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CVID in pediatric patients and milder forms

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Title: CVID in pediatric patients and milder forms


1
CVIDin 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)
    776794.

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
  • Low IgG and IgA variable IgM
  • All have recurrent bacterial infections. Clinical
    phenotypes vary autoimmune, lymphoproliferative
    and/or granulomatous disease
  • Approximately 10 have a positive family history
    (AR or AD)
  • Alterations 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
2006145204214.
  • 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 IgEs
  • IgG 6.6 IgA 0.56 IgM 0.88
  • IgG1 5.6 IgG2 0.60 IgG3 0.10 IgG4 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 IgEs IgG 6.6 IgA
    0.56 IgM 0.88 G1 5.6 IgG2 0.60 IgG3 0.10 IgG4
    0.033 g/l
  • 7 years
  • IgG 6.7 IgA 0.40 IgM 0.32
  • IgG1 5.4 IgG2 0.66 IgG3 0.10 IgG4 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
  • IgG1 3.6 IgG2 0.5 IgG3 0.25 IgG4 0.04 g/l
  • Diphtheria 0.02 -gt 2.24, Tetanus 0.13 -gt 3.06
    IU/ml
  • Pneumococci serotype 3 7 -gt 52, 4 3 -gt 22, 9 1
    -gt 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
  • IgG1 2.6 IgG2 0.5 IgG3 0.16 IgG4 lt0.04 g/l
  • Pneumococci serotype 3 7, 4 5, 9 3 U/ml
  • B-lymphocytes 0.6 x 109/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
  • IgG1 2.6 IgG2 0.5 IgG3 0.16 IgG4 lt0.04 g/l
  • Pneumococci serotype 3 7, 4 5, 9 3 U/ml
  • B-lymphocytes 0.6 x 109/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 lt0.25 IgM 0.24
  • IgG1 1.9 IgG2 0.17 IgG3 0.09 IgG4 lt0.01 g/l
  • Diphtheria 0.05 -gt0.55, Tetanus 0.07 -gt 3.60
    IU/ml
  • Pneumococci serotype 3 1, 4 lt1, lt1 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 lt0.25 IgM 0.24
  • IgG1 1.9 IgG2 0.17 IgG3 0.09 IgG4 lt0.01 g/l
  • Diphtheria 0.05 -gt0.55, Tetanus 0.07 -gt 3.60
    IU/ml
  • Pneumococci serotype 3 1, 4 lt1, lt1 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 -gt 107, 4 3 -gt 62, 9
    7 -gt 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 -gt 107, 4 3 -gt 62, 9
    7 -gt 27 U/ml
  • 8 years bronchial hyperactivity, chronic cough
    with sputum, cotrim prophylaxis some effect
  • IgG 8.0 IgA 1.52 IgM 0.8
  • IgG1 5.6 IgG2 1.0 IgG3 0.23 IgG4 0.15 g/l
  • Pneumococci serotype 3 16, 4 13, 9 6 U/ml
  • Diphtheria after booster 6.32, Tetanusgt16 IU/ml

PID? Discussion!
38
Patient 4
  • 12 years start IVIG, much better
  • IgG 8.0 IgA 1.52 IgM 0.8
  • IgG1 5.6 IgG2 1.0 IgG3 0.23 IgG4 0.15 g/l
  • Pneumococci serotype 3 14 -gt 50, 4 11 -gt 44, 9
    6 -gt 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!
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