Clinical Cognition and Practice in Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome

Abstract

Adult-onset immunodeficiency syndrome mediated by anti-interferon-gamma autoantibody (AIGA) is a rare disorder that has garnered increasing recognition in recent years. The condition is most prevalent among adults in Southeast Asia. It is characterized by recurrent disseminated opportunistic infections, frequently involving multiple organ systems such as the lungs, lymph nodes, bones, and skin. The pathogenesis is primarily attributed to the presence of neutralizing AIGAs, which impair the IFN-γ–mediated JAK–STAT1 signaling pathway, leading to compromised host defense against intracellular pathogens. Laboratory diagnosis requires both quantification of AIGA titers and assessment of their neutralizing activity. Clinical diagnosis relies on a combination of characteristic manifestations, demonstrated immunologic dysfunction, and seropositivity for AIGAs. During the acute stage, management focuses on antimicrobial therapy, while during the stable stage, it can be categorized into three clinical subtypes: high AIGA titers with immune damage, high AIGA titers without immune damage, and low AIGA titers without immune damage. Among these, patients with high AIGA titers and immune damage require immunomodulatory strategies—such as glucocorticoids and rituximab—tailored to individual AIGA levels and immune status. Due to the current absence of unified clinical guidelines, this review synthesizes available evidence and clinical expertise to provide a comprehensive overview of the epidemiology, pathogenesis, clinical presentation, diagnostic criteria, and treatment approaches related to AIGA-mediated immunodeficiency. Our aim is to assist clinicians in the recognition and management of this syndrome and to facilitate further clinical research and guideline development.

Introduction

Anti-interferon-γ autoantibody (AIGA)-associated immunodeficiency syndrome is an adult-onset immunodeficiency mediated by AIGAs that neutralize IFN-γ, blocking JAK-STAT1 signaling and impairing macrophage killing of intracellular pathogens such as Talaromyces marneffei and non-tuberculous mycobacteria (NTM) [1, 2]. First identified in 2004 [3, 4], this syndrome exhibits marked geographic clustering in Southeast Asia, with high-prevalence regions including Thailand, Vietnam, the Philippines, Japan, China, and particularly Guangxi and Guangdong provinces [5, 6].

Clinically, patients typically present with recurrent disseminated NTM/Talaromyces marneffei infections characterized by fever, lymphadenopathy, bone destruction, pulmonary lesions, and skin abscesses [5–7]. The condition is typically diagnosed upon presentation with disseminated opportunistic infections as the initial clinical manifestation, accompanied by characteristic immunodeficiency features. Despite targeted antibiotic therapy, approximately 50% develop acute exacerbations or new infections, with a mortality rate of ~ 10% [5, 7]. Notably, while clinical manifestations have been well characterized, the associated immune dysregulation, including polyclonal B-cell activation with elevated IgG and IgE and organ-specific damage to the eyes and skin [7, 8], remains underrecognized. This complex interplay between functional autoantibody-driven immune dysfunction and opportunistic infection susceptibility underlies the characteristically protracted and refractory disease course.

Currently, no established diagnostic criteria or treatment guidelines exist. This syndrome follows a chronic and complex clinical course, with management primarily involving targeted anti-infective therapy. Given these challenges, this disease warrants comprehensive characterization. This unmet need forms the basis for this clinical practice document. However, the current evidence base remains limited, drawing predominantly from case reports and clinical experience. This document is aimed at establishing a foundational framework for enhancing disease understanding and guiding the progressive refinement of diagnostic and therapeutic approaches in clinical practice.

Epidemiological

Anti-interferon-γ autoantibody (AIGA)-mediated adult-onset immunodeficiency (AOID) is a distinct clinical syndrome caused by neutralizing autoantibodies against interferon-γ (IFN-γ), and it is characterized by recurrent disseminated opportunistic infections predominantly due to NTM, Talaromyces marneffei, and Salmonella species [5, 9]. Its pathophysiology involves elevated levels of functional autoantibodies inducing immune dysfunction and consequent susceptibility to opportunistic infections, which collectively result in a characteristically protracted and clinically complex disease course.

In 2004, researchers initially identified high-titer IFN-γ neutralizing autoantibodies in patients with disseminated NTM infections [3, 4]. To date, over 1000 cases have been reported globally, with the majority occurring in Asia, particularly in the Philippines, Thailand, Vietnam, Japan, and China [6].

