1. Diagnosis and Management of Immunodeficiency in Adulthood Teresa Tarrant, MD Assistant Professor of Medicine Division of Rheumatology, Allergy, and Immunology

2. The Immune System: http://stemcells.nih.gov/info/scireport/chapter6.aspstemcells.nih.gov/info/scireport/chapter6.asp

3. Pattern of infections: Clinical Immunology T cell deficiencies  Fungi  Viruses  Pneumocystis B-cell deficiencies  S. pneumococcus  H.influenzae  Enteroviruses Complement deficiencies  Bacteremia  Meningitis  C5-9: Neisseria  C1/2/4: SLE Phagocytic disorders  Staph skin infections  Cepacia  Infections of the reticuloendothelial system  Abscesses The type of infectious agent and the location of the infection may give valuable insight into the nature of the immunologic defect... Humoral Immunodeficiencies

4. Clinical Scenario: Recurrent infections 32 yo previously healthy female who has a 3 year history of sinus drainage and recurrent sinus infections... Differential:  Allergies  Chronic sinusitis  Allergic fungal sinusitis  Antibiotic resistance  Mechanical derangement

5. Clinical Scenario: Recurrent infections 32 yo previously healthy female who has a 3 year history of sinus drainage, recurrent sinus infections, who developed bilateral otitis media requiring tympanostomy and IV antibiotics.... Differential  Allergies  Chronic sinusitis  Allergic fungal sinusitis  Antibiotic resistance  Mechanical derangement  Humoral immune deficiency  CF  Primary Ciliary Dyskinesia

6. Clinical Scenario: Recurrent infections Now it’s the same 32 yo female... who develops fevers, increased sputum, and an infiltrate seen on CXR Differential  Humoral immune deficiency  CF  Primary Ciliary Dyskinesia

7. Differential for Humoral Immune Deficiency in Adults Drugs  Antimalarials, captopril, carbamazepine, steroids, gold, penicillamine, phenytoin, sulfasalazine Systemic disorders  Chronic medical conditions CF Sickle Cell  Hypercatabolism of Ig  Excessive loss of Ig Nephrosis, burns, diarrhea, lymphangiectasia ID  HIV, EBV Malignancy  CLL  Immunodeficiency with thymoma (Good’s syndrome)  NHL CVID IgA deficiency IgG Subclass deficiency

8. Common Variable Immunodeficiency Definition: a disease characterized by low levels of immunoglobulins and recurrent sinopulmonary infections. It is a relatively common immunodeficiency with variable levels of immunoglobulins and clinical course between patients

9. CVID Heterogeneous group of disorders of humoral immunodeficiency with associated bacterial infections, autoimmune disease, and malignancy Bimodal distribution  Major peak 25-45 yo  Second peak 5-15 yo M=F Prevalence estimated at 1:25,000-50,000

10. CVID: Pathogenesis  Some molecular defects identified  TACI mutation (~20% of CVID)  Most cases are sporadic  Familial inheritance has been demonstrated □X-linked □Autosomal recessive □Autosomal dominant

11. CVID: Genetic Mutations in the genes encoding the tumor necrosis factor (TNF) superfamily receptors  TACI mutation Transmembrane activator and calcium-modulating ligand interactor  BAFF-R mutation B cell activation factor of the TNF family receptor Small number of patients with CD19 deficiency

12. TACI mutation TACI is expressed on the surface of B cells TACI interacts with  BAFF (activation factor)  APRIL (proliferation ligand) TACI-deficient mice show ↑ B cells, impaired isotype switching and develop autoimmune manifestations with (SLE)-like symptoms, lymphoproliferation,splenomegaly, and lymphoma Bacchelli et al. Clin Exp Immunol 2007; 149:1365-2249

13. CVID: Pathogenesis Familial inheritance  IgA deficiency Kindreds with IgA deficiency and CVID 15% of patients with CVID have a first degree relative with IgA deficiency Individuals with IgA deficiency who develop CVID  MHC haplotypes shown to correlate with CVID and IgA deficiency

14. CVID: Pathogenesis Environmental triggers  Viral infection  Drugs Antimalarials, captopril, carbamazepine, steroids, gold, penicillamine, phenytoin, sulfasalazine

15. CVID: Clinical Manifestations Infectious Disease  Recurrent pyogenic sinopulmonary infections  Chronic enteroviral infections  Meningoencephalitis  Chronic Giardia Lamblia  Recurrent HSV and/or VZV

16. CVID: Clinical Manifestations GI manifestations  Sprue-like syndrome (wt loss, diarrhea, vitamin deficiency, hypoalbuminemia)  Nodular follicular hyperplasia of the intestines  Gastric atrophy, achlorydria  Colitis  MALT lymphoma  Giardiasis

17. Nodular Lymphoid Hyperplasia of the Duodenum Nodules develop through lymphocyte proliferation in the lamina propria and submucosa, but are not directly linked to increased malignant potential.

