common variable immunodeficiency

COMMON VARIABLE IMMUNODEFICIENCY

Sasikarn Suesirisawad, MD

DEFINITION Presence of hypogammaglobulinemia of two

or more immunoglobulin isotype (low IgG, IgA, or IgM)

Recurrent sinopulmonary infection

Impaired functional antibody responses Absent isohaemagglutinin Poor responses to protein (diphtheria, tetanus) or

polysaccharide vaccines(S. pneumoniae)

Other finding: autoimmunity, granulomatous disease, and neoplasia

FLOW CYTOMETRY B CELL SUBPOPULATION

ASSOCIATION OF CLINICAL PHENOMENA WITH DYSREGULATED B CELL SUBPOPULATIONS

EVALUATION OF THE PARIS AND FREIBURG CLASSIFICATION SCHEME.

P=0.03

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P<0.001

P=0.04

P=0.02

P<0.001

P<0.01

P=0.02

P=0.03

P=0.016

P=0.049

P<0.01

P=0.009

T CELL AND CELLULAR ABNORMALITIES

Decreased T lymphocyte proliferation to mitogens and Ag (40 % of patients)

Clin Immunol. 1999;92(1):34.

Low CD4/CD8 T cell ratio due to decrease in CD4 or increase CD8

Reduced T regulatory cells Clin Exp Immunol. 2009;156(3):446. Clin Immunol. 2009;131(2):240.

EPIDEMIOLOGY  Usually diagnosed in the second or third

decade of life.

25 % of all CVID pts present in childhood or adolescence, earlier peak of diagnosis at 8 yrs of age.

An Pediatr (Barc). 2011;74(2):74.J Pediatr. 2009;154(6):888.

Median age of first symptom was 19 yr

Median age at CVID diagnosis was 33.9 yr

Delay between first symptom and diagnosis of CVID

73%: RS infection

Coincidence of granulomatous disease and autoimmmune cytopenia with splenomegaly in

CVID

Mary Lucas et al. JACI 2010

PULMONARY MANIFESTATIONS  73 % of CVID develop chronic structural

pulmonary complications: bronchiectasis and bronchial wall thickening

Pediatr Allergy Immunol. 2010;21(5):793.

54 children with CVID, structural lung disease was found in > 85 % of patients

Chest. 2010;138(2):371.

PULMONARY MANIFESTATIONS Obstructive flow-volume curves found in

50 - 94 % of pts. Pediatr Allergy Immunol. 2010;21(5):793.

12 CVID, 83 % asthma, none life-threatening symptoms.

Ann Allergy Asthma Immunol. 2006;97(5):653

Obstructive lung disease in children with CVID appears to be higher than adults.

ALLERGIC DISEASES 38 % of pts in one of cohorts had some

evidence of an allergic disease: food allergy, eczema, urticaria, rhinitis, asthma.

J Pediatr. 2009;154(6):888.

83 % had asthma. Ann Allergy Asthma Immunol.

2006;97(5):653

GASTROINTESTINAL PROBLEMS  Diarrhea, malabsorption, wt loss are common

problems in CVID. Clin Immunol. 1999;92(1):34.

GI infections: H. pylori and Giardia lamblia. Salmonella, Shigella, Campylobacter.

Ann Intern Med. 1993;118(9):720

Crohn's disease and ulcerative colitis Clin Immunol. 1999;92(1):34.

Nodular intestinal hyperplasia occurs relatively frequently in adolescents with CVID

Dig Dis Sci. 2007;52(11):2977.

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AUTOIMMUNE DISEASE Autoimmunity is seen in 20 - 25 % of

CVID.

Autoimmune cytopenias are more common presenting disorder in children than adults.

Autoimmune neutropenia, thrombocytopenia, hemolytic anemia

DM, psoriasis, SLE, RA, JIA

MALIGNANCY Lifetime risk of malignancy: 1.4 - 7 %

The most frequently diagnosed disorder is B cell lymphoma

Am J Hematol. 2002;69(3):171.