Notably, the higher prevalence of AIGA-associated immunodeficiency syndrome in Southeast Asian adults may reflect a convergence of regional genetic susceptibility, endemic infections with potential immune-modulatory effects, and differences in local healthcare practices, though these possibilities currently lack definitive evidence and require confirmation through future multicenter studies. Affected patients have a median age of approximately 50 years (range: 10–87 years), with no significant gender predilection [9–11]. AIGAs have been detected in 88% of Asian patients with multiple opportunistic infections [9]. Although AIGA-associated immunodeficiency syndrome is a rare disease, cohort studies from Guangxi, China have identified over 130 cases [7], which indicates that its true incidence is likely substantially underestimated.

Clinical Manifestations

To provide a comprehensive overview of the clinical manifestations of AIGA-associated immunodeficiency syndrome, we conducted a systematic literature search of PubMed, Embase, and Web of Science databases up to April 2026, using the following search terms: "anti-interferon-gamma autoantibody", "AIGA", "acquired immunodeficiency", and "adult-onset immunodeficiency". Excluding 11 studies with overlapping data published by our research team, a total of 99 studies were identified and included in the synthesis, encompassing 1,113 patients with detailed clinical data.

Recurrent Disseminated Opportunistic Infections as Primary Presentation

Patients with AIGA-associated immunodeficiency syndrome typically present with recurrent disseminated opportunistic infections caused predominantly by intracellular pathogens. Based on a systematic review of published cohorts and 938 case series with pathogen-related information, the most frequently reported pathogens include NTM and Talaromyces marneffei, followed by Mycobacterium tuberculosis, Salmonella species, Cryptococcus species, and Burkholderia species (Fig. 1). In addition, eight other pathogens were reported in fewer than three cases (1–2 cases each), including Legionella, Nocardia, Enterobacter cloacae, Pseudomonas aeruginosa, Bacillus cereus, Listeria, Strongyloides stercoralis, and Toxoplasma (as detailed in the figure legend). This characteristic pattern of disseminated infections serves as a crucial diagnostic indicator for the condition.

Fig. 1.

Distribution of causative pathogens among 938 cases. Only pathogens reported in three or more cases are shown in this figure. Eight additional pathogens were reported in fewer than three cases (1–2 cases each): Legionella (2 cases), Nocardia (2 cases), Enterobacter cloacae (1 case), Pseudomonas aeruginosa (1 case), Bacillus cereus (1 case), Listeria (1 case), Strongyloides stercoralis (1 case), and Toxoplasma (1 case)

Multisystem Disseminated Infections with Frequent Diagnostic Challenges

Infection frequently involves multiple organ systems. Among 941 cases with available organ involvement data, the most commonly affected sites were lymph nodes (69.7%), lung/airway (49.4%), skin/soft tissue (37.6%), and bone/joint (29.9%), followed by bloodstream (18.0%), pleura (8.8%), liver (7.0%), bone marrow (6.3%), and spleen (5.5%) (Table 1). Less frequently involved sites included the brain/nervous system, pericardium, nasopharynx, and gastrointestinal tract.

Table 1.

Distribution of organ/system involvement in AIGA-associated immunodeficiency syndrome

Organ/System	Cases (n)	Percentage (%) †
Lymph nodes	656	69.7
Lung/airway	465	49.4
Skin/soft tissue	354	37.6
Bone/joint	281	29.9
Blood	169	18.0
Pleura	83	8.8
Liver	66	7.0
Bone marrow	59	6.3
Spleen	52	5.5
Brain/nervous system	24	2.6
Pericardium	23	2.4
Nasopharynx	15	1.6
Gastrointestinal tract	10	1.1
Others*	37	3.9

†Percentage calculated based on 941 cases with available organ involvement description out of 1,113 total cases

*Others includes: muscle (9), eye (8), urinary system (6), breast (4), biliary tract (2), parotid gland (2), pelvis (1), pancreas (1), heart valve (1), uterus/adnexa/vagina (1), ear (1), and oral cavity (1)

Patients commonly present with fever (64.6%), lymphadenopathy (53.4%), cough/expectoration (52.5%), and weight loss (44.2%). Other frequent manifestations include skin lesions (32.5%), pain involving the back, ribs, neck, or joints (23.7%), dyspnea (18.4%), chest tightness or pain (14.4%), fatigue (13.3%), anorexia (10.7%), hepatomegaly (10.7%), pallor (10.2%), and chills (9.0%) (Table 2). Less common symptoms include moist rales, abdominal pain or diarrhea, sweet syndrome, dizziness or headache, splenomegaly, hemoptysis, night sweats, and subcutaneous nodules.

