Dittus, Mitchell

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a major cause of morbidity and mortality in common variable immunodeficiency (CVID), yet its pathophysiology remains incompletely understood, and no Food and Drug Administration (FDA)-approved therapies exist. Cellular senescence, a state associated with inflammation and fibrosis, has been implicated in chronic lung diseases, including idiopathic pulmonary fibrosis, where senolytic therapies have shown benefit. Cellular senescence has also been described in some cases of GLILD. Objective To evaluate the efficacy of fisetin, a senolytic flavonoid, compared with placebo in adults with CVID-associated GLILD. Methods We conducted a randomized, double-blind, placebo-controlled pilot trial in 10 adults with GLILD (Figure 1). Participants received fisetin 20 mg/kg or placebo on days 0–1 and 28–29, with follow-up over 180 days. Assessments included pulmonary function testing (PFT) and Short Form Health Survey (SF-36). Results Fisetin was well tolerated, with no adverse events. SF-36 Mental Health scores were numerically higher in fisetin participants (day 28: −0.28; day 180: 0.00) than placebo (day 28: −0.56; day 180: −0.28). Mental Component Summary scores remained stable in the fisetin group (−0.65 to −0.70) but declined in the placebo group (−1.09 to −1.94). All other SF-36 domains were comparable between groups. Mean spirometry measures were stable in both groups. With fisetin, lung volumes increased over time, with increases in mean total lung capacity (5.46 to 5.76 L), residual volume (1.69 to 2.09 L), and residual volume (RV)/total lung capacity (TLC) (0.31 to 0.37). In contrast, the placebo group demonstrated decreases in total lung capacity (4.72 to 4.62 L), residual volume (1.89 to 1.72 L), and RV/TLC (0.41 to 0.38). Diffusion capacity corrected increased from baseline to day 90 in the fisetin group (13.9 to 15.9) and remained stable at day 180, whereas it declined in the placebo group by day 180 (19.1 to 17.6). Discussion In this randomized pilot study, fisetin was well tolerated and showed benefit in diffusion capacity, lung volumes, and mental health–related outcomes compared to placebo in GLILD. The temporal pattern of changes suggests that alternative dosing strategies may warrant further evaluation, in addition to potentially larger future studies. Figure 1. CONSORT flow diagram.

Introduction Loss of interferon-γ (IFN-γ) function through the development of neutralizing autoantibodies results in a late-onset immunodeficiency characterized by disseminated opportunistic infection. While rare, there is a higher prevalence in patients of Southeast Asian ancestry. Treatment is aimed at B cell depletion; however, relapse is common. Here we describe two cases of anti–IFN-γ autoantibody-associated immunodeficiency. Case Descriptions Patient 1: A 42-year-old female originally from Laos presented with a 30-lb weight loss and fatigue over the course of 8 months. Cultures grew Mycobacterium hassiacum. Testing by National Jewish was positive for anti–IFN-γ autoantibody via ELISA and for IFN-γ neutralizing ability via pSTAT1 phosphorylation. Autoantibodies were treated with rituximab 375 mg/m2 weekly for 4 weeks. She had subsequent negative autoantibody levels for 6 months until positive autoantibodies were again detected. She was treated with an additional 3 rituximab 375 mg weekly infusions and maintained remission for an additional 15 months until autoantibody levels were again positive without associated symptoms or infection (see table for timeline). She is currently undergoing additional 4 rituximab infusions. Table Patient 2 A 59-year-old female originally from Laos who presented for an immunodeficiency workup with a history of disseminated Mycobacterium avium infection, with pulmonary, lymph node, and parotid gland involvement. Anti–IFN-γ autoantibody testing from National Jewish was positive. She was treated with rituximab 375 mg/m2 weekly for 4 weeks. Autoantibody levels were negative 3 months later, and she has maintained remission since by serial monitoring. Discussion In our experience, anti–IFN-γ autoantibody-associated secondary immunodeficiency should be suspected in middle-aged patients with disseminated opportunistic infection, especially women of Southeast Asian ancestry. Rituximab rapidly depletes autoantibody levels; however, maintenance of remission is variable. The average duration of response in patient 1 was 10.5 months compared with persistent remission in patient 2. Thus, serial monitoring with autoantibody levels, markers of inflammation, and symptom assessments should be performed with consideration for repeated doses of rituximab.