Heterogenous Immune Response to TB is Not a False Negative.

Dear Sir,

The article by Drs. Wang and Liu[1] should be commended for evaluating the epidemiologic risks for culture-positive pediatric tuberculosis (TB) with a negative interferon-gamma release assay (IGRA). Pediatric TB is notoriously challenging to diagnose, with the minority of cases microbiologically confirmed by culture or Xpert.[2] Therefore, identifying younger age, lower weight, and hypoproteinemia as risk factors for a negative IGRA is beneficial to clinicians.

However, I would warn against calling the IGRA “false negative” as this suggests a fault of the assay and not a clinically relevant aberration in the immune system. In fact, the assay is likely operating as it should, identifying IFN-γ production from immune cells after stimulation with Mtb-specific peptides (ESAT-6 and CFP-10) and mitogen stimulation. Since the 1940s, we have known that 5–25% of TB patients fail to mount a cell-mediated immune response to Mtb antigens or nonspecific stimuli, such as Candida and histoplasmin antigens.[3-10] TB induces immune suppression and anergy, and in this setting, a negative test should not be referred to as a “false-negative” assay. By contrast, this is clinically interesting: why are some TB patients anergic and more importantly, how should they be treated? Despite most TB patients becoming culture negative 4–8 weeks after commencing anti-TB therapy (ATT), therapy must be continued for 6 months so that subculturable amounts of Mtb do not cause disease relapse.[11,12] With evidence that > 85% of TB patients could successfully be treated with only 4 months of ATT,[13] we should evaluate how IGRA status determines the requisite duration of ATT. Similarly, with increasing work to identify host-directed therapies to improve ATT, it is likely that IGRA-negative TB patients will need to be considered differently than TB patients able to mount antigen-specific IFN-γ production. TB is a heterogenous disease, with the ability of host immunity to produce IFN-γ likely critical in stratifying clinical outcomes.

Compared with IGRA-positive individuals with TB, IGRA-negative TB patients have worse outcomes[14] and, therefore, deserve increased clinical attention, and future researchers should address the biologic underpinnings of their immune suppression. Instead of labeling it “false negative,” we should embrace characterizing the complexity of the disease process and continue research as implemented by Wang and Liu,[1] while also exploring the clinical implications. If the authors have access to clinical outcome data, was IGRA-status associated with slower time to culture conversion or increased risk of treatment failure?