Table 2.

Symptoms and signs in AIGA-associated immunodeficiency syndrome

Symptom/Sign	Cases (n)	Percentage (%) #
Fever	404	64.6
Lymphadenopathy	334	53.4
Cough/Expectoration	328	52.5
Weight Loss	276	44.2
Skin Lesions	203	32.5
Pain (including back, rib, neck, joint pain)	148	23.7
Dyspnea	115	18.4
Chest Tightness/Chest Pain	90	14.4
Fatigue	83	13.3
Anorexia	67	10.7
Hepatomegaly	67	10.7
Pallor	64	10.2
Chills	56	9.0
Moist Rales	44	7.0
Abdominal Pain/Diarrhea	44	7.0
Sweet Syndrome	42	6.7
Dizziness/Headache	36	5.8
Splenomegaly	36	5.8
Hemoptysis	28	4.5
Night Sweats	27	4.3
Subcutaneous Nodules	17	2.7
Signs of Pleural Effusion	12	1.9
Others (< 10 cases each)	30	4.8

#Percentage calculated based on 625 cases with available symptom/sign description

*Others includes: Wheeze (7), Lower Extremity Edema (3), Nausea/Vomiting (3), Visual Impairment/Blindness (3), Hematochezia (2), Jaundice (2), Photophobia (2), Dysphagia (1), Hoarseness (1), Pharyngeal Foreign Body Sensation/Sore Throat (1), Epilepsy (1), Ear Pain/Tinnitus (1), Epiphora (1), Numbness of Hands (1), Absent Breath Sounds (1)

NTM and Talaromyces marneffei are the most frequent pathogens, and they often cause multiorgan involvement. The most commonly affected sites comprise the lungs (49.4%), lymph nodes (69.7%), bone/joint (29.9%), and skin/soft tissue (37.6%) (Table 2). Bone manifestations represent a characteristic clinical feature, with manifestations of bone pain, restricted movement, and pathological fractures [12, 13]. Whole-body bone scintigraphy demonstrates an increased radiotracer uptake in affected regions (Fig. 2). Characteristic radiographic findings include osteopenia, moth-eaten bone destruction, and periosteal reactions. Cutaneous manifestations of Talaromyces marneffei infection predominantly affect the face, upper trunk, and upper extremities (Fig. 3). The dermatologic presentation shows high variability and encompasses papular lesions, subcutaneous abscesses, nodules, necrotic papules, acneiform eruptions, and folliculitis [13, 14]. The pathognomonic finding is a centrally necrotic, umbilicated papule with depressed center.

Fig. 2.

Bone scintigraphy findings in disseminated Mycobacterium avium infection: The whole-body bone scan demonstrates multiple patchy areas of increased radiotracer uptake in the skull, sternum, bilateral scapulae, multiple vertebrae, ribs, pelvis, and right proximal femur. Osteolytic bone destruction is observed in the sternum, right 2nd anterior rib, right 8th posterior rib, left 1 st and 6th anterior ribs, and left scapula

Fig. 3.

Cutaneous manifestations of Talaromyces marneffei and nontuberculous mycobacterial (NTM) infections. (A1-A2) Skin lesions on the lower extremities and trunk in a patient with Talaromyces marneffei infection. (B1-B2) Cutaneous lesions on the forehead in another patient with Talaromyces marneffei infection. (C1-C2) Disseminated skin lesions on the lower extremities in a patient with NTM infection. The corresponding pathogens were identified from all skin lesions

Patients with severe disseminated infection may display detectable bloodstream infection caused by various pathogenic microorganisms, such as Salmonella species, Burkholderia species, Talaromyces marneffei, Nocardia species, and NTM. Bloodstream involvement was documented in 18.0% of cases with available organ involvement data (Table 2).