18. CVID: Clinical Manifestations Autoimmune manifestations (22-50%)  Pernicious anemia  Vitiligo  Autoimmune thrombocytopenia  Autoimmune hemolytic anemia  Autoimmune thyroiditis  Alopecia areata  Keratoconjunctivitis sicca  Inflammatory Arthritis

19. CVID: Clinical Manifestations Hematologic manifestations  Granulomatous disease Noncaseating epithelioid granulomas of liver, lung, spleen, skin, gut  Amyloidosis  Tonsilar tissue normal or enlarged  Lymphadenopathy  25% splenomegaly

20. CVID: Clinical Manifestations Malignancy  300+ fold increase in lymphomas in women between 50-60 yo  50 fold increase in gastric carcinoma  Thymoma  MALT lymphoma  Lymphoreticular malignancy

21. CVID: Clinical Manifestations Pulmonary manifestations  Pneumonia  Asthma  Bronchiectasis  Lymphoid interstitial pneumonia (LIP)  Pulmonary Fibrosis Best predictor of improved pulmonary outcome is early diagnosis and aggressive treatment. J. de Gracia, et al., Int Immunopharmacol 4 (2004), 745–753.

22. Laboratory evaluation of Humoral Immune Deficiency Targetted H&P for recurrent infections and autoimmunity Quantitative serum Ig (age and sex matched controls) Measurement of Ab production  Pneumococcal polysaccharide  HIB polysaccharide  Tetnus toxoid Measurement of quantitative Ag-specific Ig titer pre- and post-immunization  4 week post-immunization level within protective range and >4 fold rise from baseline Peripheral blood lymphocyte subset analysis

23. Quality not Quantity Measurement of Antigen-specific (i.e. tetanus, HIB, pneumococcal) IgG titer pre- and post-immunization  4 week post-immunization level within protective range and/or >4 fold rise from baseline

24. Immunoglobulin Defects <2 SD below the mean in IgG and another Ig class or <5 th percentile of total IgG for a given age Poor or absent response to immunization  <Two-fold increase in Ag-specific titer

25. CVID: Clinical Surveillance PFT’s High resolution CT of the chest to evaluate for bronchiectasis Stool O&P, bacterial cx, C. difficile for changes in GI sx CBC q6 mo for autoimmune cytopenias Low threshold for lymphoma

26. Treatment of CVID IVIG  Higher doses to keep trough IgG levels >500 mg/dl decreases infections, hospitalizations, need for abx therapy and improves pulmonary function  0.2-0.6 g/kg/mo or 300-500 mg/kg/q2-4 weeks IV  IV and subcutaneous routes equally effective  Pre-existing chronic lung disease is not improved by IVIG Stiehm, E et al. Pediatr Infect Dis J, 1997. 16 (7): 696-707.

27. IVIG First licensed in 1981 for primary antibody deficiencies as an improved, less painful alternative to IM injections of IG Subtle differences in Ab titers, IgA depletion, and IgG subclass that vary between lots as well as manufacturers  Gammagard-SD, Polygam-SD: IgA def patients Preparations with high titer specific IG against infectious pathogens  Cytogam: High titered IVIG for CMV  Respigam: High titered IVIG for RSV Increased toxicity with live virus vaccines (MMR)  Do not administer within 3 months of vaccination T ½ 15-30 days

28. Side Effects of IVIG Mild side effects occur in approximately 10% of infusions Side effects often preventable with ASA (15 mg/kg/dose) or acetominophen (15 mg/kg/dose) with diphenhydramine (1mg/kg/dose). Occasionally, hydrocortisone (6mg/kg/dose, max=100mg) 1hr prior Stiehm, E et al. Pediatr Infect Dis J, 1997. 16 (7): 696-707.

29. Infectious Disease Transmission with IVIG Hepatitis C has been reported after administration of certain lots of IVIG  Cases appeared after Hep C Ab+ patients were excluded as donors  Hypothesis is that Hep C Ab neutralizes virus in donor pools  Consequently new pasteurization +/- solvent/detergent processing and testing for HCV RNA to reduce viral transmission Several IVIG lots were recalled after donors developed Creutzfeldt-Jakob disease  No cases were reported of CJD transmission No cases have been reported of HIV transmission

30. Subcutaneous IgG (Vivaglobulin) Ochs HD et al; Subcutaneous IgG Study Group. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006 May;26(3):265-73. Ochs HD et al; Subcutaneous IgG Study Group. Moller G et al: Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet. 1995 Feb 11;345(8946):365-9.

