COMMON VARIABLE IMMUNODEFICIENCY

1. COMMON VARIABLE IMMUNODEFICIENCY INTERNAL MEDICINE RESIDENT’S GRAND ROUNDS MARCH 9, 1995 JAMES W. SCHNELL, MD

2. INTRODUCTION • First case of hypogammaglobulinemia was reported by Bruton in 1952. • First case reports of common variable immunodeficiency in 1954. • Term “common variable immunodeficiency” coined by WHO in 1971.

3. INTRODUCTION • Common variable immunodeficiency is characterized by hypogammaglobulinemia and recurrent respiratory infections. • Normal numbers of circulating B cells which fail to produce adequate levels of antibodies. • Present with recurrent sinusitis, otitis media, bronchitis, and pneumonia. • Can develop bronchiectasis and cor pulmonale.

4. INTRODUCTION • Also have defects in cell mediated immunity. • Can develop opportunistic infections. • Strong association with autoimmune diseases. • Increased risk of developing maligancies.

5. EPIDEMIOLOGY • Estimated prevalence of 1:50,000 to 1:200,000. • Biphasic age of onset with peaks at 1-5 years and 16-20 years. • Not clinically apparent until 2nd or 3rd decades.

6. GENETICS • CVID has classically been considered an acquired disorder. • Kindred studies suggest possible inheritence and genetic association with IgA deficiency. • High incidence of deletions of C4A or C2 alleles in MHC class III genes. • High incidence of neutral amino acids in HLA-DQB region of MHC class II genes.

7. PATHOGENESIS • Hallmark of CVID is reduced IgG levels. • Early mitogen studies suggest a primary B cell defect. • B cell defect in immunoglobulin production is not absolute. • Most B cells have the ablility to secrete some immunoglobulin, if given the appropriate stimulus.

8. PATHOGENESIS • Many patients also have T cell defects. • 30% of patients are cutaneously anergic. • 50% of patients have depressed lymphocyte transformation responses to T cell mitogens.

9. PATHOGENESIS • T cell defects function decreases with age. • Two types of T cell defects identified. 1. Increased CD8+ T cells. 2. Depressed levels of T cell cytokines(IL2). • IL2 is an important T cell growth factor.

10. CLINICAL FEATURES • INFECTIONS • AUTOIMMUNE DISEASES • GASTROINTESTINAL DISEASE • MALIGNANCIES • LYMPHOPROLIFERATIVE DISORDERS

11. INFECTIONS • Clinical Hallmark is recurrent infections of the respiratory tract. • Encapsulated bacteria, Streptococcus pneumoniae and Haemophilusinfluenzae. • Can develop chronic sinusitis and bronchiectasis. • Bordetella pertussis in children.

12. INFECTIONS • Cellulitis, urinary tract infections, septic arthritis and meningitis much less common than respiratory infections. • Ureaplasma UTI’s frequently occur. • Mycoplasma most commonly isolated organism in synovial fluid. • Meningitis rare in adults.

13. INFECTIONS • Tolerate viral infections well with the exception of Herpes zoster. • Herpes zoster occurs in 20%. • Severe cases of Herpes simplex, CMV and Molluscum contagiosum reported. • Severe enteroviral encephalitis has been described. • Vaccinate with killed polio virus.

14. AUTOIMMUNITY • 20 % of patients will develop autoimmune disease. • Hemolytic anemia and idiopathic thrombocytopenic purpura are the most common autoimmune disorders. • Treat blood dyscrasias with high dose IV immunoglobulin.

15. AUTOIMMUNITY • Arthritis is the 3rd most common autoimmune manifestation. • Clinically resembles rheumatoid arthritis. • Responds to IV immunoglobulin.

16. AUTOIMMUNITY • Pernicious anemia occurs in 10 % of patients. • Younger age of onset than general public. • No detectable antiparietal cell antibodies. • Other disorders include: Addison’s, SLE, hepatitis, and thyroid disease.

17. GASTROINTESTINAL • Diarrhea occurs in 60% of patients. • Giardiasis is the most common etiology. • Diagnosis often requires biopsy. • Treatment with metronidazole or qiunacrine. • Increase in more common bacterial enteric pathogens: Salmonella, Shigella, Campylobacter, Yersinia.

