1. A Patient with Recurring Infections Julia Wright, M.D. Clinical Associate Professor of Medicine Section of General Internal Medicine

2. Case Illustration 62-year-old woman with PMH rheumatoid arthritis, seizures and malabsorption Healthy before gastrectomy; recurrent hospitalizations for multiple acute issues, predominantly infectious. Infections are recurrent, relapsing, do not respond to outpatient management—very challenging

3. Evaluating the Patient with Recurrent Infections Criteria for “recurrent” Causes –Therapeutic failure: resistant organism, atypical infection –Patient-specific: underlying structural or immunologic impairment

5. Case Patient’s Evaluation Immunodeficiency suspected—recurrent sinopulmonary infections, poorly responsive, severe, multisystem illnesses, ? Family history. Frequently neutropenic, rarely febrile Results of immunoglobin panel = –IgA 138 (85-450 mg/dL) –IgG 302 (700-1600 mg/dL) –IgM 44.3 (40-230 mg/dL) T cell profile = –CD4% 318 (>490) –CD8 62 (>180) –CD3 53 (>840)

6. Common Variable Immunodeficiency (syndrome) Paradoxically named—1:40 patients with recurrent infections have CVID Variable immunodysregulation; T cell and B cell defects; monocyte as well A syndrome—common endpoint of multiple conditions/defects

7. Clinical Features: Multisystem Disease Infections: –B cell predominant; encapsulated organisms, sinopulmonary All types, recurrent, refractory or poorly responsive Unusual/nonpathologic (septic arthritis, meningitis) Autoimmune: –CVD, IBD, ITP, hepatitis, thyroid, cytopenias Inflammatory: –Malabsorption (GI atrophy), granulomatous disease Malignancy: –T and B cell lymphoma, MALT

8. CVID Specifics Phenotype varies—course, infection types Serologies negative; cultures may be negative Subtypes—several classification schemata

9. Diagnostic Criteria for CVID Immunodeficiency: –Ig levels: IgG less than 500, 2 SD below mean B cell function: –Illness/immunization status and serology –Post-vaccination Ig levels Exclusion of other diagnoses: –Primary immunodeficiencies –Drugs –Protein losing states –Lymphoproliferative d/o –Post-infection; asplenia

12. Practical Approach Clinical Features, Family History, Medications Ig levels; T cell Profile Flow cytometry; Ig subclass Post-vaccination Ab response Exclusion—Clinical Grounds (flow cytometry, HIV, complement, UA, SPEP, CBC, sprue, genetic testing?)

13. Management Vaccination Infections –Prevention –Treatment Biopsy enlarged lymph nodes Pulmonary –PFTs and CT, chest physiotherapy, surgery

15. Treatment: Immune Globulin Data on Efficacy –Decreased infections, end organ damage/autoimmune –Dosing and frequency –Risks: Infection Dementia?!! Infusion Reactions

16. Other Treatments Immunomodulating Therapies Gene Therapy? Indications for glucocorticoids Indications for prophylactic antibiotics

17. Case Patient’s Results Abnormal T cells, nonresponsive to pneumovax/Td Our patient’s course: –Phenytoin induced? Not reversible; progressive Two other patients

18. Conclusions A rare disease that is not rare in the primary care setting Multisystem disease Easy to diagnose—at first Treatment is challenging Refer, refer, refer.

19. References 1.Weiler CR, Bankers-Fulbright JL. Common Variable Immunodeficiency: Test Indications and Interpretations. Mayo Clin Proc. 2005;80(9):1187- 1200. 2.Carrock Sewell WA, Buckland MS, Jolles SRA. Therapeutic Strategies in Common Variable Immunodeficiency. Drugs. 2003;63(13):1359-1371. 3.Spickett GP. Current perspectives on common variable immunodeficiency (CVID). Clinical and Experimental Allergy. 2001;31:536-542. 4.Travin, et al. Reversible Common Variable Immunodeficiency Syndrome Induced by Phenytoin. Arch Intern Med. 1989;149:1421-1422.