Pathogenic Mechanisms

IFN-γ, a cytokine produced by T cells, natural killer cells, and other immune effectors, mediates essential innate and adaptive immune functions. During infection, IFN-γ primarily targets tissue-resident macrophages, activating them via the JAKs-STAT1 signaling pathway to induce interferon-stimulated genes (ISGs). The protein products of ISGs exert antimicrobial effects through multiple mechanisms, including the generation of toxic metabolites (e.g., reactive oxygen/nitrogen species, acidic pH, itaconate), direct microbial cell wall degradation, and synergistic interactions with other immune mediators such as TNF-α and IL-12—both of which are also upregulated upon JAKs-STAT1 activation. Collectively, these responses orchestrate host defense against invading pathogens, including bacteria, parasites, and fungi [2].

However, when neutralizing anti-interferon-γ autoantibodies (AIGAs) bind IFN-γ, they disrupt JAKs-STAT1 signaling in macrophages (Fig. 4). This inhibition leads to diminished production of antimicrobial effector molecules and key cytokines (e.g., TNF-α, IL-12), as well as impaired downstream signaling [9, 15]. This condition leads to compromised antimicrobial immunity and disseminated opportunistic infections. The pathogenesis remains unclear, particularly whether AIGAs arise secondary to infection or predispose to subsequent infections, a key distinction for comprehending disease initiation.

Fig. 4.

Pathogenesis of AIGA-associated immunodeficiency syndrome. IFN-γ normally activates macrophages via JAK-STAT1 signaling to induce antimicrobial ISG products (ROS, RNI, itaconate) and proinflammatory cytokines (TNF-α/IL-12). Neutralizing AIGAs block IFN-γ signaling, impairing microbial clearance and leading to disseminated infections by intracellular pathogens like Talaromyces marneffei and mycobacteria. (ISGs: interferon-stimulated genes; ROS: reactive oxygen species; RNI: reactive nitrogen intermediates)

AIGA-associated immunodeficiency syndrome predominantly affects adults in Southeast Asia. Genetic studies have demonstrated significant associations of the disease with specific HLA haplotypes [16–18]. Notably, multiple HLA class II alleles—including DRB1*16:02, DRB1*15:02, DQB1*05:02, and DQB1*05:01—show strong linkage disequilibrium with AIGA production. These risk alleles exert synergistic effects on disease pathogenesis.

AIGA Identification and Correlated Immune Marker Changes

AIGA Detection

Current AIGA detection involves the measurement of antibody titer/concentration and neutralizing activity. The diagnosis of AIGA-associated AOID requires confirmation of the neutralizing activity given that AIGAs in healthy individuals typically lack this function [19]. Neutralization occurs during the binding of AIGAs to IFN-γ, which blocks the Janus kinase (JAK)-STAT1 signaling pathway and consequently impairs macrophage activation, antimicrobial function, and cytokine production [7, 20, 21].

The detection of AIGAs primarily relies on antigen–antibody binding. Commonly employed methods include enzyme-linked immunosorbent assay (ELISA) [22], bead-based multiplex assays [23, 24], the QuantiFERON-TB Gold In-Tube test [25, 26], and immunochromatographic strips [27]. The QuantiFERON-TB Gold In-Tube test, originally designed for latent tuberculosis screening, has been repurposed as an indirect functional assay for AIGA detection. The key lies in the mitogen tube: healthy individuals show robust IFN-γ elevation following mitogen stimulation, whereas AIGA-positive patients exhibit markedly reduced or undetectable IFN-γ levels due to autoantibody-mediated neutralization. An indeterminate or negative mitogen result—particularly when IFN-γ is also low in the TB antigen tube despite clinical suspicion for tuberculosis—suggests neutralizing antibody activity rather than immune anergy, technical failure, or true negative TB status. Thus, this assay serves as a qualitative functional screen for IFN-γ autoantibodies, with definitive AIGA diagnosis requiring confirmatory tests such as anti-IFN-γ autoantibody ELISA. ELISA is the most widely used method due to its operational simplicity, rapid processing, and suitability for large-scale screening. This technique employs enzyme-labeled secondary antibodies for colorimetric detection. By contrast, bead-based multiplex assays enable the simultaneous and quantitative measurement of plasma concentrations of multiple anticytokine autoantibodies using cytokine-coupled microspheres [23, 24]. Qualitative screening normally involves the QuantiFERON-TB Gold In-Tube test [25, 26]and immunochromatographic strips [27]. Notably, indeterminate QuantiFERON-TB Gold results—characterized by absent or low IFN-γ production in both TB antigen and mitogen tubes due to neutralization by circulating anti-IFN-γ autoantibodies—should prompt clinical suspicion for AIGA [25, 26].

