common variable immunodeficiency (cvid)

L/O/G/O

Common variable immunodeficiencyCommon variable immunodeficiency

King Chulalongkorn Memorial Hospital

Jaichat Mekaroonkamol, MD.

Outlines

Pathophysiology

Clinical phenotype

Epidemiology

Common variable immunodeficiency: CVID

Genetic defects

Management

Prevalence

• PID are rare and have an overall prevalence of approximately 1:500-1:10,000 live births

• However, a much higher rate is observed among populations with high consanguinity rates or among genetically isolated populations

Elsevier Saunders, 2004J Allergy Clin Immunol ,2010

Incidence and trends of PID

Mayo Foundation for Medical Education and Research, 2009

Family history of PID

• 17% in the 2007 survey• 22% in the 2002 survey• 24% in the 1996/97 survey.

• 4.5% reported a family history of primary immunodeficiency disease

• 16.4% reported a family history of death at young age

• 9% reported consanguineous marriage

J Clin Immunol, 2009

Male to female ratio was 1.9

Overall percentage distribution of various types PIDs

Mayo Foundation for Medical Education and Research, 2009

10.4%12%

When to suspect immunodeficiency

If infections are

•Chronic

•Recurrent

•Unusual

•Invasive

•Severe

•Evaluate

10 warning signs10 warning signs

10 warning signs: adult (>18 year old)10 warning signs: adult (>18 year old)

B-cell development and B-cell development and differentiation differentiation

1. B cell receptor gene Rearrangement

2. Receptor editingand negative selection

Lancet 2008; 372: 489–502

1. PRO B cell - No surface immunoglobuliin/ B cell receptor

Lancet 2008; 372: 489–502

2. PRE B cell - RAG: Recombination activating gene - TdT: Terminal deoxynucleotidyl transferase - µ chain + surrogate light chain(λ5) = Pre B cell receptor

Lancet 2008; 372: 489–502

3. Immature B cell - µ chain + light chain(κλ) = B cell receptor: IgM

Lancet 2008; 372: 489–502

Recognized self antigen1.Receptor editing2.Negative selection3.Functional unresponsiveness

Selective polyadenylation and alternative splicing of constant gene

Mature B cell: IgM + IgD

Lancet 2008; 372: 489–502

Common variable immune deficiency disorders

• Prevalence 1 in 25,000 to 1 in 50,000• Most patients are diagnosed between the ages

of 20 and 40 years– but approximately 20% are under the age of 20

Cunningham-Rundles C. Blood. 2012.

CVID: Clinical phenotype

Lancet 2008; 372: 489–502

Charlotte Cunningham-Rundles. Blood. 2010;116(1):7-15

Clinical complication

RS 86%

CVID: Definition

• Reduced serum IgG, IgA and/or IgM, by at least 2 SDs below the mean for age

• Poor or absent antibody production to both protein and carbohydrate vaccines

• Exclusion of other causes of hypogammaglobulinemia

Clin Immunol. 1999Curr Allergy Asthma Rep. 2001

Clin Immunol. 2009Blood. 2010

British Journal of Haematology, 2009

Bacterial infection(RS/GI)

OI Enlarge LN

Autoimmune

CVID √ X possible √ vary

XLA √ X X X ↓

HIM √ √ possible √ ↔

SIgAD √ X possible possible ↔

YU-Lung Lau, Hong Kong. APAPARI, 2013

www.themegallery.com

Average delay of 6-7 years in diagnosis

Cunningham-Rundles C. Blood. 2012

Clinical Infectious Diseases 2008; 46:1547–54

Median age of first symptom was 19 yr

Median age at CVID diagnosis was 33.9 yr

Median delay of Dx was 6.9 yr (0-55 yr)

Delay between first symptom and diagnosis of CVID

15.6 yr for 138 patients

2.9 yr for 114 patients

3.7 yr

CVID: Clinical phenotype

Resnick et al. Blood. 2012;119:1650-1657

• 473 subjects with CVID- 208 males and 265 females

• Cohort study: 1974-2010• The diagnosis of CVID was made

by standard criteria

68% had one or more of the inflammatory/autoimmune

complication

Autoimmune disease

ESID US France

Patients (n) 334 473 69

F/U (years) 25.5 40 40

autoimmune 12-46% 28.6% 20%

Cunningham-Rundles C. Blood. 2012.

Autoimmune disease

Clinical complication

Pediatr Allergy Immunol 2010

• 26 articles including 587 patients with CVID

• 73 % develop chronic structural pulmonary complications:– Bronchiectasis– Bronchial wall thickening

• HRCT is the most sensitive method– CXR and PFT miss in 2–59% of patients

• Obstructive flow-volume curves found in 50 - 94 % of patients(Child>Adult)

• Chronic lung disease : 28.5% • leading to radiographic changes with

or without functional impairment• equally in males and females

• Bronchiectasis: 11.2%• Progressive lung disease led to the need

for chronic oxygen therapy: 6.1%

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.

Autoimmune disease

• Autoimmunity is seen in 20 - 25 % of CVID.

