Immunodeficiencies in Adults

 

Immunodeficiencies in Adults: Key Considerations for Diagnosis and Management

Dr Neeraj Manikath , claude.ai

Abstract

Primary and secondary immunodeficiencies in adults represent a diagnostic challenge that is often underrecognized in clinical practice. While traditionally considered pediatric conditions, primary immunodeficiencies (PIDs) are increasingly diagnosed in adulthood, with approximately 25-30% of cases presenting after age 20. This review provides a comprehensive approach to recognizing, diagnosing, and managing immunodeficiencies in adult patients, emphasizing practical clinical pearls and evidence-based management strategies essential for internists.

Introduction

The adult immunodeficiency landscape has evolved dramatically over the past two decades. With improved survival of pediatric PID patients and enhanced diagnostic capabilities, internists encounter immunodeficiency disorders far more frequently than previously recognized. The global prevalence of PID is estimated at 1:1,000 to 1:5,000, though many cases remain undiagnosed until adulthood[1]. Secondary immunodeficiencies, driven by medications, malignancies, and systemic diseases, are even more common in adult practice.

Clinical Pearl #1: The "SPUR" mnemonic helps identify patients warranting immunodeficiency evaluation: Severe infections, Persistent infections, Unusual organisms, and Recurrent infections (≥2 pneumonias yearly, ≥8 otitis media episodes, or ≥2 deep-seated infections)[2].

Classification and Pathophysiology

Immunodeficiencies are broadly categorized into primary (genetic) and secondary (acquired) disorders. PIDs are classified according to the International Union of Immunological Societies (IUIS) into nine major categories:

1. Immunodeficiencies affecting cellular and humoral immunity
2. Combined immunodeficiencies with associated syndromic features
3. Predominantly antibody deficiencies
4. Diseases of immune dysregulation
5. Congenital defects of phagocyte number or function
6. Defects in intrinsic and innate immunity
7. Autoinflammatory disorders
8. Complement deficiencies
9. Phenocopies of PID[3]

Oyster #1: Common Variable Immunodeficiency (CVID) is the most frequently diagnosed symptomatic PID in adults, yet diagnosis is delayed by an average of 6-8 years from symptom onset. Many patients are misdiagnosed with asthma, chronic bronchitis, or recurrent "viral infections" for years[4].

Clinical Presentation: Pattern Recognition

Predominantly Antibody Deficiencies

These account for 50-60% of adult PIDs. CVID typically presents between ages 20-40 with:

• Recurrent sinopulmonary infections (90% of patients)
• Chronic lung disease/bronchiectasis (30-40%)
• Chronic diarrhea and malabsorption (20-60%)
• Autoimmune manifestations (25-50%)
• Lymphoproliferative disease (10-15%)
• Increased malignancy risk (particularly lymphoma and gastric cancer)[5]

Clinical Hack #1: In adults with recurrent pneumonia, always check immunoglobulin levels BEFORE administering rituximab or other B-cell depleting therapies. These agents can unmask or exacerbate underlying antibody deficiencies, complicating both diagnosis and management.

Selective IgA deficiency (1:300-1:700 prevalence) is often asymptomatic but can present with:

• Recurrent respiratory infections
• Allergic disorders
• Autoimmune diseases (4-6 times higher risk)
• Anaphylactic reactions to blood products containing IgA[6]

Combined Immunodeficiencies

While classically presenting in infancy, milder variants present in adulthood:

• Late-onset combined immunodeficiency (LOCID)
• Partial DiGeorge syndrome
• Good syndrome (thymoma with immunodeficiency)

Oyster #2: Good syndrome deserves special mention. Occurring in 6-11% of thymoma patients, it presents with hypogammaglobulinemia, low B-cells, and inverted CD4:CD8 ratios. Unlike other PIDs, thymectomy does NOT correct the immunodeficiency—in fact, the immunodeficiency often worsens post-thymectomy and requires lifelong immunoglobulin replacement[7].

Complement Deficiencies

Terminal complement deficiencies (C5-C9) present with:

• Recurrent Neisseria infections (meningitidis, gonorrhoeae)
• Disseminated infections with non-typeable serotypes
• Family history of invasive meningococcal disease

Clinical Pearl #2: Any patient with recurrent or unusual Neisseria infections should undergo complement testing. This includes total hemolytic complement (CH50) and individual complement component levels[8].

