LAUSR

is diagnosed, chemoprophylaxis may be indicated to prevent active TB. Regarding the research implications, the host–pathogen interaction is finely balanced, with only a small subset of Mtbexposed individuals developing pulmonary disease to continue transmission (1, 4). The clinical observations that are emerging from the biologic treatment era provide entirely novel and highly relevant insights into human immune function and host–pathogen interactions. The increase in active TB after immune checkpoint inhibition suggests that excessive immunity may be just has harmful as insufficient immunity. Supporting this concept, Comstock and colleagues demonstrated in a study of 82,000 individuals that a strong response to TB antigens, which should be considered protective, actually associates with progression to active TB (8). Infection of mice deficient in PD-1 results in rapidly lethal inflammation (9, 10), consistent with a protective role in TB. Perhaps the most sobering implication is that it reinforces the finely balanced knife edge of the human–Mtb interaction. Simply driving an exaggerated immune response, without first defining determinants of progression versus protection in TB, risks inadvertently accelerating transmission and worsening the pandemic in the longer term (4). n