Simultaneous disseminated infections with intracellular pathogens: an intriguing case report of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

Abstract

Background Severe and disseminated non-tuberculous mycobacterial (NTM) infections are frequently linked to a genetic predisposition but acquired defects of the interferon gamma (IFNγ) / interleukin 12 (IL-12) pathway need to be considered in adult patients with persistent or recurrent infections. Neutralizing anti-IFNγ autoantibodies disrupting IFNγ signalling have been identified as the cause of a severe and unique acquired immunodeficiency syndrome with increased susceptibility to NTM and other intracellular pathogens. Case presentation An adult Asian female with a previous history of recurrent NTM infections presented with persistent diarrhea, abdominal pain, night sweats and weight loss. Severe colitis due to a simultaneous infection with cytomegalovirus (CMV) and Salmonella typhimurium was diagnosed, with both pathogens also detectable in blood samples. Imaging studies further revealed thoracic as well as abdominal lymphadenopathy and a disseminated Mycobacterium intracellulare infection was diagnosed after a lymph node biopsy. Further diagnostics revealed the presence of high-titer neutralizing anti-IFNγ autoantibodies, allowing for the diagnosis of adult-onset immunodeficiency with anti-IFNγ autoantibodies (AIIA). Conclusions We here present a severe case of acquired immunodeficiency with anti-IFNγ autoantibodies with simultaneous, disseminated infections with both viral and microbial pathogens. The case illustrates how the diagnosis can cause considerable difficulties and is often delayed due to unusual presentations. Histological studies in our patient give further insight into the pathophysiological significance of impaired IFNγ signalling. B-cell-depleting therapy with rituximab offers a targeted treatment approach in AIIA.

Tissue-localized immune responses in people with cystic fibrosis and respiratory nontuberculous mycobacteria infection

“…The most unexpected observation was that CF-NTM POS airways contained higher frequencies of B cells relative to CF-NTM NEG airways. Although B cells' contribution to the most common form of mycobacterial disease (TB) has long been a topic of controversy, in the context of NTM infection, there are clinical studies that support B cells having a pathogenic role, including the positive correlation between pulmonary NTM infection status and circulating IgG levels (29,30) and their suppression of anti-mycobacterial immune responses via autoantibodies that neutralize cytokines (31,32) or weaken epithelial integrity (33). The increased B cell frequencies and associated cytokines (sCD40L, IL-10, IL-5, and BCA1) observed in CF-NTM POS airways is also noteworthy because these individuals are more likely to die or experience morbidity following removal of their CF lung and replacement with a healthy allogeneic lung (34)(35)(36)(37).…”

Disseminated Mycobacterium chimaera infection in a patient with adult-onset immunodeficiency syndrome: case report

“…Despite geographically varied distribution of NTM species, the dominant NTM species resulting in disseminated infection among patients with AIGAs is MAC (30.7%) [2]. In addition to the main species of MAC (M. avium and M. intracellulare), new MAC species (M. colombiense and M. mantenii) have been reported to cause disseminated infection in patients with AIGAs [13][14][15]. M. chimaera, a recently identified species of MAC, has a lower virulence than the two original species of MAC [3].…”

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

“…In addition, AIGA-positive patients are not exclusive to Southeast Asia. AIGA-positivity has also been reported in America, the United Kingdom, and Germany (5)(6)(7).…”

“…Before the introduction of AIGArelated immunotherapy, the overall improvement rate was 45.1%, and >50% of patients could not achieve remission; there was a 12.3% mortality rate, 8.7% recurrence rate, and 33.9% persistent infection rate. In this study, 67 patients underwent immunotherapy for AIGA (Supplementary Table 2) (6,7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), and the duration of anti-NTM or antifungal treatment in 29 patients was clearly described. The median duration of anti-NTM therapy was 15 (interquartile range: 7, 36) months, and in all of the 67 cases, infection was caused by persistent infection or deterioration after long-term regular antimicrobial therapy.…”

“…However, obvious skin damage, particularly sweet syndrome, can be observed in patients with high AIGA titers, which supports possible autoimmune diseases (35). Therefore, immunotherapy, including corticosteroids, immunosuppressive drugs, and biological agents (rituximab), should be considered when the infection continues to worsen (6,7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). However, these treatment options also affect protective immunity and often lead to serious side effects.…”