Phagocytic Disorders

Chronic Granulomatous Disease (CGD) in adults presents with:

• Catalase-positive organism infections (Staphylococcus aureus, Burkholderia cepacia, Aspergillus, Nocardia)
• Liver abscesses (often with unusual organisms)
• Inflammatory bowel disease-like colitis (40% of patients)
• Granulomatous complications

Clinical Hack #2: The dihydrorhodamine (DHR) flow cytometry test has replaced the nitroblue tetrazolium (NBT) test for CGD diagnosis. It's more sensitive, quantitative, and can identify female carriers. Order this test in patients with recurrent abscesses or infections with the organisms listed above[9].

Diagnostic Approach

Initial Screening

A systematic approach prevents missed diagnoses:

First-tier investigations:

• Complete blood count with differential
• Quantitative immunoglobulins (IgG, IgA, IgM, IgE)
• Total lymphocyte count and subset analysis (CD3, CD4, CD8, CD19, CD16/56)
• CH50 and AH50 (alternative pathway)
• HIV testing

Clinical Pearl #3: Normal total immunoglobulin levels do NOT exclude antibody deficiency. Specific antibody responses must be assessed through:

• Pre- and post-pneumococcal vaccination titers (measure 4-8 weeks post-Pneumovax 23)
• Anti-tetanus and anti-diphtheria antibodies
• Isohemagglutinins (if patient not blood group AB)

A protective response is defined as a 4-fold rise in titers or post-vaccination levels >1.3 μg/mL for ≥70% of serotypes tested[10].

Advanced Testing

Second-tier investigations (guided by initial results):

• T-cell proliferation assays (mitogens and specific antigens)
• DHR test for CGD
• Natural killer cell function
• Complement functional assays
• Genetic testing (whole exome or targeted gene panels)

Oyster #3: Lymphocyte subset analysis timing matters. Transient lymphopenia can occur with acute viral infections, stress, or corticosteroid use. If lymphopenia is detected, repeat testing after 2-4 weeks. Persistent CD4 counts <300 cells/μL warrant comprehensive immunological evaluation even if HIV-negative[11].

Secondary Immunodeficiencies

These are far more prevalent than PIDs in adult medicine:

Medication-Induced

• Corticosteroids: >20 mg prednisone daily for >2 weeks increases infection risk
• Biologics: TNF-α inhibitors, rituximab, alemtuzumab
• Chemotherapy: Prolonged neutropenia, hypogammaglobulinemia
• Immunosuppressants: Mycophenolate, calcineurin inhibitors, JAK inhibitors

Clinical Hack #3: Before initiating immunosuppressive therapy, obtain baseline immunoglobulins, lymphocyte subsets, and ensure appropriate vaccinations. For rituximab specifically, check immunoglobulins at 6 months post-treatment and annually thereafter—up to 15% of patients develop persistent hypogammaglobulinemia requiring IgRT[12].

Disease-Associated

• Protein-losing states: Nephrotic syndrome, protein-losing enteropathy
• Hematologic malignancies: CLL (most common cause of secondary hypogammaglobulinemia), multiple myeloma, lymphoma
• Chronic infections: HIV, hepatitis C
• Metabolic: Diabetes mellitus, uremia, malnutrition

Management Strategies

Immunoglobulin Replacement Therapy (IgRT)

Indications:

• IgG <400 mg/dL with recurrent infections
• Impaired specific antibody responses with significant infections
• Good syndrome, protein-losing enteropathy with infections

Routes and dosing:

• Intravenous (IVIG): 400-600 mg/kg every 3-4 weeks
• Subcutaneous (SCIG): 100-150 mg/kg weekly or biweekly
• Facilitated subcutaneous (fSCIG): Uses hyaluronidase, allows monthly dosing

Clinical Pearl #4: Target trough IgG levels >500-600 mg/dL, though some patients require higher levels (>800 mg/dL) for optimal protection. Adjust dosing based on infection frequency, not arbitrary IgG targets alone[13].

Oyster #4: SCIG offers significant advantages often overlooked: improved quality of life, fewer systemic side effects, stable IgG levels, and home administration. Many patients prefer SCIG once educated about self-administration, which most master within 2-3 training sessions[14].

Antimicrobial Prophylaxis

Evidence-based recommendations:

• Antibody deficiencies: Azithromycin 250 mg three times weekly or amoxicillin 500 mg daily reduces pneumonia incidence by 40-50%[15]
• CGD: Trimethoprim-sulfamethoxazole (5 mg/kg/day TMP) + itraconazole 200 mg daily reduces infections by 60-70%[16]
• Complement deficiencies: Penicillin prophylaxis (if not vaccinated) plus meningococcal vaccination

Clinical Hack #4: For breakthrough infections despite prophylaxis, consider alternating antibiotics monthly (e.g., alternating azithromycin and amoxicillin-clavulanate) to prevent resistance while maintaining coverage.

