This condition—often called Adult-Onset Immunodeficiency Syndrome (AOIDS)—is one of the most important but overlooked causes of severe opportunistic infections in HIV-negative adults with normal CD4 counts. Awareness remains low, especially outside Asia, despite an increasing number of global cases.
🔎 Quick Summary: When to Suspect Adult-Onset Immunodeficiency
Adult-onset immunodeficiency due to anti–interferon-gamma (anti–IFN-γ) autoantibodies should be considered in HIV-negative adults—especially those with Asian ancestry—who develop unexplained, recurrent, or disseminated intracellular infections despite normal lymphocyte counts.
Key clinical clues
- Disseminated or recurrent NTM infections (M. abscessus, MAC)
- Recurrent Salmonella bacteremia
- Severe or disseminated varicella-zoster virus (VZV)
- Very high CRP/ESR with normal lymphocyte counts
- Suppurative lymphadenitis, osteomyelitis, or septic arthritis
- Neutrophilic dermatoses: Sweet-like plaques, EN-like nodules, panniculitis
- Indeterminate Quantiferon in a symptomatic adult
- Exaggerated TB skin test with pustulation
Pneumocystis jirovecii pneumonia (PJP) can occur but is significantly less common than in HIV/AIDS.
What Is Adult-Onset Immunodeficiency From Anti–IFN-γ Autoantibodies?
Adult-onset immunodeficiency (AOIDS) occurs when the immune system produces neutralizing autoantibodies against IFN-γ, a cytokine essential for macrophage activation and intracellular pathogen control.
Because IFN-γ pathways are blocked, patients develop severe defects in cell-mediated immunity—despite appearing immunologically normal on routine blood tests.
Common opportunistic infections
- Rapid-grower NTM (M. abscessus) and MAC
- Recurrent Salmonella bacteremia
- Severe VZV or progressive zoster
- Talaromyces marneffei (endemic areas)
- Histoplasmosis (endemic areas)
- Severe HPV infections
Because CD4 counts are normal, AOIDS is frequently missed unless specifically tested for.
🌏 Geographic Distribution and Global Relevance
Most cases have been reported in:
- Thailand
- Taiwan
- Southern China
- Japan
This clustering correlates with HLA-DRB1*15:02 / 16:02 and HLA-DQB1*05:01 / 05:02.
However, AOIDS is not limited to Asia. Cases are increasingly reported in:
- Caucasian patients
- African patients
- Hispanic patients
Why clinicians worldwide must recognize AOIDS
Misdiagnosis is common, often mistaken for:
- HIV infection
- Steroid-induced immunosuppression
- Tuberculosis or sarcoidosis
- Hematologic malignancy
- Primary immunodeficiency
With global mobility and migration, AOIDS should be on the differential whenever adults present with recurrent intracellular infections but test HIV-negative with normal CD4 counts.
🧭 Clinical Clues: When to Suspect Anti–IFN-γ Autoantibody Syndrome
1. Opportunistic infections despite normal CD4 counts
A highly characteristic pattern includes:
- Rapid-grower NTM or MAC
- Recurrent/persistent Salmonella
- Severe or disseminated VZV
- Talaromyces marneffei in endemic regions
- Disseminated histoplasmosis
- Severe or recalcitrant HPV
Unlike HIV/AIDS, PJP is rare.
2. Markedly high CRP/ESR with normal lymphocyte counts
The paradox of extreme inflammation + near-normal lymphocytes is one of the most useful diagnostic clues.
3. Suppurative lymphadenitis and bone/joint infections
Common presentations:
- Necrotizing or granulomatous lymphadenitis
- Mandibular or vertebral osteomyelitis
- Septic arthritis
These are frequently misdiagnosed as TB, atypical infections, lymphoma, or sarcoidosis.
4. Neutrophilic dermatoses (seen in ~40–45%)
Dermatoses include:
- Sweet-like plaques
- EN-like nodules
- Panniculitis
🔸 Clinical pitfall: These lesions are frequently misinterpreted as drug eruptions (e.g., AGEP), making it challenging to distinguish true drug allergy from reactive cutaneous lesions, particularly in patients receiving antibiotics during infection.
A dedicated piece will discuss dermatologic differentiation.
5. Indeterminate or weak Quantiferon
Not universal but often encountered in symptomatic adults.
6. Exaggerated tuberculin skin test reaction
Findings include:
- Pustular or ulcerative reaction
- Very large induration
This reflects disrupted IFN-γ signaling essential for granulomatous responses.
🔬 Diagnosis: How to Confirm Anti–IFN-γ Autoantibody Syndrome
Diagnosis requires demonstrating anti–IFN-γ autoantibodies through:
- ELISA — detects presence of antibodies
- Functional neutralization assay — confirms blocking activity
These specialized assays typically require referral to immunology reference centers.
🩺 How AOIDS Compares With Other Causes of Impaired Cell-Mediated Immunity
| Feature | AOIDS (Anti–IFN-γ Autoantibodies) | AIDS (Advanced HIV) | Steroid-Induced CMI Defect | Hematologic Malignancy | Primary CMI Defects |
| Typical Onset | Adults 30–60 | After HIV infection | Depends on steroid exposure | Variable | Childhood/young adult |
| CD4 Count | Normal | Low (<200) | Normal–mildly low | Low/abnormal | Often normal |
| Key Infections | Rapid NTM, Salmonella, VZV, TM | PCP, MAC, toxo | TB, HSV/VZV | Opportunistic + cytopenias | NTM, BCG |
| Inflammatory Markers | Very high CRP/ESR | Variable | Often blunted | Elevated | Variable |
| Lymph Nodes | Suppurative / necrotizing | Generalized | Usually absent | Enlarged | Granulomatous |
| Bone/Joint | Osteomyelitis, septic arthritis | Rare | Possible | Occasional | Possible |
| Skin | Sweet-like, EN-like, panniculitis | PPE, folliculitis | Acne/atrophy | Non-specific | Variable |
| HIV Test | Negative | Positive | Negative | Negative | Negative |
| Diagnostic Clue | Anti–IFN-γ autoantibodies | CD4 <200 | Steroid exposure | Cytopenias | Early onset |
💊 Treatment Overview
1. Pathogen-directed antimicrobial therapy
- Long-term treatment is often required
- Multiple infections may coexist
- Therapy may continue for months to years
2. Immunomodulatory therapy
Aims to suppress production of anti–IFN-γ autoantibodies.
Options include:
- Cyclophosphamide + steroids
- Rituximab (alternative or adjunct)
Goal: achieve immunologic remission and reduce recurrence of opportunistic infections.
🎯 Why Early Recognition Matters
AOIDS is increasingly recognized as a major cause of severe opportunistic infection in HIV-negative adults, especially across Asia.
However, delayed diagnosis leads to prolonged infections, repeated hospitalizations, and irreversible complications.
Think of AOIDS when an adult presents with:
- Disseminated or recurrent intracellular infections
- Very high CRP/ESR + normal lymphocyte counts
- Suppurative lymphadenitis
- Osteomyelitis without clear cause
- Neutrophilic dermatoses
- Indeterminate Quantiferon
- HIV-negative status with normal CD4 counts
Earlier recognition enables prompt immunomodulation and better long-term outcomes.
📌 Key Takeaways for Clinicians
- Consider AOIDS in HIV-negative adults with recurrent intracellular infections.
- Normal CD4 count + very high CRP/ESR is a diagnostic red flag.
- Confirm diagnosis through testing for anti–IFN-γ autoantibodies.
- Treat with both antimicrobials and immunomodulation to prevent ongoing immune dysfunction.
References
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