Common variable immunodeficiency

Common Variable Immunodeficiency
Athipat Athipongarporn
Department of Pediatric Allergy and Immunology
King Chulalongkorn Memorial Hospital

Outline
• Definition
• Epidemiology
• Diagnosis and Differential Diagnosis
• Clinical Manifestation
• Management

History
20161971
Definition CVID by WHO
“less well-defined
antibody deficiency
syndromes”
The International Union of
Immunological Societies Expert
Primary Immunodeficiency
Committee 2009 : heterogeneous
nature of these
hypogammaglobulinemic states
2009
Francisco A. Bonilla et. al. JACI in practice. 2015
1999
Conley et al
Ig G, IgA, IgM< -2SD
Ameratunga et al
Age > 4 Y
Clinical and immunological criteria
Histological markers
2013 2014
ESID Registry
Age > 4 Y
Clinical and immunological criteria
ICON

R. Ameratunga. Clinical and Experimental Immunology, 174: 203–211

Diagnosis
• A 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
• Onset of immunodeficiency at greater than 2 years of age
• Absent isohemagglutinins and/or poor response to vaccines
• Defined causes of hypogammaglobulinemia have been excluded according to
a list of differential diagnosis

Consensus definition of CVID
• Most patients will have
• At least 1 of the clinical manifestations (infection, autoimmunity,
lymphoproliferation)
• A diagnosis of CVID may be conferred on asymptomatic individuals who fulfill criteria
2 to 5, especially in familial cases.
• Hypogammaglobulinemia should be defined according to the age adjusted
• The IgG level must be repeatedly low in at least 2 measurements more than 3 weeks
apart in all patients.
• Repeated measurement may be omitted if the level is very low (<100-300 mg/dL
depending on age), other characteristic features are present, and it is considered in
the best interest of the patient to initiate therapy with IgG as quickly as possible.
• IgA or IgM level must also be low.
• Note that some experts prefer a more narrow definition requiring low IgA level in all
patients

Consensus definition of CVID
• All patients with an IgG level of more than 100 mg/dL should be studied for
responses to T-dependent (TD) and T-independent (TI) antigens
• In all patients undergoing such testing, there must be a demonstrable impairment of
response to at least 1 type of antigen (TD or TI).
• At the discretion of the practitioner, specific antibody measurement may be dispensed with if
all other criteria are satisfied and if the delay incurred by prevaccination and postvaccination
antibody measurement is thought to be deleterious to the patient’s health.
• Other causes of hypogammaglobulinemia must be excluded (Table I).
• Genetic studies to investigate monogenic forms of CVID or for disease-modifying
polymorphisms are not generally required for diagnosis and management in most
of the patients,
• Especially those who present with infections only without immune dysregulation,
autoimmunity, malignancy, or other complications.
• In these latter groups of patients, however, single gene defects may be amenable to specific
therapies (eg, stem cell therapy) and molecular genetic diagnosis should be considered when
possible.

Epidemiology
• Almost every primary immunodeficiency registry available for
consultation reports a predominance of antibody defects (generally
>50%)
• CVID is the most frequent symptomatic antibody deficiency diagnosed in
adulthood
• IgA deficiency and CVID reported as the most frequent types
• The United States Immunodeficiency Network registry contains 3,459
subjects, with 1,049 subjects with CVID (30%).

Pathogenesis
• B cell defect
• T cell defect
• DC defect
• Chronic immune activation

B cell defect
• Decrease isotype-switched B cells in a majority (not all) and a loss of
plasma cells in both bone marrow and mucosal tissues.
• B cells of some subjects produce normal amounts of immunoglobulin
in culture, others produce only IgM, and others are unable to produce
any immunoglobulin at all
• These defects are variably present in patients with CVID, underlying
the significant heterogeneity of this disease population

T cell defect
• Relative loss of T-cell function in many subjects
• Defects in thymic maturation, monocyte/dendritic cell defects and
impaired innate immune responses48 including loss of natural killer
cells
• Several studies have identified
• Decreases in the number of naive CD4 cells in the peripheral blood
• Defective generation of T-cell precursors in the bone marrow
• Decreased numbers of Treg in the peripheral blood