NEURODEGENERATIVE DISEASES OR ENCEPHALOPATHY  adults with CVID, enteroviral and JC

virus infection can cause neurodegeneration.

Enteroviral infection has not described in pediatric CVID.

In contrast, neurodegenerative diseases described in other pediatric immunodeficiencies (esp. X-linked agammaglobulinemia)

Ann Allergy Asthma Immunol. 2007;98(5):483Brain. 1996;119 ( Pt 1):1.

TACI

BAFF-R

ICOS DEFICIENCYICOS DEFICIENCY

2% of patients with CVID

Autosomal recessive trait

Serum IgG and IgA levels were markedly

reduced in all patients

IgG<1.9-2.55 g/L

IgA<0.06-0.58g/L

Serum IgMlevel

reduced in 6/9 patients

low normal values in 3/9 patients

C.Bacchellietal.ClinicalandExperimentalImmunology2007, 149:401–409.Yongetal.ImmunologicalReviews2009;229:101–113.Park MA et al. Lancet

2008;372:489-502

TACI MUTATION 10-20% of CVID patients Associated with

Lymphoproliferation splenomegaly Tonsillar hyperplasia follicular nodular hyperplasia of GI

Autoimmunity hemolytic anaemia Autoimmune thrombocytopaenia thyroiditis

TACI MutationTACI MutationPark MA et al. Lancet 2008;372:489-502.Young PFK et al. ImmunolAllergy ClinN Am 2008;28:367-86.C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.

BAFF-R DEFICIENCY

Described in only 1 patient 60-year-old male with

hypogammaglobulinaemia Profound reduction of both class switch

(CD27+, IgM-, IgD-) and non-switched memory (CD27+, IgM+, IgD+) Transitional B cell (CD38+++, IgM++) Plasmablasts(CD38+++, IgM-)

Park MA et al. Lancet 2008;372:489-502.

C.Bacchellietal.ClinicalandExperimentalImmunology2007;149:401–409.

MUTS5(MSH5)

A gene encoded in MHC classIII region

A critical role in regulating meiotic

homologous recombination

A role in class switch recombination

Msh5 Mutation: associated with CVID

and selective IgA deficiency

MANAGEMENT

IMMUNE GLOBULIN IgG replacement therapy started early,

cycle of recurrent infections leading to progressive lung damage can be mitigated.

Non-infectious complications of CVID,

such as autoimmune cytopenias prevented or treated by immune globulin therapy

IMMUNE GLOBULIN Ig should not be given until evaluation

of patient's immune system including specific antibody responses.

Plans should be made to discontinue infusions for at least 4 mo, in order to reassess patient’s current immune status.

EVALUATION OF ILLNESSES Children generally have higher rate of

viral infection than adults, due to increased exposure and other factors

CVID and fever should be evaluated promptly. identify organisms such as rapid viral identification kits for influenza or RSV.

Choice of ATB on culture data and test results and using narrow-spectrum drugs, avoid bacterial resistance.

MONITORING PULMONARY STATUS Monitoring child for progressive but

subclinical pulmonary damage is important since pts can develop chronic pulmonary disease.

HRCT of chest may be of value in detecting early and progressive pulmonary structural damage

Repeat exams for decision such as administration of ATB or immune suppressants or increase in dose of Ig.

VACCINATION Live viral vaccines contraindicated in CVID.

Killed viral and bacterial vaccines: hope that generate T cell-mediated immune responses that may afford some additional protection beyond that obtained with Ig replacement therapy.

Many children will retain ability to mount responses to some polysaccharide Ag, while they are non-responsive to others.

Immunization against transmissible infectious agents is encouraged for close family members.

Passive protection with hyperimmune globulin preparations, such as tetanus and varicella, is usually not necessary in patients already receiving standard Ig replacement therapy.

PROGNOSIS Life span of children with CVID has been

significantly lengthened since Ig replacement therapy became standard of care

Prognosis is good.

Death during childhood from complications of CVID is extremely rare once immune globulin therapy is instituted.

Those children diagnosed after irreversible pulmonary disease has developed may have shorter life span

Thank you