The neutralization activity of AIGAs is typically evaluated through Western blot [7], flow cytometry [20, 21], and immunofluorescence [15]. These techniques are used to assess the capacity of AIGAs to inhibit IFN-γ-mediated JAK-STAT1 signaling, in which IFN-γ binding normally triggers STAT1 phosphorylation (p-STAT1). In in vitro models, patient serum incubated with cell lines is used to simulate the immune microenvironment, followed by Western blot analysis of the target proteins. Flow cytometry offers a more direct and reproducible approach: healthy donor PBMCs or whole blood are pre-incubated with patient serum, stimulated with recombinant IFN-γ, and stained for intracellular p-STAT1. Reduced p-STAT1 mean fluorescence intensity compared to controls indicates neutralizing activity, with serial dilutions enabling semi-quantitative titer determination. This method directly reflects functional blockade of the IFN-γ signaling pathway and is suitable for routine clinical laboratory assessment given its standardization potential and widespread platform availability.Alternatively, flow cytometry or immunofluorescence can be utilized to directly quantify p-STAT1 levels in patient-derived peripheral blood mononuclear cells [15, 20, 21].

More recently, commercial reporter cell-based assays have been developed to enable standardized, cross-laboratory quantification of IFN-γ neutralization capacity through reporter gene expression and IC50 calculation, facilitating diagnostic harmonization and accessibility [28].

Immunological Alterations in AIGA-Associated Immunodeficiency

Elevated levels of AIGAs, which are produced by plasma cells, induce distinct immunological changes. Patients typically demonstrate polyclonal hyperglobulinemia, which is characterized by increased immunoglobulin G (IgG), IgE, and IgG4 levels [7, 9]. Notably, some patients exhibit concurrent autoantibodies (e.g., antinuclear antibodies) [29].

T cell phenotyping reveals preserved CD4⁺ and CD8⁺ T cell counts and proportions [7]. However, most patients show elevated nonspecific inflammatory markers, including significantly increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [7].

Diagnosis and Evaluation

Diagnosis of AIGA-Associated Immunodeficiency Syndrome

Note: The following diagnostic criteria are proposed by the authors based on current literature and clinical experience, and should be considered as suggested criteria rather than universally established guidelines. Prospective multicenter studies are needed for further validation.

Diagnostic Components:

1. Clinical Presentation: Recurrent or disseminated opportunistic infections, particularly Talaromyces marneffei and/NTM infections.

2. Laboratory Findings: Elevated levels of globulin, IgG, IgE, and/or IgG4.

3. Immunological Confirmation: Increased AIGA levels with demonstrable neutralizing activity.

4. Exclusion Criterion: Negative HIV serology (to exclude HIV-related opportunistic infections and hypergammaglobulinemia).

Diagnostic Criteria: (Fig. 5)

• Suspected diagnosis: (1) + (2) + (4).

• Definitive diagnosis: (1) + (2) + (3) + (4).

Fig. 5.

Diagnostic algorithm for AIGA-associated immunodeficiency syndrome. The diagnostic evaluation comprises four components: (1) clinical presentation with recurrent or disseminated opportunistic infections (particularly Talaromyces marneffei and/or nontuberculous mycobacteria); (2) laboratory findings showing elevated globulin, IgG, IgE, and/or IgG4 levels; (3) immunological confirmation with increased anti-IFN-γ autoantibody (AIGA) levels and demonstrable neutralizing activity; and (4) mandatory exclusion of HIV infection. Suspected diagnosis requires criteria (1), (2), and (4); definitive diagnosis requires all four criteria (1)– (4)

Rationale: HIV infection represents a critical differential diagnosis given its overlapping features (opportunistic infections, hyperglobulinemia). Mandatory HIV exclusion ensures diagnostic specificity. The tiered approach allows early clinical recognition while reserving definitive diagnosis for immunologically confirmed cases.