31. Selective IgA deficiency Severe deficiency or total absence of the IgA class of immunoglobulins Estimated prevalence 1:500-1:1000 persons Spectrum of clinically affected  Asymptomatic  Recurrent infections: sinopulmonary, diarrhea

32. Selective IgA deficiency Higher incidence of autoimmunity  RA  SLE  ITP Atopy  Asthma  Food allergy

33. Selective IgA Deficiency Treatment  Supportive Risk of anaphylaxis to blood products  Formation of IgG or IgE anti-IgA antibodies Subset with IgG2 subclass deficiency

34. IgG Subclass Deficiency The IgG class of antibodies is composed of four different subtypes of IgG molecules  IgG1, IgG2, IgG3, and IgG4 Patients who lack, or have very low levels of, one or two IgG subclasses, but whose other immunoglobulin levels are normal, are said to have a selective IgG subclass deficiency.

35. IgG Subclass Deficiency The clinical significance of abnormal IgG subclass levels in patients with recurrent infections is unclear A low level of at least 1 IgG subclass has been found in approximately 2% of a given population, and Impaired antibody production may not be seen among adult patients with IgG3 subclass deficiency A low level of 1 or more IgG subclasses alone is generally not considered sufficient for a diagnosis of immunodeficiency In individuals with recurrent infections and 1 or more low levels of IgG subclasses, a demonstrable impairment in antibody response to vaccination or natural exposure is considered the most important determinant of disease Bonilla F et al, Ann Allergy Asthma Immunol. 2005 May;94(5 Suppl 1):S1-63.

36. Putting it all together... H&P:  Pattern of recurrent infections Rule out secondary causes of immune dysfunction  Medications  Other chronic diseases  Protein wasting states Laboratory assessment: quality not quantity.  Measurement of antigen-specific Ig titers pre- and post-immunization

37. Primary Humoral Immunodeficiency Referral to a Clinical Immunologist IVIG or SQ Ig only where there is demonstrable impairment in IgG production of antigen-specific antibody titers (quality not quantity) Supportive antibiotics Vaccinations: Prevnar, HIB, influenza Surveillance for associated clinical conditions

38. Key References Immune Deficiency Foundation website: http://www.primaryimmune.org/ http://www.primaryimmune.org/ Orange JS et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53. Bonilla F et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May;94(5 Suppl 1):S1-63.

39. Additional References Conley, ME et al. Diagnostic criteria for primary immunodeficiencies. Clin Immunol 1999. 93 (3): 190-7. Stiehm, E et al. Human intravenous immunoglobulin in primary and secondary antibody deficiencies. Pediatr Infect Dis J, 1997. 16 (7): 696- 707. Spickett, GP et al. Common variable immunodeficiency: how many diseases? Immunol Today, 1997. 18 (7): 325-8. Rosen, FS et al. Medical progress: the primary immunodeficiencies. NEJM 1995. 333 (7): 431-40. Spickett, GP. Current persepctives on common variable immunodeficiency (CVID). Clin & Exper Immunol 2001. 31 (4): 536-42. Middleton, E (ed) et al. Allergy Principles and Practice. 5 th Ed. Mosby 1998. 724-5. Ballow, M. Primary immunodeficiency disorders: antibody deficiency. Curr Rev Allergy and Clin Immunol 2002. 109 (4): 581-91. Bacchelli et al. Clin Exp Immunol 2007; 149:1365-2249.

40. Additional References Cunningham-Rundles, C et al. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999. 92: 34-48. Sweinberg SK et al. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy and Clin Immunol 1991. 88 (1) 96-104. Buckley, RH et al. The use of intravenous immne globulin in immunodeficiency diseases. NEJM 1991. 325 (2): 110-116. Punnonen, J et al. IL-4 synergizes with IL-10 and anti-CD40 MoAbs to induce B-cell differentiation in patients with common variable immunodeficiency. Scand J Immunol 1997. 45: 203-12. Farrington, M et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. PNAS 1994. 91: 1099- 1103. Schaffer, FM et al. Individuals with IgA deficiency and common variable immunodeficiency shar polymorphisms of major histocompatibility complex class III genes. PNAS 1989. 86: 8015-9. Massimo, M et al. Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency. Blood 2001. 98 (5): 1321-5.