What is the appropriate next step in evaluating a 24‑year‑old woman with recurrent respiratory infections, mildly elevated C‑reactive protein, mild lymphocytosis, and a negative antinuclear antibody test?

Evaluation of Recurrent Respiratory Infections with Mild Inflammatory Markers

Order quantitative immunoglobulin levels (IgG, IgA, IgM) and specific antibody responses to prior vaccines as the immediate next step, as this clinical presentation—recurrent respiratory infections in a young adult with mildly elevated inflammatory markers—suggests possible primary antibody deficiency, most likely Common Variable Immunodeficiency (CVID) or selective antibody deficiency. 1

Rationale for Immunologic Workup

The combination of recurrent respiratory infections with only mildly elevated CRP (5.7 mg/L) and lymphocytosis points toward an underlying immunodeficiency rather than an acute inflammatory or autoimmune process. The negative ANA effectively excludes systemic lupus erythematosus and related connective tissue diseases as primary drivers. 1

Key Diagnostic Steps

Immediate laboratory evaluation should include:

• Quantitative serum immunoglobulins (IgG, IgA, IgM): CVID is defined by IgG < 450–500 mg/dL plus IgA or IgM below the 5th percentile for age in patients ≥ 4 years old with recurrent sinopulmonary infections 1

• Functional antibody assessment: Measure pre-existing vaccine-specific antibodies (tetanus, diphtheria, pneumococcal). If low, administer the 23-valent pneumococcal polysaccharide vaccine and re-measure 4–8 weeks later; failure to achieve protective titers confirms functional antibody deficiency 1

• B-cell enumeration (CD19+) by flow cytometry: CVID patients typically have normal or only moderately reduced B-cell numbers (distinguishing it from X-linked agammaglobulinemia which shows < 2% B cells), while the lymphocytosis noted may reflect compensatory changes 2, 1

• Complete lymphocyte subset analysis (CD3, CD4, CD8, CD19): T-cell abnormalities frequently coexist with CVID and must be characterized 1

Why CVID is Most Likely

At 24 years old, this patient fits the typical CVID demographic. CVID is the most common symptomatic primary immunodeficiency in adults, characterized by recurrent bacterial sinopulmonary infections with impaired antibody production. 1, 3 The pattern of bacterial respiratory infections without opportunistic infections (which would suggest SCID or combined immunodeficiency) strongly supports an antibody deficiency disorder. 2, 4

Key distinguishing features:

• Age of presentation: CVID typically manifests after age 4 years and is frequently diagnosed in young adults, unlike X-linked agammaglobulinemia which presents in infancy 2, 1

• Infection pattern: Recurrent bacterial respiratory infections (Streptococcus pneumoniae, Haemophilus influenzae) are hallmark features, occurring in the majority of CVID patients 1, 5

• Mild inflammatory markers: The CRP of 5.7 mg/L suggests chronic low-grade inflammation consistent with recurrent infections rather than acute severe infection or autoimmune disease 1

Critical Exclusions Before Diagnosis

Rule out secondary causes of hypogammaglobulinemia: 1

• Review medications (phenytoin, carbamazepine, valproic acid, sulfasalazine, hydroxychloroquine, NSAIDs can cause hypogammaglobulinemia)
• Screen for B-cell lymphoproliferative disorders with serum protein electrophoresis
• Test for HIV infection
• Evaluate for bone-marrow failure syndromes

Imaging and Pulmonary Assessment

Obtain baseline chest CT scan to evaluate for bronchiectasis, which develops in 10–20% of CVID patients and is strongly associated with delayed diagnosis. 1, 5 Patients with bronchiectasis have significantly longer diagnostic delays and are older at diagnosis. 5 Early detection allows for aggressive pulmonary management to prevent progression.

Perform pulmonary function testing to establish baseline lung function and detect early restrictive or obstructive changes, which occur in over 50% of CVID patients. 5

Management if Immunodeficiency Confirmed

If immunoglobulin levels confirm antibody deficiency:

• Initiate immunoglobulin replacement therapy (IVIG or SCIG) immediately without waiting for complete genetic workup, as infection risk outweighs diagnostic delays 1

• IVIG dosing: 0.4–0.6 g/kg every 3–4 weeks, targeting trough IgG > 500–600 mg/dL (higher targets of 800–1000 mg/dL for patients with established lung disease) 1

• Treat acute respiratory infections aggressively with antibiotics covering S. pneumoniae, H. influenzae, Mycoplasma, and Ureaplasma 1

• Consider antibiotic prophylaxis for patients with frequent breakthrough infections despite adequate IgG replacement 1

Common Pitfalls to Avoid

• Do not delay immunoglobulin replacement while awaiting genetic testing or complete immunologic workup if antibody deficiency is confirmed—the immediate infection risk and prevention of bronchiectasis development are paramount 1

• Do not dismiss mildly elevated inflammatory markers as insignificant; in the context of recurrent infections, they may reflect chronic antigenic stimulation from impaired pathogen clearance 1, 5

• Do not assume normal total lymphocyte count excludes immunodeficiency—the lymphocytosis may represent reactive changes, and specific B-cell and T-cell subset analysis is required 1

• Recognize that patients lacking IgA may develop anti-IgA antibodies, increasing anaphylaxis risk with blood products; use IgA-depleted products when transfusion is required 1

Long-term Monitoring Priorities

If CVID is diagnosed, establish surveillance for complications: 1

• Pulmonary: Monitor for bronchiectasis progression and granulomatous-lymphocytic interstitial lung disease (GLILD), which affects ~10% of patients and carries increased mortality
• Gastrointestinal: Screen for chronic gastritis, inflammatory bowel disease, and liver involvement (nodular regenerative hyperplasia occurs in ~40%)
• Autoimmune: Watch for autoimmune cytopenias (ITP, AIHA), which occur in 11–12% of patients
• Malignancy: Maintain vigilance for lymphoproliferative disease with regular examinations