Prednisone for the Prevention of Paradoxical Tuberculosis-associated IRIS
Meintjes G, Stek C, Blumenthal L, et al. N Engl J Med. 2018;379:1915-1925.
Transplantation for human immunodeficiency virus (HIV)-positive patients in developing countries has become a reality with the use of organ donors from HIV-positive recipients.1 Managing coinfected patients with a diagnosis of HIV as well as tuberculosis (TB) can be challenging as there are cytochrome P450 inhibiting and enhancing drugs present in antiretroviral therapy (ART), rifampicin, as well as calcineurin inhibitors. The combination of these drugs can be difficult to manage and patients with coinfection might suffer from complications secondary to increased or decreased drug levels. Furthermore, the prognosis of these patients is poor in comparison to HIV-positive patients without TB.2
Paradoxal TB-associated immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response characterized by new inflammatory features of TB shortly after initiation of antiretroviral therapy. Early initiation of ART more than doubles the risk of TB associated IRIS. In this study, the authors randomized 240 HIV-positive patients with TB and CD4 counts lower than 100 into a double-blind study to receive either 40 mg of prednisone for 14 days followed by 20 mg of prednisone for 14 days or placebo treatment. Prednisone treatment was started at the time of diagnosis of TB and within 30 days before ART was started. The endpoint of the trial was the development of IRIS.
Of 120 patients in each arm, 106 and 107, respectively, completed the 12-week visit. In the prednisone group, 39 (32.5%) patients developed IRIS compared with 56 (46.7%) in the placebo group.
The significantly reduced cumulative incidence of IRIS in the prednisone group represents an important message to physicians and surgeons managing HIV-positive transplant patients with coinfections and opportunistic TB. Although prednisone and immunosuppression levels are often reduced in these patients, increasing prednisone may, in fact, be beneficial to prevent IRIS.
- Muller E, Barday Z, Kahn D. HIV positive-to-positive kidney transplantation. N Engl J Med. 2017;372:2070–2071.
- Muller E, Barday Z. HIV-positive kidney donor selection for HIV-positive transplant recipients. J Am Soc Nephrol. 2018;29:1090–1095.
Antibiotics Induce Sustained Dysregulation of Intestinal T-cell Immunity by Perturbing Macrophage Homeostasis
Scott NA, Andrusaite A, Andersen P, et al. Sci Transl Med. 2018;10(464).
Here, the authors investigated effects of broad-spectrum antibiotics on the disruption of the intestinal microbiota and subsequent modifications of intestinal immune responses. Mice received an antibiotic cocktail of ampicillin, metronidazole, neomycin, gentamycin, and vancomycin added to their drinking water for 7 days when they received fecal transplants from control mice. Animals treated with antibiotics demonstrated increased infiltrates of monocytes, eosinophils, and neutrophils in the colon. These infiltrates normalized after 10 to 13 days of fecal transfer when a sustained increase in interferon-γ producing CD4+ T cells and specifically TH1 CD4+ T-cell responses was observed.
Monocytes and macrophages isolated from animals that had received antibiotics expressed increased levels of tumor necrosis factor-α after fecal recolonization. Moreover, mature colonic macrophages from antibiotic treated mice showed a dysregulated cytokine production. This dysregulation was long standing, as animals were less effective in clearing both, Citrobacter rednetium and Trichus muris when infected 60 days after recolonization.
These data indicate a long-term disruption of immune function and susceptibility to infections after antibiotic administration. An analysis of ribonucleic acid in the bacterial community of the colonic lumen revealed sustained disruption of the intestinal microbiota for 60 days after recolonization.
The authors showed that an intact gut microbiota is critical in regulating intestinal macrophages, thus providing a mechanistic link between antibiotic use and the predisposition of intestinal inflammation via a sustained dysregulation of intestinal immunity. Restoring macrophage homeostasis after antibiotic treatment may represent a novel and effective strategy to prevent intestinal immune dysfunction.