Reconsidering adjuvant immunotherapy for tuberculosis

Background. Shortened regimens for treatment of pulmonary tuberculosis ( TB) are urgently needed to facilitate its global eradication. Prolonged treatment is presently required to prevent relapse, which is thought to arise from persisting foci of semidormant infection contained within granulomas. Methods. The medical literature was reviewed to identify clinical trials of adjuvant TB immunotherapy, as well as other studies of the relationship between immune status and TB relapse or reactivation. Results. Four studies of therapeutic interferon indicated its inability to effectively augment the mycobactericidal capacity of lung macrophages. One randomized, placebo-controlled trial of therapeutic interleukin-2 found that it delayed the microbiologic response to treatment, whereas 2 controlled trials of anti-tumor necrosis factor (TNF) therapies (high-dose prednisolone and etanercept [a soluble TNF receptor]) found that these interventions significantly accelerated the response to treatment. Four retrospective studies were identified in which the response to TB therapy was accelerated and/or the relapse risk was reduced in persons with human immunodeficiency virus coinfection; one study reported that immune reconstitution syndrome due to use of antiretroviral therapy was associated with increased risk of relapse. Several studies indicated that granulomas may be efficiently targeted and disrupted by the anti-TNF antibody infliximab, apparently because of its ability to bind to cell-surface TNF and to induce apoptosis in TNF-expressing cells. Conclusions. These findings support the hypothesis that the granulomatous host response to TB may paradoxically protect sequestered mycobacteria from administered anti-TB therapy and that treatment may be improved by therapeutic disruption of granulomas. Clinical trials to test this hypothesis are warranted.