CVID in pediatric patients and milder forms

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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.

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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)

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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')

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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')

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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.

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CVID (ESID/PAGID criteria)

• Differential diagnosis of hypogammoglobulinemia
• Drug Induced
• Antimalarial agents
• Captopril
• Carbamazepine
• Glucocorticoids
• Fenclofenac
• Gold salts
• Penicillamine
• Phenytoin
• Sulfasalazine

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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

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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

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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

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CVID

• So now we know!
• Or not?
• How do these patients present themselves?
• And when and where?
• Discussion!

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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

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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

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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
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Milder forms

• IgA deficiency
• IgG-subclass deficiency
• Specific antibody deficiency
• Anti-protein
• Anti-polysaccharide

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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.

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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.

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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.

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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

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Specific antibody deficiency

• Protein antigen tetanus, diphtheria
• Polysaccharide antigen pneumococci (Pneumo-23)
• Conjugated polysaccharide antigen Hib
• Isohemagglutinins (IgM)

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Patient 1

• Boy

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Patient 1

• Boy
• 2-3 years atopic eczema, recurrent upper airway
  infections adenotonsillectomy Henoch Schönlein
  purpura
• PID? Discussion!

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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!

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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

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Patient 2

• Girl

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Patient 2

• Girl
• 2 years recurrent upper airway infections,
  bronchial hyperreactivity, adenoidectomy,
  tympanostomy tubes
• PID? Discussion!

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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!

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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!

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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)

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Patient 3

• Boy

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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!

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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!

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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

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Patient 4

• Girl

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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!

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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!
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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

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CVID and milder forms

• Quite a challenge for the pediatric immunologist!
• Thank you for your attention!