Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States

Abstract

Background: The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood.

Methods: Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples.

Results: Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001).

Conclusions: Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

Keywords: adult-onset immunodeficiency; anti-interferon-γ autoantibodies; anticytokine autoantibodies; disseminated nontuberculous mycobacterial infection; opportunistic infection.

Figure 1.

Data collection time points. Clinical data collection timepoints (A) and anti-IFN-γ autoantibody level analysis time points (B) in the Thai and US cohorts. Abbreviation: IFN, interferon.

Figure 2.

Isolated organisms at presentation in Thailand and the United States. Abbreviations: B, Burkholderia; C, Cryptococcus; H, Histoplasma; M, mycobacterium; NTM, nontuberculous mycobacteria; P, penicillium; RGM, rapid-growing mycobacteria; SGM, slow-growing mycobacteria; VZV, varicella-zoster virus.

Figure 3.

Sites of infections at presentation in Thailand and the United States. * P < .05, ** P < .01, *** P < .001.

Figure 4.

Anti-interferon (IFN)-γ autoantibody levels in Thailand and the United States. Anti-IFN-γ autoantibody levels at up to 4 time points were measured using a particle-based assay [22] for 67 patients in Thailand (A, B) and for 23 patients in the United States (C). A, Thai patients who were alive at the end of the follow-up period. B, Thai patients who died during the study. Each patient is represented by a separate line on the graph.

Figure 5.

Individual trends in anti-interferon (IFN)-γ autoantibody levels over time. A linear mixed model adjusting for sex, age at presentation, and presence of infection was used to determine the individual trends in autoantibody levels over time. The y-axis shows the annual change in anti-IFN-γ autoantibody levels for each patient in Thailand (A) and the United States (B). Dotted lines represent the overall group trend for the Thai and US cohorts.

Figure 6.

Probability of infection based on anti-interferon-γ autoantibody levels at 2 consecutive visits in the Thai cohort. A model including a term for lagged neat fluorescence intensity was used to assess whether autoantibody levels at 2 consecutive visits inform the presence of infection at the latter visit in the Thai cohort. The y-axis shows the probability of infection at the incident visit based on the autoantibody levels at a previous visit (x-axis) and the incident visit (lines on the graph).