Clinical Stages and Subtypes

Acute Exacerbation Stage

During the acute exacerbation stage of AIGA-associated immunodeficiency syndrome, patients typically present with disseminated opportunistic infections that affect multiple organ systems, including the lungs, lymph nodes, skin, bones, bloodstream, liver/spleen, nervous system, and eyes.

Depending on disease severity, patients in the acute exacerbation stage can be stratified into nonsevere and severe phenotypes. The former cases maintain stable vital signs with either single or polymicrobial persistent infections, which are associated with relatively low mortality rates. By contrast, severe cases typically present with life-threatening polymicrobial sepsis and considerable elevated mortality.

Stable Stage

Typically, after 3–4 weeks of acute infection effective control of the opportunistic infection is achieved, and pathogen-specific treatment is continued based on the causative microorganism [7].

During the stable stage, AIGAs persist at varying levels with heterogeneous immune profiles and clinical presentations. Based on the interplay between AIGAs titers and immune status, patients can be stratified into three dynamic subtypes that may transition over time (Fig. 6). First, low-level AIGA without immune damage is characterized by relatively low AIGAs titers, normal B-cell function markers (globulin, IgG, IgE, IgG4) and inflammatory indices (white blood cells, ESR, CRP, eosinophils), and minimal clinical symptoms; these patients remain stable with rare infection exacerbation. Second, high-level AIGA with immune damage presents with markedly elevated AIGAs titers, deranged B-cell or inflammatory markers, and systemic manifestations including fatigue, weight loss, anorexia, and rash; this group is at high risk for reinfection and new opportunistic infections. Third, high-level AIGA without immune damage shows elevated AIGAs titers but preserved immunological parameters and stable clinical status; however, these patients remain functionally immunodeficient and may progress to the immune-damaged subtype, leading to disease recurrence.

Fig. 6.

Interconversion among the three subtypes of AIGA-associated immunodeficiency syndrome

Treatment and Disease Management

General Therapeutic Approach

A dual-phase approach is implemented in the treatment of AIGA-associated immunodeficiency syndrome: during active infection, pathogen-specific antimicrobial therapy is prioritized, and the stable phase is focused on reducing AIGA levels, restoring IFN-γ/STAT1 signaling pathway function, and preventing disease recurrence through immunomodulation, with the ultimate goals of attaining sustained remission and reduced mortality. Current management strategies remain investigational and require individualized protocols based on disease stage and immune status (Fig. 7).

Fig. 7.

Diagnostic and therapeutic workflow for AIGA-associated immunodeficiency syndrome

Drug Therapy, Clinical Monitoring, and Prognostic Outcomes

Management of Acute Infections

Empirical Antimicrobial Therapy

For acute infections, the initiation of empirical antibiotic therapy is based on pathogen susceptibility patterns, infection site, and disease severity, with primary coverage targeting common pathogens, including NTM, Talaromyces marneffei, and Salmonella. In severe cases with suspected polymicrobial infection, combination antibiotic therapy is recommended. Such treatment typically incorporates anti-NTM agents (e.g., macrolide-ethambutol regimens) and anti-TM medications (e.g., amphotericin B), with treatment selection guided by clinical response and microbiological findings.

Targeted Antimicrobial Therapy

Treatment of Talaromyces marneffei infection:

The induction phase requires intravenous administration of amphotericin B at recommended doses of 0.6–1.0 mg/kg/day (approximately 50 mg daily for a 60 kg adult) or intravenous administration of voriconazole for 2 weeks. The consolidation phase comprises oral itraconazole or voriconazole treatment for 3 months, followed by a maintenance phase lasting approximately 1 year [30].

Treatment of NTM:

Therapeutic regimens for NTM infections require species-specific approaches due to varying drug resistance patterns, which necessitate pretreatment mycobacterial identification and drug susceptibility testing. During treatment, rigorous therapeutic drug monitoring and safety surveillance are performed to detect and manage adverse effects, including QT prolongation, hepatotoxicity, nephrotoxicity, peripheral neuropathy, and thrombocytopenia, with treatment duration maintained for ≥ 1-year postsputum culture conversion [31].

For slow-growing mycobacteria (including M. avium complex, M. kansasii, and M. gordonae): Standard oral regimens combine clarithromycin/azithromycin with rifabutin/rifampin and ethambutol, supplemented with amikacin during the initial 3-month phase.

