1. CVID in pediatric patients and milder forms Dr. Esther de Vries consultant in pediatric immunology and infectious diseases Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands

2. CVID  What is CVID?  Discussion!  What are ‘milder forms’?  Discussion!

3. CVID (IUIS)  Common Variable Immunodeficiency Disorders  The International Union of Immunological Societies (IUIS) Primary Immunodeficiency Diseases (PID) Classification Committee: Raif. S. Geha, M.D., Luigi. D. Notarangelo, M.D., Co-chairs, Jean-Laurent Casanova, M.D., Helen Chapel, M.D., Mary Ellen Conley, M.D., Alain Fischer, M.D., Lennart Hammarström, M.D., Shigeaki Nonoyama, M.D., Hans D. Ochs, M.D., Jennifer Puck, M.D., Chaim Roifman, M.D., Reinhard Seger, M.D., and Josiah Wedgwood, M.D  J Allergy Clin Immunol. 2007 October; 120(4): 776–794.

4. CVID (IUIS)  Predominantly antibody deficiencies  2. Severe reduction in serum IgG and IgA with normal, low or very low numbers of B cells  CVID: oLow IgG and IgA; variable IgM oAll have recurrent bacterial infections. Clinical phenotypes vary: autoimmune, lymphoproliferative and/or granulomatous disease oApproximately 10% have a positive family history (AR or AD) oAlterations in TACI, BAFFR, Msh5 may act as contributing polymorphisms (A disease-causing effect has been identified for homozygous C140R and A181E TACI mutations)

5. CVID (ESID/PAGID criteria)  Probable  Male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria:  1) Onset of immunodeficiency at greater than 2 years of age  2) Absent isohemagglutinins and/or poor response to vaccines  3) Defined causes of hypogammaglobulinemia have been excluded (see ' Differential Diagnosis of Hypogammaglobulinemia')

6. CVID (ESID/PAGID criteria)  Possible  Male or female patient who has a marked decrease (at least 2 SD below the mean for age) in one of the major isotypes (IgM, IgG and IgA) and fulfills all of the following criteria:  1) Onset of immunodeficiency at greater than 2 years of age  2) Absent isohemagglutinins and/or poor response to vaccines  3) Defined causes of hypogammaglobulinemia have been excluded (see ' Differential Diagnosis of Hypogammaglobulinemia')

7. CVID (ESID/PAGID criteria)  Spectrum of disease  Most patients with CVI are recognized to have immunodeficiency in the second, third or fourth decade of life, after they have had several pneumonias; however children and older adults may be affected. Viral, fungal and parasitic infections as well as bacterial infections may be problematic. The serum concentration of IgM is normal in about half of the patients. Abnormalities in T cell numbers or function are common. The majority of patients have normal numbers of B cells; however, some have low or absent B cells. Approximately 50% of patients have autoimmune manifestations. There is an increased risk of malignancy.

8. CVID (ESID/PAGID criteria)  Differential diagnosis of hypogammoglobulinemia  Drug Induced –Antimalarial agents –Captopril –Carbamazepine –Glucocorticoids –Fenclofenac –Gold salts –Penicillamine –Phenytoin –Sulfasalazine

9. CVID (ESID/PAGID criteria)  Genetic Disorders –Ataxia Telangiectasia –Autosomal forms of SCID –Hyper IgM Immunodeficiency –Transcobalamin II deficiency and hypogammaglobulinemia –X-linked agammaglobulinemia –X-linked lymphoproliferative disorder (EBV associated) –X-linked SCID –Some metabolic disorders –Chromosomal Anomalies –Chromosome 18q- Syndrome –Monosomy 22 –Trisomy 8 –Trisomy 21

10. CVID (ESID/PAGID criteria)  Infectious Diseases –HIV –Congenital Rubella –Congenital infection with CMV –Congenital infection with Toxoplasma gondii –Epstein-Barr Virus  Malignancy –Chronic Lymphocytic Leukemia –Immunodeficiency with Thymoma –Non Hodgkin's lymphoma –B cell malignancy

11. CVID (ESID/PAGID criteria)  Systemic Disorders –Immunodeficiency caused by hypercatabolism of immunoglobulin –Immunodeficiency caused by excessive loss of immunoglobulins (nephrosis, severe burns, lymphangiectasia, severe diarrhea)  Last updated 2005

