Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review

Abstract

BackgroundAnti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data.MethodsThis systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity.ResultsWe included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%).ConclusionsIntracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicella-zoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases.

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…Again, the discovery of this immunologic defect underlying susceptibility to an infectious disease was first found in patients with a mycobacterial disease, namely, tuberculosis [ 222 ]. Subsequently, high-titer aa-IFN-γ concentrations were found in patients with no other immunocompromising condition in association with other severe disseminated infections, including NTM [ 223 , 224 , 225 , 226 , 227 ], and germane to TDEF, H. capsulatum, and T.( P. ) marneffei [ 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 ] (as well as Cryptococcus , see below). aa-IFN-γ is an emerging, adult-onset form of immunodeficiency that is typically recognized in the fourth to sixth decades of life.…”

“…The management of aa-IFN-γ has been challenging; standard broad-spectrum immunosuppressants (e.g., steroids) or immunomodulatory dosing of IVIG have been unsuccessful. Cyclophosphamide has been used with some success [ 240 , 248 ]. Given that this immunodeficiency is due to the presence of rogue autoantibodies, drugs specifically depleting B cells, such as Rituximab (anti-CD20) or Daratumumab (anti-CD38), have been reported to be effective in terms of reducing aa-IFN-γ levels and clearing infection [ 240 , 249 ].…”

A rare presentation of Legionella pneumophila and Mycobacterium intracellulare co‐infection masquerading as metastatic lung cancer in a patient with positive anti‐interferon gamma antibody

“…One proposed treatment was Rituximab, an anti‐CD20 monoclonal antibody, which works by depleting B‐cells that produce AIGA. Other immunotherapies including glucocorticoid, cyclophosphamide, daratumumab or even plasmapheresis have also been used in the past 1 . Clinical trials are urgently needed in this area.…”

From Mendel to mycoses: Immuno‐genomic warfare at the human–fungus interface

“…It has also provided rationale for adjunctive IFN‐γ therapy to treat such infections, although this is dependent on the underlying defect 176,209 . Paradoxically, targeting the production of aab:IFN‐γ with either cyclophosphamide or rituximab may be required to control the associated infection, demonstrating the translational value of such immunological investigations 208,210–214 . Whether autoantibodies to IFN‐γ, GM‐CSF, or their respective receptors account for extra‐pulmonary cases of other TDF begs investigation.…”

“…176,209 Paradoxically, targeting the production of aab:IFNγ with either cyclophosphamide or rituximab may be required to control the associated infection, demonstrating the translational value of such immunological investigations. 208,[210][211][212][213][214] Whether autoantibodies to IFNγ, GM-CSF, or their respective receptors account for extra-pulmonary cases of other TDF begs investigation. Lastly, the identification that defects in IL-12/-23/IFNγ render humans susceptible to disseminated TDF also reminds us that our understanding of the immune pathways governing the other TDF syndromes are far from well understood, but are likely to involve distinct or lung-specific pathways.…”