What is the diagnostic and treatment approach for a patient suspected of having an underlying immune deficiency, presenting with symptoms and signs of immune deficiency?

Symptoms and Signs of Underlying Immune Deficiency

Suspect primary immunodeficiency when patients present with recurrent sinopulmonary infections (≥8 new ear infections, ≥2 serious sinus infections, or ≥2 pneumonias per year), severe bacterial infections requiring IV antibiotics, infections with opportunistic or unusual organisms, failure to thrive, or associated autoimmune/lymphoproliferative complications. 1, 2

Key Clinical Warning Signs ("Red Flags")

Infection Patterns That Demand Investigation

• Recurrent sinopulmonary infections: ≥8 new ear infections within 1 year, ≥2 serious sinus infections within 1 year, or ≥2 pneumonias within 1 year suggest antibody deficiency 1
• Severe bacterial infections: Deep-seated abscesses, meningitis, osteomyelitis, or sepsis requiring IV antibiotics indicate possible phagocytic defects or combined immunodeficiency 1
• Opportunistic infections: Pneumocystis jirovecii pneumonia, disseminated fungal infections, or severe viral infections (especially in infants) strongly suggest severe combined immunodeficiency (SCID) or T-cell defects 1, 2
• Infections with specific organisms: Severe mycobacterial or Salmonella infections suggest Mendelian susceptibility to mycobacterial disease (MSMD); recurrent Neisseria infections suggest complement deficiency 1

Non-Infectious Manifestations

• Autoimmune complications: Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, neutropenia), inflammatory arthropathies, or vasculitides occur in many primary immunodeficiencies and may precede infectious complications 1
• Malignancies: Hematologic malignancies (lymphoma, leukemia) occur with increased frequency in certain immunodeficiencies 1
• Failure to thrive: Poor growth, chronic diarrhea, and malabsorption in infants/children strongly suggest SCID or combined immunodeficiency 1, 3
• Characteristic physical findings: Partial oculocutaneous albinism (Chediak-Higashi syndrome), eczema with thrombocytopenia (Wiskott-Aldrich syndrome), telangiectasias (ataxia-telangiectasia), or absence of tonsils (agammaglobulinemia) 1

Diagnostic Approach Algorithm

Step 1: Initial Screening Laboratory Tests

Order these tests first for any suspected immunodeficiency 2, 4:

• Complete blood count with differential: Identifies lymphopenia (<1500 cells/μL suggests T-cell defect), neutropenia (phagocytic defect), or thrombocytopenia (immune dysregulation) 2, 4
• Quantitative serum immunoglobulins: Measure IgG, IgA, IgM, and IgE levels; hypogammaglobulinemia in ≥2 isotypes suggests antibody deficiency 1, 2, 5
• Specific antibody titers: Measure responses to protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal vaccine); poor responses despite normal immunoglobulin levels indicate specific antibody deficiency 2, 5

Step 2: Pattern Recognition and Advanced Testing

Based on initial results, pursue targeted evaluation 1, 2:

If Recurrent Bacterial Infections with Normal/Low Immunoglobulins:

• Flow cytometry for B-cell subsets: Enumerate total B cells, switched memory B cells, and marginal zone B cells to distinguish between X-linked agammaglobulinemia (absent B cells) and common variable immunodeficiency (normal/low B cells with poor function) 2, 5
• Vaccine challenge: Administer 23-valent pneumococcal polysaccharide vaccine and measure serotype-specific responses 4-8 weeks later; abnormal response is <70% of serotypes with concentration >1.3 μg/mL in adults 5

If Severe/Opportunistic Infections with Lymphopenia:

• Flow cytometry for T-cell subsets: Enumerate CD3+, CD4+, CD8+ T cells and NK cells; very low/absent T cells (<300 CD3+ cells/μL in infants) indicate SCID 2
• T-cell proliferation assays: Test in vitro response to mitogens (PHA, ConA) and antigens; absent proliferation confirms T-cell dysfunction 2, 4
• SCID phenotyping: Determine T-B-NK+ vs T-B+NK- vs T-B-NK- patterns to guide genetic testing 2

If Severe Bacterial/Fungal Infections with Normal Lymphocytes:

• Neutrophil oxidative burst: Abnormal dihydrorhodamine (DHR) test confirms chronic granulomatous disease (CGD) 1, 4
• Leukocyte adhesion defect testing: Marked leukocytosis (>20,000/μL) even without infection suggests LAD; confirm with CD18/CD11 expression by flow cytometry 1
• Neutrophil count monitoring: Cyclic or persistent severe neutropenia (<500/μL) indicates congenital neutropenia syndromes 1