18. GASTROINTESTINAL • Campylobacter fetus has been reported as a cause of diarrhea and septicemia. • Increase in Cryptosporidium. • Must consider Dysgonic Fermenter-3. • Grows on Cefperazone-Vancomycin agar plates.

19. GASTROINTESTINAL • Malabsorption in the absence of infection occurs in 10% of patients. • Small bowel biopsy histologically resembles celiac sprue. • Treatment is supportive.

20. GASTROINTESTINAL • Increased incidence of Crohn’s disease and ulcerative colitis. • 30%-50% will develop achlorhydria. • 13% will develop hepatitis, usually transfusion related. • 25% will develop cholelithiasis. • Nodular lymphoid hyperplasia and gastric carcinoma are common.

21. MALIGNANCIES • Increased risk of gastric carcinoma and lymphoma. • Kinlin et al: - 7/220 pts with stomach CA. - 3/220 pts. with lymphoma. - 47 fold increase in stomach CA. - 30 fold increase in lymphoma.

22. MALIGNANCIES • Cunningham-Rundles et al: - 7/98 pts with lymphoma (all females). - 1/98 pts with stomach CA. - 438 fold increase in lymphomas in females. • All lymphomas of the non-Hodgkin’s type.

23. MALIGNANCIES • Defects in cell mediated immunity may contribute to increased lymphoma. • Most patients who develop malignancies have proliferative T cell defects. • Earlier onset of atrophic gastritis and achlorhydria may contribute it increased risk of stomach CA.

24. LYMPHOPROLIFERATIVE • Benign lymphoproliferative disorders are common. • 30% will develop diffuse lymphadenopathy, splenomegaly or both. • Two histologic forms of adenopathy: 1. Reactive lymphoid hyperplasia. 2. Atypical lymphoid hyperplasia.

25. LYMPHOPROLIFERATIVE • Atypical lymphoid hyperplasia resembles lymphoma and the two may be mistaken for each other. • Can be differentiated by immunohistochemical staining.

26. LYMPHOPROLIFERATIVE • Nodular lymphoid hyperplasia is very common. • Discrete nodules in the submucosa of the GI tract consisting of B cells. • Usually found in the small intestine. • Often found in the presence of Giardiasis. • Not a premalignant lesion.

27. OTHER FEATURES • Patients with CVID often develop granulomatous disease and a sarcoid-like condition. • Often develop cutaneous disease, an eczema-like condition is well described. • CD4+ lymphopenia/ “HIV negative AIDS.”

28. DIAGNOSIS • Consider the diagnosis in any patient with recurrent infections of the respiratory tract. • Draw quantitative immunoglobulins. -Most patients have panhypoglobulinemia. -IgG is consistently low. -IgA and IgM may sometimes be normal.

29. DIAGNOSIS • Confirm the diagnosis measuring pre and post immunization titers to protein and polysacharide antigens. • Tetanus toxoid(protein) and Pneumococcal vaccine(polysacharide). • Fourfold rise in anti-tetanus titers at 4 wks is normal, a twofold increase in anti -Pneumococcal titers is normal.

30. DIAGNOSIS • Treat only if unable to mount an adequate antibody response. • Diagnosis is often delayed for many years.

31. DIFFERENTIAL • Consider other causes of hypogammaglobulinemia: primary immunodeficiency disorders, drugs, infection and malignancy. • Other conditions which predispose to infection: allergies, ciliary dysmotility, cystic fibrosis and complement deficiencies.

32. DIFFERENTIAL • Chronic lymphocytic leukemia, multiple myeloma, lymphoma. • Nephrotic syndrome and protein losing enteropathy often result in selective loss of IgG. • Nephrotic syndrome is probably the most common cause of moderate hypogammaglobulinemia.

33. IVIG • The primary form of treatment is IV immune globulin replacement. • Immunoglobulin therapy initiated shortly after the first patient was diagnosed in 1952 with hypogammaglobulinemia. • Markedly reduced the number and severity of infections.

