What are the initial lab tests for a patient presenting with immunocompromise?

Initial Laboratory Workup for Immunocompromise

Begin with a complete blood count with differential, quantitative immunoglobulin levels (IgG, IgA, IgM, and IgG subclasses), and HIV testing as the foundational screening tests for any patient presenting with suspected immunocompromise. 1, 2

Core Initial Laboratory Tests

First-Tier Screening (Order Immediately)

• Complete blood count with differential to assess absolute lymphocyte count, neutrophil count, and identify cytopenias that suggest bone marrow suppression or consumption 2, 3
• Quantitative serum immunoglobulins including IgG, IgA, IgM, and IgG subclasses to detect antibody deficiencies 1, 2
• HIV serology (fourth-generation antigen/antibody test) as HIV is a critical and treatable cause of immunocompromise; if acute infection suspected, add plasma HIV RNA testing 4, 5
• Lymphocyte subset enumeration by flow cytometry including CD4+ T cells, CD8+ T cells, B cells (CD19+), and NK cells to quantify specific immune cell populations 1, 2

Second-Tier Functional Assessment

• Vaccine-specific antibody titers to assess functional antibody responses, including tetanus, diphtheria, and pneumococcal serotypes (protein and polysaccharide antigens) 1, 2
• Complement testing with CH50 (classical pathway) and AH50 (alternative pathway) if recurrent bacterial infections, particularly encapsulated organisms or Neisseria species 1

Clinical Context-Specific Testing

If Recurrent Sinopulmonary Infections

• Prioritize immunoglobulin levels and vaccine responses, as these suggest antibody deficiency syndromes like common variable immunodeficiency (CVID) or specific antibody deficiency 1, 2
• A normal total IgG does not exclude immunodeficiency; measure IgG subclasses and functional antibody responses 1

If Opportunistic Infections or Severe Viral Infections

• CD4+ T cell count is critical; counts <200 cells/mm³ indicate severe cellular immunodeficiency requiring prophylaxis against opportunistic infections 1, 5
• Consider flow cytometry for intracellular protein expression (e.g., BTK for X-linked agammaglobulinemia) if combined immunodeficiency suspected 2

If Autoimmunity or Autoinflammation Present

• Autoimmune cytopenias, inflammatory bowel disease, or granulomatous disease alongside infections suggest immune dysregulation syndromes 1, 2
• Consider expanded lymphocyte phenotyping and genetic testing for monogenic disorders 3

Critical Interpretation Pitfalls

Normal immunoglobulin levels do not exclude immunodeficiency—functional antibody responses to vaccines are essential, as patients can have normal or even elevated total immunoglobulins but fail to produce specific protective antibodies 1, 2. For pneumococcal responses, protective levels are defined as concentration >1.3 mg/mL for >70% of serotypes tested in patients over 6 years old 1.

Normal lymphocyte counts do not exclude cellular immunodeficiency—absolute counts can be normal while specific subsets (particularly CD4+ T cells or B cells) are profoundly depleted 2, 3. Always obtain lymphocyte subset enumeration by flow cytometry rather than relying on total lymphocyte count alone.

CSF findings in immunocompromised patients are often misleadingly normal—if CNS infection is suspected, CSF may be acellular despite active infection, so microbiological testing should proceed regardless of cell count 1.

Advanced Testing Considerations

When Initial Workup is Abnormal or Suspicion Remains High

• Neutrophil oxidative burst assay (dihydrorhodamine flow cytometry) if chronic granulomatous disease suspected based on catalase-positive bacterial or fungal infections 2
• NK cell cytotoxicity assays if severe or atypical viral infections (particularly herpesviruses) 2
• Genetic testing via targeted gene panels or whole exome sequencing when clinical phenotype and initial testing suggest monogenic primary immunodeficiency 2, 3

Specialized Functional Assays

• Lymphocyte proliferation studies to mitogens (PHA, ConA) and antigens (tetanus, Candida) assess T cell function 2, 3
• Specific antibody responses post-immunization with pneumococcal polysaccharide vaccine (PPSV23) or protein-conjugate vaccines to definitively assess B cell function 1

Algorithmic Approach Based on Clinical Presentation

For recurrent bacterial infections: Start with immunoglobulins → vaccine titers → complement testing 1, 2

For opportunistic infections: Start with HIV testing → CD4 count → lymphocyte subsets → consider genetic testing if HIV-negative 1, 5

For combined features (infections + autoimmunity): Start with CBC → immunoglobulins → lymphocyte subsets → genetic evaluation 1, 3

For severe/unusual infections in infancy: Urgent lymphocyte subsets → TREC/KREC screening for SCID → genetic testing 2, 3

The workup should be guided by infection patterns: encapsulated bacteria suggest antibody deficiency, opportunistic pathogens suggest T cell defects, catalase-positive organisms suggest phagocyte defects, and Neisseria infections suggest complement deficiency 1, 2.