HomeThe elegant studies of R. G. Ferguson in the first half of the 20th century strongly suggest that it takes up to 18 months after the initial infection for cell-mediated immunity to fully mature.75,76 During this period, each successive exposure and infection appears to carry its own inherent risk of disease; the cumulative risk thus becomes a function of the number of infections. This may explain why disease is so much more common in newly infected close contacts of smear-positive cases than it is in newly infected close contacts of smear-negative cases; the former has a greater likelihood than the latter of repeated exposure and reinfection.11,77,78More recent studies have also reported a higher risk of disease with greater intensity of exposure.79,80
A meta-analysis of 23 cohorts from the pre-antibiotic era — largely health care workers — estimated that subsequent reinfection (after the first 18 months) of immunocompetent hosts carries a much lower risk of progression to TB disease, estimated to be 21% of the risk of an initial infection progressing to disease.81 It remains unknown whether prior infection without development of overt disease is simply a marker for people who are less susceptible to disease development, or whether it truly induces immunity that is better able to prevent progression after reinfection.
In Canada, repeated exposure is rare in most settings, such that active TB generally reflects an initial infection — recent or remote — rather than reinfection.82 However, there is clear evidence for the important role of reinfection causing TB morbidity in high-incidence, high-transmission settings. This has been most consistently documented among persons living with HIV who are not receiving anti-retroviral therapy, among whom high rates of recurrent TB disease have been observed long after microbiologic cure of an initial disease episode.83,84 DNA fingerprinting has confirmed that many recurrent episodes relate to new infecting strains rather than to late relapse. Strong supporting evidence also comes from clinical trials among persons living with HIV in high-transmission settings. These demonstrated high rates of TB disease after completion of preventive therapy, attributable to reinfection after treatment.85
Reinfection can also lead to repeated illness in HIV-negative persons who were cured after an initial episode of TB disease, if they are in settings with extremely high TB incidence and transmission85 This may be relevant in a few, very specific Canadian settings (eg, isolated communities with extensive outbreaks). Some persons in those settings with documented prior treatment for TB disease experienced recurrent disease that was shown by whole genome sequencing to reflect reinfection.86,87 These observations can lead to consideration, on a case-by-case basis, of retreatment of TB infection after new exposure to highly infectious source patients (see Chapter 6: Tuberculosis Preventive Treatment in Adults and Chapter 11: Tuberculosis Contact Investigation and Outbreak Management).
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