For rapid-growing mycobacteria (including M. abscessus complex, M. fortuitum, and M. chelonae): The intensive phase requires intravenous administration of amikacin combined with tigecycline, imipenem/cilastatin, and oral macrolides (clarithromycin/azithromycin) for 1–6 months, transitioning to a continuation phase with nebulized amikacin treatment plus oral macrolides, linezolid, fluoroquinolones (ciprofloxacin/moxifloxacin), and either rifabutin, clofazimine, or TMP-SMX.

Immunotherapy

In patients who experience persistent fever despite appropriate antimicrobial therapy (including combination regimens), along with normal neutrophil counts and procalcitonin levels but persistently elevated immune/inflammatory markers (AIGAs, globulins, immunoglobulins, ESR, and CRP), elevated AIGA-mediated immune injury should be considered. For such cases, treatment involving methylprednisolone 40–80 mg/day (or equivalent glucocorticoids) for 7–10 days can be initiated [7].

Stable Stage Treatment

This stage necessitates continued anti-infective therapy targeting the identified pathogen, accompanied with close monitoring of immune status and infection dynamics. Individual treatment adjustment is performed based on disease subtype, serial immune marker assessments (performed every 3–4 weeks), and inflammatory indicators [7].

1. Low AIGA Levels without Immune Damage

   When the disease remains stable with low AIGA levels and intact immune function, routine surveillance of immune and inflammatory markers is sufficient without additional intervention.

2. High AIGA Levels with Immune Damage

   Active intervention is required. First, whether the original infection remains under control or whether new infections have emerged must be assessed. If neither is present, immunomodulatory therapy must be initiated:

   • ① Glucocorticoids: Low-dose prednisone acetate (0.5–1 mg/kg/day) or equivalent must be administered. The typical treatment duration lasts approximately 3 months, with gradual tapering after symptom resolution and stabilization of ESR and immunoglobulin levels. CBC, ESR, CRP, and immunoglobulin levels are monitored throughout treatment [7].
   • ② Rituximab: This agent reduces AIGA levels and restores IFN-γ–STAT1 signaling. The risk of relapse after discontinuation necessitates multicourse maintenance therapy [32, 33]. Given that B-cell depletion may increase infection risk, close immune monitoring is essential. The optimal timing and duration remain undefined, with current evidence derived primarily from case reports. Notably, rituximab is already established in other B-cell–driven autoimmune diseases, including ANCA-associated vasculitis, rheumatoid arthritis, systemic sclerosis, and lupus nephritis, supporting its broader immunomodulatory applicability [34–39].
   • ③ Cyclophosphamide: This treatment effectively lowers AIGA titers and improves clinical outcomes (with most evidence coming from case studies) [40, 41].
   • ④ Emerging B-cell–targeting therapies: Given the relapse risk with current regimens, newer therapeutic strategies are warranted. Anti-CD19 monoclonal antibodies (e.g., inebilizumab) offer broader B-cell depletion, including plasmablasts that may persist after CD20-targeted therapy [42]. Combination approaches targeting CD20/CD22/CD38 (e.g., rituximab + epratuzumab + daratumumab) enable multi-epitope B-cell eradication. Bispecific T-cell engagers (e.g., CD3 × CD19 or CD3 × CD20 constructs) redirect cytotoxic T cells to eliminate pathogenic B-cell clones. These modalities, increasingly validated in systemic lupus erythematosus, rheumatoid arthritis, and other B-cell–driven autoimmune disorders, represent promising future directions for refractory or relapsing AIGA, though clinical trials in this specific population are needed [42, 43].

3. High AIGA Levels without Immune Damage

   Patients demonstrate elevated AIGA levels while maintaining stable clinical and inflammatory markers. However, they remain at risk of progression to the High AIGA Level with Immune Damage subtype; therefore, intensified monitoring is required to detect early immune impairment or disease relapse.

Patients demonstrate elevated AIGA levels while maintaining stable clinical and inflammatory markers. However, they remain at risk of progression to the High AIGA Level with Immune Damage subtype; therefore, intensified monitoring is required to detect early immune impairment or disease relapse.

Therapeutic Efficacy, Outcomes, and Limitations

As a result of the insidious onset of AIGA-associated immunodeficiency syndrome, most patients remain undiagnosed until recurrent opportunistic infections manifest, which results in substantial diagnostic and therapeutic delays. Clinical data demonstrate that approximately 50% of patients experience recurrent acute infectious exacerbations during treatment [7, 23].

