How can immunology help rule out immune-related disorders in a patient with symptoms such as unexplained infections, autoimmune symptoms, or allergic reactions?

How Immunology Can Rule Out Immune-Related Disorders

Immunologic evaluation systematically rules out primary immunodeficiency disorders (PIDDs) through a structured diagnostic approach that identifies specific defects in antibody production, cellular immunity, phagocytic function, complement pathways, and immune regulation—each presenting with characteristic infection patterns, autoimmune manifestations, or allergic phenotypes. 1

Diagnostic Framework for Ruling Out Immune Disorders

Initial Assessment: Pattern Recognition

The first step is identifying the clinical pattern that suggests which immune compartment may be defective:

• Recurrent sinopulmonary infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) suggest antibody deficiency, which accounts for approximately 50% of all PIDDs 1, 2
• Severe, disseminated, or opportunistic infections indicate combined B- and T-cell defects or severe combined immunodeficiency (SCID) 1
• Deep-seated abscesses with granuloma formation point toward phagocytic cell defects like chronic granulomatous disease (CGD) 1
• Severe mycobacterial or Salmonella infections suggest Mendelian susceptibility to mycobacterial disease (MSMD) 1

Ruling Out Secondary Causes First

Before pursuing PIDD evaluation, you must systematically exclude secondary immunodeficiency and non-immunologic causes: 1

• Secondary immunodeficiency from HIV/AIDS, immunosuppressive medications, malnutrition, protein-losing disorders, malignancies, or infiltrative diseases 1
• Anatomic abnormalities including cystic fibrosis, ciliary dyskinesia, abnormal lung anatomy 1
• Allergic inflammation predisposing to otitis media and sinusitis 1
• Environmental factors such as daycare attendance, older siblings, smoke exposure 1

Antibody Deficiency Evaluation

To rule out antibody deficiencies (the most common PIDD category): 1, 2

• Measure quantitative immunoglobulins (IgG, IgA, IgM, IgG subclasses) 1
• Assess vaccine-specific antibody responses to protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal) 1
• Enumerate B-cell populations by flow cytometry 1
• Selective IgA deficiency (IgA <7 mg/dL with normal IgG/IgM) is the most common PIDD, occurring in 1:300-700 live births in white Americans, though >50% remain asymptomatic 2

Combined Immunodeficiency Evaluation

For suspected T-cell or combined defects (accounting for 10-20% of PIDDs): 1, 2

• Complete blood count with differential to assess lymphocyte counts 1
• Lymphocyte subset analysis (CD3, CD4, CD8, CD19, CD16/56) by flow cytometry 1
• T-cell proliferation assays to mitogens and antigens 1
• SCID presents with failure to thrive, chronic diarrhea, severe/disseminated infections, and opportunistic infections with panhypogammaglobulinemia and occurs in approximately 1:58,000 live births 3, 2

Phagocytic Defect Evaluation

To rule out phagocytic disorders (10-20% of PIDDs): 1, 2

• Absolute neutrophil count to detect neutropenia 1
• Neutrophil oxidative burst testing (dihydrorhodamine or nitroblue tetrazolium test) to diagnose CGD 1
• Leukocyte adhesion molecule expression (CD11/CD18) for leukocyte adhesion deficiency 1
• CGD occurs in 1:200,000 live births and presents with deep-seated infections and abscess formation 2

Immune Dysregulation Disorders

For suspected immune dysregulation (characterized by autoimmunity, lymphoproliferation, or hypersensitivity): 1

• Evaluate for hemophagocytic lymphohistiocytosis (HLH) if acute presentation with fever, lymphadenopathy, hepatosplenomegaly 1
• Consider autoimmune lymphoproliferative syndrome (ALPS) if chronic lymphadenopathy with autoimmune cytopenias 1
• Assess for IPEX syndrome or APECED if polyendocrine autoimmunity with chronic mucocutaneous candidiasis 1

Innate Immunity and Autoinflammatory Disorders

For recurrent fevers or specific infection patterns: 1

• Herpes simplex encephalitis (HSE) suggests TLR3 pathway defects 1
• Chronic mucocutaneous candidiasis (CMCC) indicates IL-17 pathway abnormalities 1
• Recurrent fevers with rash, arthritis, or serositis suggest autoinflammatory syndromes requiring genetic testing 1

Critical Diagnostic Principles

Documentation of Infections

Precise microbiologic documentation is essential for accurate diagnosis: 1

• Obtain imaging, biopsy, and culture data to confirm infection focus and organism 1
• Distinguish true bacterial infections from viral illnesses or allergic symptoms 1
• Up to 26% of children >2 years with invasive pneumococcal disease have an identifiable PIDD 1

Associated Manifestations

PIDDs frequently present with non-infectious complications that aid diagnosis: 1

• Autoimmune diseases (cytopenias, arthropathies, vasculitides) occur in many PIDDs due to the same immunologic defect causing infection susceptibility 1
• Malignancies, particularly hematologic (lymphoma, leukemia), occur with increased frequency 1
• Characteristic syndromic features (eczema in Wiskott-Aldrich, ataxia in ataxia-telangiectasia, cardiac defects in DiGeorge) provide diagnostic clues 1

Common Pitfalls to Avoid

• Do not dismiss recurrent infections as "normal childhood illnesses" without quantifying frequency, severity, and response to therapy 1
• Do not overlook family history of early childhood deaths, recurrent infections, or diagnosed PIDDs, as many are inherited 1
• Do not assume normal total immunoglobulin levels exclude antibody deficiency—specific antibody responses and IgG subclasses must be assessed 1
• Do not delay evaluation in children with invasive infections, as this population has high PIDD prevalence 1
• Do not confuse transient hypogammaglobulinemia of infancy with true PIDD—maternal IgG provides variable early protection 1

When Immunologic Evaluation is Normal

If comprehensive immunologic testing is normal but clinical suspicion remains high: 1

• Reconsider secondary causes and anatomic abnormalities 1
• Evaluate for anticytokine autoantibodies (anti-IFN-γ, anti-IL-6, anti-GM-CSF) causing acquired immunodeficiency phenotypes 1
• Consider repeat testing, as some defects evolve over time 1
• Pursue genetic testing for rare or newly described PIDDs if phenotype is compelling 1

The systematic application of this diagnostic framework allows clinicians to efficiently rule out specific categories of immune dysfunction, guiding appropriate management and avoiding unnecessary interventions.