CVIDin pediatric patients and milder forms

Dr. Esther de Vries

consultant in pediatric immunology and infectious diseases

Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands

CVID

What is CVID?

Discussion!

What are ‘milder forms’?

Discussion!

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.

CVID (IUIS)

Predominantly antibody deficiencies 2. Severe reduction in serum IgG and IgA with normal, low or

very low numbers of B cells CVID:o Low IgG and IgA; variable IgM

o All have recurrent bacterial infections. Clinical phenotypes vary: autoimmune, lymphoproliferative and/or granulomatous disease

o Approximately 10% have a positive family history (AR or AD)

o Alterations in TACI, BAFFR, Msh5 may act as contributing polymorphisms (A disease-causing effect has been identified for homozygous C140R and A181E TACI mutations)

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')

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')

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.

CVID (ESID/PAGID criteria)

Differential diagnosis of hypogammoglobulinemia Drug Induced

– Antimalarial agents– Captopril– Carbamazepine– Glucocorticoids– Fenclofenac– Gold salts– Penicillamine– Phenytoin– Sulfasalazine

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

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

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

CVID

So now we know!

Or not?

How do these patients present themselves?

And when and where?

Discussion!

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

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

Clinical and Experimental Immunology Clinical and Experimental Immunology 2006;145:204–214.2006;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

Milder forms

IgA deficiency IgG-subclass deficiency Specific antibody deficiency

– Anti-protein

– Anti-polysaccharide

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.

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.

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.

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

Specific antibody deficiency

Protein antigen: tetanus, diphtheria

Polysaccharide antigen: pneumococci (Pneumo-23)

Conjugated polysaccharide antigen: Hib

Isohemagglutinins (IgM)

Patient 1

Boy

Patient 1

Boy 2-3 years: atopic eczema, recurrent upper airway infections;

adenotonsillectomy; Henoch Schönlein purpura

PID? Discussion!

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

IgG1 5.6 IgG2 0.60 IgG3 0.10 IgG4 0.033 g/l

PID? Discussion!

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 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

Patient 2

Girl

Patient 2

Girl 2 years: recurrent upper airway infections, bronchial

hyperreactivity, adenoidectomy, tympanostomy tubes

PID? Discussion!

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 -> 2.24, Tetanus 0.13 -> 3.06 IU/ml

Pneumococci serotype 3: 7 -> 52, 4: 3 -> 22, 9: 1 -> 16 U/ml

PID? Discussion!

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 <0.04 g/l

Pneumococci serotype 3: 7, 4: 5, 9: 3 U/ml

B-lymphocytes 0.6 x 109/l

PID? Discussion! Therapy? Discussion!

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 <0.04 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)

Patient 3

Boy

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!

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

IgG1 1.9 IgG2 0.17 IgG3 0.09 IgG4 <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!

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

IgG1 1.9 IgG2 0.17 IgG3 0.09 IgG4 <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

Patient 4

Girl

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!

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

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, Tetanus>16 IU/ml

PID? Discussion!

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 -> 50, 4: 11 -> 44, 9: 6 -> 26 U/ml

15 years: switched to scIG

CVID and milder forms

Quite a challenge for the pediatric immunologist!

Thank you for your attention!