12. CVID  So now we know!  Or not?  How do these patients present themselves?  And when and where?  Discussion!

13. Clinical presentation of PIDs  Recurrent ENT and airway infections  Failure-to-thrive from early infancy  Recurrent pyogenic infections  Unusual infections or unusually severe course of infections  Recurrent infections with the same type of pathogen  Autoimmune or chronic inflammatory disease; lymphoproliferation  Characteristic combinations of clinical features in eponymous syndromes  Angioedema

14. Clinical presentation of PIDs  Recurrent ENT and airway infections  Failure-to-thrive from early infancy  Recurrent pyogenic infections  Unusual infections or unusually severe course of infections  Recurrent infections with the same type of pathogen  Autoimmune or chronic inflammatory disease; lymphoproliferation  Characteristic combinations of clinical features in eponymous syndromes  Angioedema

15. Clinical and Experimental Immunology 2006;145:204–214.  Picking up the signs of PID  Recognizing the different clinical presentations of PID  Following the appropriate diagnostic protocol  Protocol 1: –Rule out severe antibody deficiency and neutropenia –Perform booster responses (specific antibodies), consider IgG-subclasses and M-proteins –Consider lymphocyte subpopulations and further tests –If problems persist, repeat the tests! www.sanquin.nl

16. Milder forms  IgA deficiency  IgG-subclass deficiency  Specific antibody deficiency –Anti-protein –Anti-polysaccharide

17. IgA deficiency (ESID/PAGID criteria)  Definitive  Male or female patient greater than 4 years of age who has a serum IgA of less than 7 mg/dl (0.07 g/L) but normal serum IgG and IgM, in whom other causes of hypogammaglobulinemia have been excluded (see 'Differential Diagnosis of Hypogammaglobulinemia'). These patients have a normal IgG antibody response to vaccination.

18. IgA deficiency (ESID/PAGID criteria)  Probable  Male or female patient greater than 4 years of age who has a serum IgA at least 2 SD below normal for age but normal serum IgG and IgM, in whom other causes of hypogammaglobulinemia have been excluded (see 'Differential Diagnosis of Hypogammaglobulinemia'). These patients have a normal IgG antibody response to vaccination.

19. IgA deficiency (ESID/PAGID criteria)  Spectrum of disease  Patients with IgA deficiency have an increased incidence of upper respiratory tract infections, allergies and autoimmune disease. Many individuals with IgA deficiency are asymptomatic. Others have persistent or recurrent infections and some develop CVI over time.

20. IgG-subclass deficiency (ESID/PAGID criteria)  Draft  Male or female patient with recurrent/severe infections and all of the following:  aged 7 years  normal levels of IgM and IgA and at least two of IgG1-3 sublasses less than the 5th centile for age  Poor responses to some vaccines

21. Specific antibody deficiency  Protein antigen: tetanus, diphtheria  Polysaccharide antigen: pneumococci (Pneumo-23)  Conjugated polysaccharide antigen: Hib  Isohemagglutinins (IgM)

22. Patient 1  Boy

23. Patient 1  Boy  2-3 years: atopic eczema, recurrent upper airway infections; adenotonsillectomy; Henoch Schönlein purpura  PID? Discussion!

24. Patient 1  Boy  2-3 years: atopic eczema, recurrent upper airway infections; adenotonsillectomy; Henoch Schönlein purpura  5 years: bronchial hyperreactivity (cough), glue ears; inhalers; no specific IgE’s; IgG 6.6 IgA 0.56 IgM 0.88 IgG 1 5.6 IgG 2 0.60 IgG 3 0.10 IgG 4 0.033 g/l  PID? Discussion!

25. Patient 1  Boy  2-3 years: atopic eczema, recurrent upper airway infections; adenotonsillectomy; Henoch Schönlein purpura  5 years: bronchial hyperreactivity (cough), glue ears; inhalers; no specific IgE’s; IgG 6.6 IgA 0.56 IgM 0.88 G 1 5.6 IgG 2 0.60 IgG 3 0.10 IgG 4 0.033 g/l  7 years: IgG 6.7 IgA 0.40 IgM 0.32 IgG 1 5.4 IgG 2 0.66 IgG 3 0.10 IgG 4 0.018 g/l  Started in trial cotrim vs IVIG prophylaxis

26. Patient 2  Girl

27. Patient 2  Girl  2 years: recurrent upper airway infections, bronchial hyperreactivity, adenoidectomy, tympanostomy tubes  PID? Discussion!

