Immunodeficiency Workup for Adults with Chronic Upper Respiratory Infections
Adults with chronic or recurrent upper respiratory infections failing aggressive medical management should undergo immunologic testing including quantitative immunoglobulins (IgG, IgA, IgM), pre- and post-immunization antibody responses to tetanus toxoid and pneumococcal polysaccharide vaccines, and consideration of allergy evaluation. 1
When to Suspect Immunodeficiency
Immunodeficiency should be considered in the following clinical scenarios:
- Recurrent sinusitis or pneumonia despite aggressive medical management 1
- Chronic rhinosinusitis associated with otitis media, bronchiectasis, or pneumonia 1
- Recurrent or persistent purulent infections 1
- Upper respiratory infections occurring ≥4 times per year in adults 2
- History of pneumonia requiring hospitalization 2
The median delay to diagnosis of common variable immunodeficiency (CVID) historically has been 15.6 years for patients with symptoms before 1990, though this has improved to 2.9 years for more recent cases—still an unacceptable delay. 2
Initial Laboratory Workup
Quantitative Immunoglobulin Assessment
Obtain quantitative measurements of IgG, IgA, and IgM as the first-line screening test. 1
- In one study of 79 patients with recurrent/refractory rhinosinusitis, 10% had CVID and 6% had selective IgA deficiency 1
- Low titers were found in 18% (IgG), 17% (IgA), and 5% (IgM) of patients with refractory disease 1
- The most common primary immunodeficiencies associated with chronic upper respiratory infections are humoral immunodeficiencies: selective IgA deficiency, CVID, and specific antibody deficiency 1
Functional Antibody Assessment
Measure pre-immunization antibody titers to tetanus toxoid and pneumococcal polysaccharide antigens, then re-immunize and measure post-immunization titers 4-6 weeks later. 1
- This identifies specific antibody deficiency, which features normal IgG levels but defective responses to polysaccharide vaccines 1
- Specific antibody deficiency was found in 11% of patients failing medical therapy and undergoing sinus surgery 1
IgG Subclass Testing: A Critical Caveat
Do NOT routinely check IgG subclasses as part of the initial immunodeficiency workup. 1
- The connection between IgG subclass deficiency and recurrent/chronic rhinosinusitis is controversial 1
- The clinical significance of abnormal IgG subclasses in patients with recurrent infections is unclear 1
- IgG subclass testing should only be considered if quantitative immunoglobulins are normal but functional antibody responses are impaired 1
Additional Immunologic Testing
T-Cell Assessment
When humoral immunodeficiency is suspected or confirmed, assess T-cell function: 1
- Flow cytometric enumeration of T cells 1
- Delayed hypersensitivity skin testing 1
- CH50 (complement activity) 1
HIV Testing
Consider HIV testing in patients with chronic rhinosinusitis, as 30-68% of HIV-infected patients develop chronic or recurrent rhinosinusitis. 1
Allergy Evaluation
When to Test for Allergies
Evaluate for allergies in patients with chronic rhinosinusitis whose symptoms are not controlled by saline irrigations and intranasal medications, especially before considering sinus surgery. 1
- Up to 60% of patients with chronic rhinosinusitis have substantial allergic sensitivities, primarily to perennial allergens (house dust mites, cockroaches, pet dander, fungi) 1
- Skin prick testing is the preferred method for detecting IgE-mediated sensitivity 1
- In vitro allergen-specific immunoassays have 70-75% sensitivity compared to skin testing 1
Clinical Context Matters
A common pitfall is performing allergy evaluation only after surgical failure. Many patients with perennial allergies could have better responses to medical management if allergies were identified before surgery. 1
Treatment Implications
For Confirmed Humoral Immunodeficiency
Intravenous immunoglobulin (IVIG) replacement therapy substantially reduces respiratory infections in patients with antibody deficiency. 3
- In CVID patients, episodes of lower respiratory tract infection decreased from 0.28 per patient-year before IVIG to 0.16 per patient-year after treatment 3
- Before IVIG therapy, 84% of CVID patients had suffered at least one episode of pneumonia 3
- Long-term IVIG administration (mean 7.5 years) provides sustained benefit 3
Monitoring Treatment Response
Persistent infections requiring antibiotics despite immunoglobulin substitution correlate with severe defects in memory switched B cells (P=0.003) but not with IgG trough levels (P=0.55). 2 This suggests that some patients may need additional interventions beyond standard IVIG replacement.
Clinical Patterns by Pathogen
Most Common Infections in CVID
The most frequent presenting infections in CVID are: 2
Documented Pathogens
In patients with documented pneumonia: 2
Gastrointestinal infections (Giardia, Salmonella, Campylobacter) are more frequent in patients with undetectable serum IgA (P<0.001). 2
Long-Term Complications
Bronchiectasis develops in 58% of CVID patients, with 42% having multi-lobar involvement. 3
- Chronic airflow limitation is present in 53% of patients 3
- Decreased diffusing capacity (DLCO) occurs in 58% 3
- IgG3 deficiency is the most common subclass deficiency (88.1%) in patients with chronic airway diseases 4
Patients with IgG subclass deficiency meeting ≥2 Jeffrey Modell Foundation warning signs have significantly more infections, hospitalizations, and exacerbations, with progressive decline in FEV1 despite treatment (P=0.036). 4
Practical Algorithm
Screen all adults with recurrent/chronic upper respiratory infections failing standard therapy with quantitative IgG, IgA, IgM 1
If immunoglobulins are low or borderline, measure functional antibody responses (pre- and post-vaccination titers) 1
If immunoglobulins and functional responses are normal, consider allergy testing with skin prick tests 1
If humoral deficiency is confirmed, assess T-cell function and consider HIV testing 1
Do NOT routinely check IgG subclasses unless specifically indicated 1
Refer confirmed immunodeficiency patients to immunology for IVIG consideration 3