Vaccination Strategies

General principles:

• Live vaccines are CONTRAINDICATED in severe T-cell deficiencies (CD4 <200) and combined immunodeficiencies
• Inactivated vaccines are safe but may have reduced efficacy
• Administer vaccines BEFORE immunosuppressive therapy when possible

Recommended vaccinations:

• Pneumococcal: PCV20 or PCV15 + PPSV23
• Influenza (inactivated): Annually
• COVID-19: Complete primary series plus boosters
• Meningococcal: MenACWY and MenB (especially complement deficiencies)
• Recombinant zoster vaccine (Shingrix): Generally safe even in mild immunodeficiency

Clinical Pearl #5: Antibody responses to vaccination can serve dual purposes: assessing immune function AND providing protection. However, patients on IgRT receiving PPSV23 will have falsely elevated pneumococcal titers from the replacement therapy—time testing appropriately before next IgRT dose[17].

Novel and Emerging Therapies

• Interferon-gamma (IFN-γ): Reduces infections in CGD by 70%[16]
• Gene therapy: Curative for select PIDs (X-linked SCID, ADA-SCID, CGD)
• Hematopoietic stem cell transplantation (HSCT): Curative option for severe PIDs
• Targeted therapies: Ruxolitinib for CTLA-4 deficiency, sirolimus for activated PI3K delta syndrome (APDS)

Oyster #5: HSCT in adults with PID has improved dramatically. Five-year survival rates now exceed 75% for most conditions with matched donors. Consider early referral to specialized centers for adults with severe, life-limiting PIDs[18].

Monitoring and Complications

Regular Surveillance

Quarterly:

• Infection diary review
• IgG trough levels (if on IgRT)
• Pulmonary function tests (if lung disease)

Annually:

• Complete blood count
• Comprehensive metabolic panel
• Liver function tests
• Quantitative immunoglobulins (if not on IgRT)
• High-resolution chest CT (if bronchiectasis)
• Screening for autoimmune complications

Every 2-3 years:

• Endoscopy (for CVID patients with GI symptoms)
• Lymphoma screening (clinical examination, imaging if indicated)

Clinical Hack #5: Establish a "medical home" with multidisciplinary care including immunology, pulmonology, gastroenterology, and infectious diseases. Patients with complex PIDs benefit from coordinated care plans that prevent fragmented management[19].

Long-term Complications

• Bronchiectasis: Develops in 30-40% of patients with antibody deficiencies despite treatment
• Autoimmunity: 25-50% of CVID patients develop autoimmune cytopenias, arthritis, or organ-specific autoimmunity
• Malignancy: 10-15% of CVID patients develop lymphoma; gastric cancer risk increased 10-fold
• Granulomatous disease: Occurs in 10-20% of CVID, mimicking sarcoidosis
• Hepatic disease: Nodular regenerative hyperplasia, portal hypertension

Special Populations

Pregnancy

Key considerations:

• IgRT is safe during pregnancy—continue therapy
• Avoid live vaccines
• Increased infection risk requires vigilant monitoring
• Some PIDs (CGD) have increased maternal morbidity requiring high-risk obstetric care[20]

Elderly Patients

Secondary immunodeficiency from immunosenescence, medications, and comorbidities complicates diagnosis. Late-onset PIDs may present for the first time after age 60. Maintain high clinical suspicion in elderly patients with recurrent infections.

Conclusion

Adult immunodeficiencies represent a growing area of internal medicine requiring vigilant clinical suspicion, systematic evaluation, and evidence-based management. Early diagnosis dramatically impacts outcomes, preventing irreversible complications like bronchiectasis and reducing infection-related morbidity. Internists must maintain a low threshold for immunological evaluation in patients with recurrent or unusual infections. With expanding therapeutic options including optimized IgRT protocols, antimicrobial prophylaxis, targeted therapies, and potentially curative interventions, outcomes for adults with immunodeficiencies continue to improve.

Final Clinical Pearl: When in doubt, refer. Specialized immunology centers provide expert evaluation, access to advanced diagnostics, and enrollment in registries that advance understanding of these conditions. Early referral changes outcomes.

References

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