ZSFG AM Report Pearls 3/27/18: 2 Steps Forward, 2 Steps Back: Paradoxical Reactions & IRIS in TB Tx in HIV+ Pts

Hey Team! Playing a little catch up on these awesome pearls from late March. We discussed an interesting case of an HIV+ pt who was diagnosed with TB. After starting TB tx, they ended up looking more sick and had to pause treatment. This brought up discussion about paradoxical reactions in treating TB as well as a few other pearls:
Epidemiology of TB in the US:
In the US, only 3.2% of the population is estimated to have latent TB
There are only 11,000 cases annually of active TB (remember though what your base population is – San Francisco, CA is not Dayton, OH)
>50% of cases are are in individuals born outside of the US
In the US, only 10% of cases in the US are coinfected with HIV
Extrapulmonary TB:
Prevalence = 10-42% worldwide depending on the race or ethnic background, age, presence/absence of underlying disease, genotype of the M. tuberculosis strain, and immune status (note that this is probably lower given US population)
Can affect any part of the body with a wide range of clinical presentations
TB Treatment and Paradoxical Reactions:
Paradoxical reactions to TB treatment – defined as the worsening of existing lesions or presentation of new lesions during anti-TB therapy nad typically associated with exaggerated inflammatory symptoms like fever, lymphadenitis and pulmonary manifestations
Epidemiology: Frequency somewhere between 2% and 23%
  • HIV infection is also associated with a syndrome in which paradoxical inflammatory consequences occur during therapy: the immune reconstitution inflammatory syndrome (IRIS).
    • Here, the commencement of HAART leads to an exacerbation of an existing opportunistic disease, or unmasking of a previously subclinical infection.
  • IRIS is most frequently observed in mycobacterial infections
    • Several forms have been described in HIV/TB co-infected individuals
      • The commonest of these is paradoxical TB-IRIS, in which inflammatory exacerbations of TB symptoms occur after commencement of HAART in HIV-seropositive patients being treated for active TB,15 the frequency of which was estimated to be 15.7% in a meta-analysis of 3459 individuals.
      • A second form, unmasking TB-IRIS, is when a new presentation of active TB arises after commencing HAART. The occurrence of unmasking TB-IRIS is thought to be lower than paradoxical TB-IRIS, with estimates varying between 1.4% and 23%.14,17–19 I
      • It is also suggested that HIV-seropositive individuals with active TB may have an increased incidence of PR when commencing antimycobacterial therapy, compared to HIV-seronegative individuals.
Diagnostic criteria do not yet have consensus guidelines but include worsening of clinical or radiologic findings after the initiation of appropriate antimycobaterial therapy.
The physiology behind this is not well understood and the hypotheses are based on clinical observations but are somewhat summarized in the graphic below:
  • Prior to treatment, there is a building mycobacterial load/infection, while the inflammatory system is calmed down (and likely suppressed from HIV)
  • Once you start treatment (typically for both TB and HAART for HIV) the immune system ramps up
  • In people who don’t get paradoxical reactions and IRIS, the immune system and mycobacterial load is more in sync


  • Gordin FM & Masur H. (2012). Current approaches to Tuberculosis in the United State. JAMA. 308(3):283-289.
  • Zumla A et al. (2013). Tuberculosis. NEJM. 368:745-755.
  • Bell LCK et al. (2014). Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis. International Journal of Infectious Disease. 32:39-45.

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