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

• DM, psoriasis, SLE, RA, JIA

Because of uncontrolled autoimmunity

(ITP/AIHA)

1.1%1.3%

Gastrointestinal problems

Granulomatous disease

Malignancy

non-Hodgkin B-cell lymphomas were the most common

Malignancy

Neurodegenerative diseases or encephalopathy • Adults with CVID, enteroviral and JE

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):483

Complication VS Outcome

Helen Chapel et.al, Blood, 2008

P <0 .0001

Helen Chapel et.al, Blood, 2008

Complication VS Outcome

Kaplan–Meier survival curves

for CVID patients with infections only versus those with any other complication

hazard ratio [HR] = 10.96 P <0 .0001

HOW TO EARLY DIAGNOSIS

J Pediatr 2009;154:888-94

• 10% of patients with remarkably low levels of immunoglobulins may be infection free. – ITP– AIHA– Sarcoid-like picture

• check specific antibody production in such patients– Adult-onset ITP and AIHA

Arnold et al, 2008

Lancet 2008; 372: 489–502

Peripheral blood B-cell subsets

Lancet 2008; 372: 489–502

• Low in 50–75% of CVID• Associated with

• granulomatous disease• Splenomegaly• Autoimmune cytopenias• Bronchiectasis

Lancet 2008; 372: 489–502

• Absence: Associated with• Recurrent bacterial pneumonia• Bronchiectasis

Lancet 2008; 372: 489–502

• Increases: Associated with• Lymphadenopathy• Splenomegaly

Lancet 2008; 372: 489–502

Genetic defects in CVID

• ICOS: CVID inducible T cell costimulator

• CD19

• TACI – (TNFRSF13B: tumour necrosis factor receptor

superfamily, member 13B)

• BAFF-R – (TNFRSF13C: tumour necrosis factor receptor

superfamily, member 13C )

Lancet 2008; 372: 489–502

Genetic defects in CVID

Lancet 2008; 372: 489–502

ICOS 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 IgM level

• reduced in 6/9 patients

• low normal values in 3/9 patients

C.Bacchellietal.Clinical and Experimental Immunology2007, 149:401–409

Nature Reviews Immunology, 2012

C.Bacchellietal.Clinical and Experimental Immunology2007, 149:401–409

TACI mutation

• 10-20% of CVID patients

• Associated with – Lymphoproliferation

• Splenomegaly• Tonsillar hyperplasia• Follicular nodular hyperplasia of GI

– Autoimmunity• Hemolytic anaemia• Autoimmune thrombocytopaenia• Thyroiditis

Lancet 2008; 372: 489–502

Basic Science Research , 2013

BAFF-R Deficiency

Lancet 2008; 372: 489–502

CD 19 deficiency

• 4 patients with homozygous mutations in CD19, from 2 unrelated families– Hypogammaglobulinemia– Increased susceptibility to infection– Normal numbers of CD20+ B cells– Expression of CD 19 on B cell

• Undetectable in ¼ patients• Rarely detectable in ¾ patients

Lancet 2008; 372: 489–502

CD 19 deficiency

• Decrease numbers of CD27+ memory B cells & CD5+ B cells

• Poor antibody response to rabies vaccination

• Normal germinal center formation

• No autoimmune features or signs of lymphoprolipheration

Lancet 2008; 372: 489–502

ManagementManagement

Management

• Ig replacement

• Antimicrobial drugs

• Complications and management

• Organ and stem cell transplantation

Charlotte Cunningham-Rundles. Blood,2010

usually in doses of 400 to 600 mg/kg body weight per month IV/SC

Ig replacement

• Every 2 weeks for SC route

• Every 3 or 4 weeks for IV route

• Iodinated IgG protein: half-life 21 days

• Current intravenous Igs have half-lives closer to 30 days

• Administered IgG in CVID subjects with chronic lung or gastrointestinal disease appears to have a shorter half-life

Ig replacement

• Goal: to prevent infections

• The target trough serum IgG varies depending on the baseline level of IgG– baseline serum IgG of less than 100

mg/dL, : at least 600 mg/dL– No functional antibody

: at least 900 mg/dL to supply the minimum

“normal” level of functional Ig– Serum IgG levels measured at 6- to 12-

month intervalsInt Arch Allergy Immunol 2009;150:311–324Charlotte Cunningham-Rundles. Blood,2010

Ig replacement

Most patients with CVID have little or no serum IgA

Anti IgA antibody?

Low-IgA preparations?

Testing for anti-IgA IgE?

Lancet 2008; 372: 489–502Int Arch Allergy Immunol 2009;150:311–324Charlotte Cunningham-Rundles. Blood,2010

Antimicrobial drugs

• Sinopulmonary infections– Fluoroquinolones– Amoxicillin clavulanate

Lancet 2008; 372: 489–502

Complications and management

• Chronic lung disease– Greater doses of Ig (600 mg/kg/month)– Daily antibiotic prophylaxis

• Bactrim• Macrolides: anti-inflammatory effects

Int Arch Allergy Immunol 2009;150:311–324Charlotte Cunningham-Rundles. Blood,2010

• Granulomatous/lymphoid infiltrative disease– Oral steroids 10-20 mg a day every other

day may preserve lung or liver function– 200 to 400 mg a day ( 3.5-6.5 mg/kg) of

hydroxycloroquine– Pulmonary granuloma

• twice daily inhaled beclomethasone

• Autoimmune disease– Greater doses of Ig (1 g/kg body weight)

given weekly for a short time– Intravenous steroids (1 g of

methylprednisolone) followed by moderate doses of oral steroids tapered over several weeks: ITP/AIHA

– Rituximab in standard doses for more refractory or recurrent ITP and/or AIHA

– Splenectomy is to be avoided

• Gastrointestinal disease– Initial treatment is determined on the basis

of culture results, biopsy findings• Antibiotics• Restoration of nutrients• Rehydration

Organ and stem cell transplantation

• There are a few reports of liver and lung transplant in CVID, with at least short-term survival but overall variable outcome

Monitoring patients over time

Survival

- 87% of the cohort

F/U - 19.6% had died- The median age at

death was- 44 years for

females(10-90yr) - 42 years for

males(9-79 yr)

P< 0.0001

L/O/G/O

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