28. Patient 2  Girl  2 years: recurrent upper airway infections, bronchial hyperreactivity, adenoidectomy, tympanostomy tubes  3 years: no improvement IgG 5.0 IgA 0.47 IgM 0.6 IgG 1 3.6 IgG 2 0.5 IgG 3 0.25 IgG 4 0.04 g/l Diphtheria 0.02 -> 2.24, Tetanus 0.13 -> 3.06 IU/ml Pneumococci serotype 3: 7 -> 52, 4: 3 -> 22, 9: 1 -> 16 U/ml PID? Discussion!

29. Patient 2  4 years: recurrent otitis, very tired and listless, cotrim prophylaxis little effect IgG 3.0 IgA 0.27 IgM 0.5 IgG 1 2.6 IgG 2 0.5 IgG 3 0.16 IgG 4 <0.04 g/l Pneumococci serotype 3: 7, 4: 5, 9: 3 U/ml B-lymphocytes 0.6 x 10 9 /l  PID? Discussion!  Therapy? Discussion!

30. Patient 2  4 years: recurrent otitis, very tired and listless, cotrim prophylaxis little effect IgG 3.0 IgA 0.27 IgM 0.5 IgG 1 2.6 IgG 2 0.5 IgG 3 0.16 IgG 4 <0.04 g/l Pneumococci serotype 3: 7, 4: 5, 9: 3 U/ml B-lymphocytes 0.6 x 10 9 /l  Started on IVIG and is doing very well now (after ENT-surgery of the middle ear)

31. Patient 3  Boy

32. Patient 3  Boy  2 years: very tired, upper respiratory infections; mother very tired too, lots of infections as a child, and still recurrent sinusitis  PID? Discussion!  Therapy? Discussion!

33. Patient 3  Boy  2 years: very tired, upper respiratory infections; mother very tired too, lots of infections as a child, and still recurrent sinusitis IgG 2.5 IgA <0.25 IgM 0.24 IgG 1 1.9 IgG 2 0.17 IgG 3 0.09 IgG 4 <0.01 g/l Diphtheria 0.05 ->0.55, Tetanus 0.07 -> 3.60 IU/ml Pneumococci serotype 3: 1, 4: <1, <1 U/ml  PID? Discussion!  Therapy? Discussion!

34. Patient 3  Boy  2 years: very tired, upper respiratory infections; mother very tired too, lots of infections as a child, and still recurrent sinusitis IgG 2.5 IgA <0.25 IgM 0.24 IgG 1 1.9 IgG 2 0.17 IgG 3 0.09 IgG 4 <0.01 g/l Diphtheria 0.05 ->0.55, Tetanus 0.07 -> 3.60 IU/ml Pneumococci serotype 3: 1, 4: <1, <1 U/ml  Started on IVIG, is doing very well

35. Patient 4  Girl

36. Patient 4  Girl  5 years: recurrent airway infections, bronchial hyperreactivity Diphtheria 0.74 Tetanus 2.05 IU/ml Pneumococci serotype 3: 75 -> 107, 4: 3 -> 62, 9: 7 -> 27 U/ml  PID? Discussion!

37. Patient 4  Girl  5 years: recurrent airway infections, bronchial hyperreactivity Diphtheria 0.74 Tetanus 2.05 IU/ml Pneumococci serotype 3: 75 -> 107, 4: 3 -> 62, 9: 7 -> 27 U/ml  8 years: bronchial hyperactivity, chronic cough with sputum, cotrim prophylaxis some effect IgG 8.0 IgA 1.52 IgM 0.8 IgG 1 5.6 IgG 2 1.0 IgG 3 0.23 IgG 4 0.15 g/l Pneumococci serotype 3: 16, 4: 13, 9: 6 U/ml Diphtheria after booster 6.32, Tetanus>16 IU/ml PID? Discussion!

38. Patient 4  12 years: start IVIG, much better IgG 8.0 IgA 1.52 IgM 0.8 IgG 1 5.6 IgG 2 1.0 IgG 3 0.23 IgG 4 0.15 g/l Pneumococci serotype 3: 14 -> 50, 4: 11 -> 44, 9: 6 -> 26 U/ml  15 years: switched to scIG

39. CVID and milder forms  Quite a challenge for the pediatric immunologist!  Thank you for your attention!