokine responses likely greatly influence capacity for EC.
  • Additionally polymorphisms that influence numbers and functionality of innate immune cells known to be involved in TB are likely important in TB’s EC. Such cells include the lung-associated macrophage, i.e., the Alveolar macrophage. They may also include airway epithelial cells, Neutrophil, Natural killer cell, MAIT cells (Mucosal associated invariant T cell), Gamma delta T cell, and possibly other Innate lymphoid cell (9).

Clearly how TB’s EC is mediated remains very much a conjecture since we don’t know the events that occur in the airways and lungs of healthy case contacts in the hours after they inhale copious numbers of TB bacilli. However, what meager data is available to tenuously support the existence of TB’s EC suggests innate immune gene polymorphisms are possibly the most important elements that contribute to a cascade of innate immune cell responses that effectively neutralize or maybe even prevent MTB’s typical evasive strategies.


1. Verrall, Ayesha J., et al. “Early clearance of Mycobacterium tuberculosis: a new frontier in prevention.” Immunology 141.4 (2014): 506–513. http://onlinelibrary.wiley.com/d…

2. The Lubeck catastrophy: a general review. BMJ 1931; 1:986. http://www.ncbi.nlm.nih.gov/pmc/…

3. Sakula, A. “BCG: who were Calmette and Guerin?.” Thorax 38.11 (1983): 806-812. http://www.ncbi.nlm.nih.gov/pmc/…

4. Monteiro-Maia, Renata, and Rosa Teixeira de Pinho. “Oral bacillus Calmette-Guérin vaccine against tuberculosis: why not?.” Memórias do Instituto Oswaldo Cruz 109.6 (2014): 838-845. http://www.scielo.br/pdf/mioc/v1…

5. Cobat, Aurélie, et al. “Tuberculin skin test reactivity is dependent on host genetic background in Colombian tuberculosis household contacts.” Clinical infectious diseases 54.7 (2012): 968-971. Tuberculin Skin Test Reactivity Is Dependent on Host Genetic Background in Colombian Tuberculosis Household Contacts

6. Cobat, Aurelie, et al. “Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis.” The Journal of experimental medicine 206.12 (2009): 2583-2591. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis

7. Thye, Thorsten, et al. “IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.” PLoS One 4.5 (2009): e5420. http://journals.plos.org/plosone…

8. Zembrzuski, Verônica M., et al. “Cytokine genes are associated with tuberculin skin test response in a native Brazilian population.” Tuberculosis 90.1 (2010): 44-49.

9. Lerner, Thomas R., Sophie Borel, and Maximiliano G. Gutierrez. “The innate immune response in human tuberculosis.” Cellular microbiology 17.9 (2015): 1277-1285. http://onlinelibrary.wiley.com/d…