Differing Performance of the Warning Signs for Immunodeficiency in the Diagnosis of Pediatric Versus Adult Patients in a Two-Center Tertiary Referral Population

  • Jaclyn A. Bjelac
  • Jennifer R. Yonkof
  • James Fernandez
Original Article



Primary immunodeficiency (PID) represents disorders with a spectrum of clinical presentations. The medical community seeks clinical features to prompt evaluation for immunodeficiency given improved prognosis with early identification. We hoped to identify clinical characteristics that would improve the diagnostic accuracy of the widely disseminated Jeffrey Modell Foundation warning signs for immunodeficiency.


We performed a retrospective chart review in a two-center North American cohort of patients with PID. Charts of 137 pediatric and 400 adult patients with PID were evaluated for the presence of these warning signs and compared to controls with normal preliminary biochemical immune evaluation.


Fewer than 45% of adults with PID presented with ≥ 2 warning signs, while diagnostic utility was improved in the pediatric population where the warning signs were found to be 64% sensitive. The warning signs found in a significantly increased proportion compared to controls differed for pediatric PID patients (recurrent pneumonia (OR 2.9, p < 0.001), failure to thrive (OR 2.1, p < 0.001), need for IV antibiotics (OR 2.1, p < 0.001), serious bacterial infection (OR 4.8, p < 0.001), recurrent otitis media (OR 1.5, p = 0.027)), versus adult PID patients (recurrent otitis media (OR 2.9, p < 0.001), recurrent sinusitis (OR 2.1, p < 0.001), diarrhea with weight loss (OR 2.2, p < 0.001), recurrent viral infection (OR 3.3 p < 0.001)). In evaluation for additional criteria to promote identification of immunodeficiency, linear regression models showed slightly improved diagnostic accuracy of the warning signs with the addition of autoimmunity in our pediatric PID cohort (8.7% v 2.8%, p < 0.001, ROC 0.58). Adult PID patients demonstrated atopy more frequently than controls (48.0% vs 40.3%, p = 0.011), while atopy was found to have a negative association with the presence of PID in the pediatric age group (OR 0.3, p < 0.01). No improvement in diagnostic accuracy of the warning signs was found with the addition of allergic disease, autoimmunity, or malignant and benign proliferative disease in the adult cohort.


We demonstrate poor diagnostic performance of warning signs for immunodeficiency in patients with PID in a retrospective chart review. Divergent warning signs of statistically significant diagnostic utility were found in pediatric versus adult patients. We suggest education of physicians on differing presentations of possible immunodeficiency between age groups, and expansion of the warning signs to include non-infectious comorbidities such as autoimmunity in pediatric patients.


Immunodeficiency warning signs atopy autoimmunity 



The authors gratefully acknowledge the contributions of Manshi Li, Quantitative Health Sciences, the Cleveland Clinic, and Jennifer Staley, Medical Librarian, Rainbow Babies and Children’s Hospital Case Medical Center.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatric Allergy and Clinical ImmunologyCleveland ClinicClevelandUSA
  2. 2.Rainbow Babies and Children’s Hospital Case Medical CenterClevelandUSA
  3. 3.Department of Allergy and Clinical ImmunologyCleveland ClinicClevelandUSA

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