The disease follows a chronic progressive course characterized by interwoven immune dysregulation (elevated AIGAs levels) and recurrent infections. The core pathogenic factor remains infection driven by persistently high AIGAs levels. Current therapeutic experience targeting AIGAs is primarily limited to isolated case reports, with a notable absence of cohort studies to establish evidence-based treatment protocols.

Dynamics of AIGA level: Some patient experienced decreased AIGA levels following immunosuppressive therapy (e.g., glucocorticoids, rituximab). However, relapse frequently occurs after treatment discontinuation. Only a minority achieve long-term remission, and most require ongoing therapy.

The disease follows a chronic, protracted course and is often complicated by recurrent acute exacerbations due to infections. While a small subset of patients maintains long-term stability, the majority experience a poor quality of life and a substantial disease burden. However, understanding of this condition remains limited, with its pathogenesis and natural history remaining unclear. Further clinical research and practice are needed to optimize the duration and dosing of immunosuppressive regimens.

Summary

1. AIGA-associated immunodeficiency syndrome refers to an autoimmune disorder characterized by recurrent opportunistic infections, with disseminated infections (e.g., NTM and Talaromyces marneffei) and immune dysregulation as its hallmark features. The timely detection of AIGAs is crucial for definitive diagnosis.

2. The disease course is divided into an acute infectious exacerbation phase and a stable stage, with the latter further classified into three clinical subtypes: low-level AIGA without immune damage, high-level AIGA with immune damage, and high-level AIGA without immune damage, which guides clinical assessment and management.

3. AIGA-associated immunodeficiency syndrome follows a prolonged and treatment-resistant course, where infections and immune dysfunction perpetuate each other.

4. Acute stage: Critically ill patients frequently develop polymicrobial coinfections, which contribute to high mortality rates.

5. Stable stage: Treatment strategies are tailored based on disease subtypes.

With the increased clinical recognition of AIGA-associated immunodeficiency syndrome, the absence of international diagnostic or therapeutic guidelines poses a challenge. This clinical practice recommendation aims to provide preliminary guidance, although it primarily draws from published literature and expert consensus. Given the paucity of high-quality evidence, constructive feedback is encouraged to guide future revisions.

Author Contribution

Author Contributions: S.L. (Siqiao Liang) and Z.H. (Zhiyi He) designed the study and supervised the research. X.H. (Xuemei Huang) and Z.L. (Zengtao Luo) performed data analysis and prepared figures. X.L. (Xiaona Liang), S.W. (Siyao Wu), Y.N. (Yan Ning), N.C. (Ni Chen), L.H. (Limei Hong), X.W. (Xiaoshan Wei), Q.C. (Quanfang Chen), J.D. (Jingmin Deng), M.L. (Meihua Li), M.Y. (Meiling Yang), W.Z. (Wen Zeng), P.Y. (Ping Yan), H.W. (Hongyu Wei), J.Z. (Jiujin Zhang), F.C. (Fu Cao), X.Z. (Xinxin Zhong), Z.W. (Zhen Wei), Q.W. (Qing Wei), M.J. (Ming Jiang), C.X. (Chengqiong Xu), T.C. (Ting Chen), S.L. (Shilian Liang), X.M. (Xiayan Meng), C.Q. (Chunhai Qin), D.Q. (Dongming Qu), L.Z. (Lanke Zou), and Y.L. (Yinghua Li) contributed to data collection, investigation, and methodology. S.L. (Siqiao Liang) and X.H. (Xuemei Huang) wrote the main manuscript text. All authors reviewed and approved the final manuscript.

Funding

This study was supported by the following grants:

(1) Guangxi Key Technologies R&D Program (Grant No. 2023AB22055);

(2) Central Leading Local Science and Technology Development Fund (Grant No. 2023ZYZX1021);

(3) National Key R&D Program of China (Grant No. 2024YFC2309600);

(4) Self-funded Scientific Research Project on Western Medicine, Guangxi Health Commission (Grant No. Z-A20250388).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Consent for Publication

All authors have approved the final version of the manuscript and agree to its publication.

Competing interests

The authors declare no competing interests.