34. TREATMENT • INTRAVENOUS IMMUNOGLOBULIN. • ANTIBIOTICS. • MANAGEMENT OF NON-INFECTIOUS COMPLICATIONS. • EXPERIMENTAL.

35. IVIG • Decision to treat should not be dependent on absolute antibody level but rather on functional antibody response. • IVIG dose 300-400mg/kg/month. • Follow trough levels and adjust dose to keep trough levels at 400-500mg/dl.

36. IVIG • Cost $25,000-$45,000 per year. • IVIG tolerated well. • Early side effects include: back pain, abdominal pain, nausea and vomiting. • Late side effects include: fevers, chills, haedache and myalgias. • Aseptic meningitis due to IVIG has been described.

37. IVIG • True anaphalactic reactions are rare, and usually occur in patients who have IgA antibodies. • Gammagard S/D contains very low concentrations of IgA and is tolerated well by these patients. • Subcutaneous immunoglobulin successfully used in Europe.

38. IVIG • Newborns of women with CVID are at high risk for developing neonatal infections. • Current recommendations are for these women to receive frequent high doses of IVIG in the third trimester. • Recent data suggests high dose treatment in the first trimester.

39. IVIG • Transmission of hepatitis B and C through IVIG have been reported. • Cold ethanol fractionation inactivates hepatitis B and HIV. • No cases of HIV transmission with IVIG reported. • Hepatitis C is enveloped and not inactivated, outbreaks reported.

40. IVIG • 150 cases of hepatitis C transmission over recent 5 month period. • All comercially available forms of IVIG now undergoe further viral inctivation steps.

41. ANTIBIOTICS • Patients with CVID may continue to have respiratory infections after IVIG. • Agents with activity against encapsulated organisms should be used. • Longer course recommended. • Prophylactic antibiotics with chronic lung disease.

42. OTHERS • Spirometry. • Postural drainage for bronchiectasis. • Sinus surgery. • Bronchodilators. • Corticosteroids for autoimmune or granulomatous diseases.

43. EXPERIMENTAL • Interleukin-2 infusion in vivo. • B cells in these patients secrete more IgG in vitro. • Increased T helper activity in vitro. • Clinical benefits remain to be proven.

44. PROGNOSIS • Excellent if treatment is instituted early. • Poor if chronic lung disease has developed. • Pulmonary disease and malignancies remain the leading causes of mortality.

45. CONCLUSION • CVID should be considered in any patient who presents with recurrent respiratory tract infections. • Easily screened for with Quantitative Ig. • The clinician should be aware the increased frequency of autoimmune diseases, gastrointestinal diseases and malignancies. • Early diagnosis and treatment with IVIG significantly reduces morbidity and mortality.

46. CASE REPORT HPI: W.C was a previously healthy 48yowm who presented to NCBH with a 6 mo c/o of weakness, fatigue, anorexia, diarrhea, and a 40lbs weight loss. Sx’s began after drinking contaminated water in FL. Intermittent nausea, vomiting and diarrhea. No hematochezia, hemetemesis but possibly melena. Also reported a 3 wk c/o productive cough, fevers and chills.

47. CASE REPORT PMH: None. Recently involved in a MVA in mount Airy, NC. Was started on Lodine, Trazadone, and cyclobenzaprine. SH: Recently moved to NC from New Mexico. No ETOH, Tobacco or homosexual activity. Divorced but living with girlfriend. FH: Mother died age 59 stomach CA, father died age 60 with liver CA.

48. CASE REPORT PE: T 102.4 P 104 BP 110/60 RR 20 GEN: Cachectic, pale WM in NAD HEENT: Pale MM’s NECK: Supple, no adenopathy LUNGS: Decreased BS and rales right base CVS: RRR with II/VI SEM ABD: Soft, NT, +BS. no masses. RECTAL: Heme- , no masses.

49. CASE REPORT LABS: WBC: 1,800 (50% s, 40%L) Hb: 4.8 MCV 107 Plt: 74,000 Na: 131 K: 3.2 LDH: 742 Prot: 4.0 Alb: 2.9 Chol: 80 CXR: RLL infiltrate

50. CASE REPORT IMPRESSION: Pneumonia and pancytopenia due to malignancy vs. B12 deficiency vs. myelopthisic process.