Clinical findings and predictive factors for positive anti-interferon-γ autoantibodies in patients suffering from a non-tuberculosis mycobacteria or Talaromyces marneffei infection: a multicenter prospective cohort study

We investigated the clinical features and screened for predictive factors of anti-interferon-γ autoantibody (AIGA) positivity. We enrolled 63 AIGA-positive (group 1) and 29 AIGA-negative

(group 2) HIV-negative patients. White blood cell (WBC) and neutrophil counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), globulin, immunoglobulin (Ig) G, and IgM

levels were higher, whereas CD4+T cell count and hemoglobin level were lower in group 1 than in group 2. Co-infections, multiple infections, and disseminated infections were significantly

higher in group 1 than in group 2. Prognosis was worse in group 1 than in group 2, especially for relapse and persistent infections. The number of infecting pathogens and sites involved; WBC

and neutrophil counts; globulin, IgG, IgM, and CRP levels; and ESR were significantly positively correlated with AIGA titers; however, CD4+T cell count was significantly negatively

correlated with AIGA titers. Therefore, IgG, globulin, and CRP levels; CD4+T cell and WBC counts; the number of infecting pathogens and sites involved; and ESR were considered potential

predictors for AIGA positivity. For HIV-negative hosts with double or multiple opportunistic, disseminated infections and high serum IgG and globulin levels, low CD4+T cell count, and an

increase in inflammatory marker levels, positive AIGA-associated immunodeficiency should be considered.

Adult-onset immunodeficiency syndrome (AOID), caused by anti-interferon-γ autoantibody (AIGA), has been strongly associated with intracellular opportunistic infections in human

immunodeficiency virus (HIV)-negative adults1,2,3,4,5,6. In patients with positive AIGAs, several molecular mechanisms underlie interferon (IFN)-γ dysfunction, considered to primarily

inhibit signal transducer and activator of transcription 1 (STAT1) phosphorylation and interleukin-12 production, resulting in severe dysfunction of the Th1 response1,7. Patients with

positive AIGAs manifest clinically severe mycobacterial, Talaromyces marneffei (TM), and salmonella infections, with double or multiple infections1,2,3,4,5,6.

Since 2012, an increasing number of patients have been diagnosed with AIGA, suggesting that AIGA production was previously underestimated. To date, more than 800 patients have been diagnosed

with AIGAs7. The diagnosis of AIGA disease requires the following two steps: 1) the detection of the AIGA titer by enzyme-linked immunosorbent assay (ELISA), particle-based assay, flow

cytometry analysis, or western blotting; and 2) an assessment of the neutralizing activity of these AIGAs: STAT-1 phosphorylation or human leukocyte antigen (HLA)-DR expression on

IFN-γ-responsive cell assays are the most widely used methods for assessing the neutralization potential of AIGA1,7,8. AOID has always been misdiagnosed due to the lack of clinical knowledge

about it. However, the AIGA titer is closely related to poor infection prognosis, especially in relapsed and refractory infections6. Thus, the timely detection of AIGA and diagnosis of AOID

is essential to improve the prognosis of infected patients. However, these methods of diagnosing positive AIGAs are time-consuming, require expensive instruments, and are used only for

scientific research rather than a routine clinical test.

Based on the 99th percentile of the AIGA titers in 103 healthy volunteers, the cutoff for positivity was 6402.28 ng/ml. During the study, 63 AIGA-positive cases (group 1) and 29

AIGA-negative cases (group 2) with TM and/or nontuberculosis mycobacteria (NTM) infection were enrolled. All 93 participants were HIV-negative. Sex distribution, age, and body mass index

(BMI) did not differ significantly between the groups (Table 1). The AIGA titers in group 1 (median 32,343.8 ng/ml with interquartile range 19,712.8–58,117.3 ng/ml) were significantly higher

than those in group 2 (median 3452.9 ng/ml with interquartile range 1985.7–3983.2 ng/ml) (P