Immune Reconstitution Inflammatory Syndrome in People Living with HIV Who Presented with Interstitial Pneumonitis: an Emerging Challenge in the Era of Rapid Initiation of Antiretroviral Therapy

Studies on immune reconstitution inflammatory syndrome (IRIS) in people living with HIV (PLWH) and presenting with interstitial pneumonitis (IP) are limited in the era of rapid antiretroviral therapy (ART) initiation, particularly with integrase strand-transfer inhibitor (INSTI)-containing regimens. Adult PLWH presenting with IP in whom ART was initiated within 30 days of IP diagnosis between 2015 and 2021 were retrospectively identified. The primary outcome was the occurrence of IRIS within 30 days after admission. Of 88 eligible PLWH with IP (median age, 36 years; CD4 count, 39 cells/mm(3)), Pneumocystis jirovecii and cytomegalovirus (CMV) DNA were detected via polymerase-chain-reaction assay in 69.3% and 91.7% of respiratory specimens, respectively. 22 PLWH (25.0%) had manifestations that met French’s IRIS criteria for paradoxical IRIS. There were no statistically significant differences in terms of the all-cause mortality (0.0% versus 6.1%, P = 0.24), the occurrence of respiratory failure (22.7% versus 19.7%, P = 0.76), and pneumothorax (9.1% versus 7.6%, P = 0.82) between PLWH with and those without paradoxical IRIS. In a multivariable analysis, the factors associated with IRIS were the decline of the 1 month plasma HIV RNA load (PVL) with ART (adjusted hazard ratio [aHR] per 1 log decrease, 3.45; 95% CI, 1.52 to 7.81), a baseline CD4-to-CD8 ratio of <0.1 (aHR, 3.47; 95% CI, 1.16 to 10.44), and the rapid initiation of ART (aHR, 7.95; 95% CI, 1.04 to 60.90). In conclusion, we found a high rate of paradoxical IRIS among PLWH with IP in the era of rapid ART initiation with INSTI-containing ART and this was associated with immune depletion at baseline, a rapid decline of PVL, and an interval of <7 days between the diagnosis of IP and the initiation of ART. IMPORTANCE Our study of PLWH who presented with IP mainly due to Pneumocystis jirovecii demonstrates that a high rate of paradoxical IRIS and a rapid decline of PVL with the initiation of ART, a CD4-to-CD8 ratio of <0.1 at baseline, and a short interval (<7 days) between the diagnosis of IP and the initiation of ART were associated with paradoxical IP-IRIS in PLWH. Paradoxical IP-IRIS was not associated with mortality or respiratory failure with heightened awareness among the HIV-treating physicians, rigorous investigations to exclude the possibilities of concomitant infections, or the malignancies and adverse effects of medications, including the cautious use of corticosteroids.