Step 3: Genetic Testing

Pursue molecular diagnosis when clinical and immunologic findings suggest specific disorder 2:

• Targeted gene sequencing: For suspected specific disorders (e.g., BTK for X-linked agammaglobulinemia, RAG1/RAG2 for SCID) 2, 4
• Whole exome/genome sequencing: For complex cases without clear diagnosis after initial workup 2
• Chromosomal microarray: For copy number variations in suspected syndromic immunodeficiencies 2

Critical Pitfalls to Avoid

Do Not Miss Secondary Immunodeficiency

Always exclude secondary causes before diagnosing primary immunodeficiency 1:

• HIV infection/AIDS: Test all adults with recurrent infections or opportunistic infections 1
• Medications: Immunosuppressive drugs, chemotherapy, corticosteroids, and certain biologics cause secondary immunodeficiency 1
• Protein-losing conditions: Nephrotic syndrome, protein-losing enteropathy, or severe burns can cause hypogammaglobulinemia 1, 5
• Malignancies: Hematologic malignancies (CLL, multiple myeloma, lymphoma) frequently cause secondary antibody deficiency 1
• Malnutrition: Severe malnutrition, extremes of age, and chronic diseases impair immune function 1

Do Not Overlook Structural/Anatomic Causes

Rule out non-immunologic causes of recurrent infections 1:

• Cystic fibrosis: Consider in patients with chronic sinopulmonary infections; sweat chloride test is diagnostic 1
• Ciliary dyskinesia: Chronic wet cough, situs inversus, and infertility suggest primary ciliary dyskinesia 1
• Allergic inflammation: Poorly controlled allergic rhinitis and asthma predispose to bacterial superinfections; treat aggressively before attributing infections to immunodeficiency 1
• Anatomic abnormalities: Adenoid hypertrophy, bronchiectasis, or structural lung disease cause recurrent infections independent of immune function 1

Confirm Infection Focus and Organism

Obtain objective documentation of infections 1:

• Imaging confirmation: CT scans or X-rays to document pneumonia, sinusitis, or deep-seated infections 1
• Microbiologic confirmation: Culture or PCR identification of specific pathogens guides diagnosis; many "infections" are viral or allergic in nature 1
• Biopsy when indicated: Tissue diagnosis for suspected opportunistic infections or granulomatous disease 1

Special Populations

Immunocompromised Patients with Acute Abdomen

Maintain high clinical suspicion as signs/symptoms are often atypical 1:

• Clinical signs (fever, peritoneal signs) are unreliable; the more severe the immunocompromise, the less reliable the physical examination 1
• Laboratory tests (WBC, inflammatory markers) may not reflect disease severity 1
• Contrast-enhanced CT scan is the most reliable diagnostic modality for intra-abdominal pathology in immunocompromised patients 1
• Test for Clostridioides difficile in any immunocompromised patient with diarrhea 1

AIDS Patients

AIDS patients have unique considerations for immunodeficiency evaluation 6:

• AIDS patients may not tolerate or respond to treatments (e.g., trimethoprim-sulfamethoxazole) in the same manner as non-AIDS patients 6
• Incidence of side effects (rash, fever, leukopenia, elevated transaminases) is greatly increased in AIDS patients receiving antimicrobial prophylaxis 6
• Hyperkalemia occurs more frequently in AIDS patients receiving trimethoprim-containing regimens 6

Family History Considerations

Obtain focused family history early in evaluation 1:

• Ask specifically about early childhood deaths, recurrent infections in siblings, consanguinity, or diagnosed immunodeficiencies in family members 1
• X-linked inheritance patterns (affecting only males) suggest X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, or X-linked SCID 1
• Autosomal recessive patterns (consanguinity, multiple affected siblings) suggest most other primary immunodeficiencies 1

When to Refer to Immunology Specialist

Refer immediately for 2:

• Suspected SCID (lymphopenia in infant, opportunistic infections, failure to thrive) - this is a medical emergency requiring urgent evaluation for hematopoietic stem cell transplantation 2
• Confirmed hypogammaglobulinemia requiring immunoglobulin replacement therapy 2
• Complex cases where initial screening tests are abnormal but diagnosis remains unclear 2
• Recurrent severe infections despite normal initial screening tests 2
• Any patient with confirmed primary immunodeficiency for ongoing management and genetic counseling 2