DC defect
• Both plasmacytoid and myeloid DCs are present in decreased number
in the peripheral blood of patients with CVID
• The reason for the decrease in DC number is not known
• No quantitative abnormality of DC precursors in bone marrow and
tissue
Jordan K. Abbott. Immunol Allergy Clin N Am 35 (2015) 637–658

Chronic immune activation
• T cells, invariable natural killer T cells (iNKT) and monocytes
• Elevated sCD14 levels
• Exhausted bacteria-specific T cells and detectable lipopolysaccharide
levels in the plasma who inadequate immunoglobulin replacement
suggests that bacterial translocation from the GI tract
• Adequate IVIg
• transiently decrease numbers of inflammatory monocytes
• Infection prevention
• Antiinflammatory effects

Genetics
• Most cases of CVID are sporadic.
• 5% to 25% are familial, with an AD pattern
• CVID/IgAD families : several putative susceptibility loci identified
within the HLA region on chromosome 6p
• Most of the patients inherited HLA *DQ2, *DR7, *DR3, *B8, and/or
*B44
• Monogenic causes of biallelic deleterious mutations in ICOS,
TNFRSF13C CD19, CD20, CD21, CD81, and TNFRSF13B
• Mutations in various nonredundant genes have been shown to be
disease causing in some patients who fulfill criteria for CVID

Genetics
• Particular polymorphisms in the TACI (TNFRSF13B) and MSH5 genes
may affect the phenotype of about 5% to 8% of the patients with
CVID
• Impair T-cell independent class-switch recombination because
interactions between TACI and its ligands
• APRIL [a proliferation-inducing ligand]
• BAFF [B cell activating factor]

Delfien J A Bogaert et. al. J Med Genet 2016;53:575–590

Genes encoding
receptors ligands

Genes encoding
intracellular signal
molecules

Group Gene Inherit
ance
Onset Clinical spectrum
Gene encoding
receptor and ligands
ICOS deficiency
(3.74%)
AR Infant and
childhood
RTI, GI infections, bacterialskin infections, localised herpes simplex
infections,bronchiectasis, AI (incl. AI cytopenia,
rheumatic disease, IBD), organomegaly, granulomata, malignancy.
TACI Monoall
elic/
biallelic
Early
childhood to
adulthood
BAFF-R Monoall
elic/
biallelic
Infancy to late
adulthood
LRBA (26.4%) AR Infancy to
childhood
Severe AI (incl. AI cytopenia, severe IBD, type 1 diabetes mellitus),
severe (EBV-induced) lymphoproliferation with generalised BLH and
lymphocytic infiltration of organs (eg, kidney, brain), LIP, GLILD,
granulomata
Gene encoding
intracellular signal
molecules
Protein kinase C
delta (2.14%)
AR Infancy to
early
childhood
Severe systemic AI with features reminiscent of SLE , severe (EBV/
CMV-induced) lymphoproliferation with generalized BLH, splenomegaly,
hepatomegaly, RTI, GI infections, UTI, failure to thrive
PIK3 CD (26.7%) AD Infancy to
early
childhood
RTI, GI infections, bacterial skin infections, deep abscesses, warts,
persistent CMV/EBV viraemia, failure to thrive, bronchiectasis, AI (AI
cytopenia, IBD, AI primary sclerosing cholangitis)

Genetics
• Molecular genetic analysis of patients is not a requirement for
conferring the diagnosis
• In light of the possible definitive or supportive therapies (HSCT,
cytokine therapy) that may be afforded to patients with specific
genetic defects

Unusual infections
• Recurrent urinary tract or uterine cervical infections due to
Ureaplasma urealyticum
• Arthritides and lung infections may also be caused by Ureaplasma or
Mycoplasma organisms
• Enteroviral infections may cause meningoencephalitis or a
dermatomyositis- like syndrome
• Opportunistic infections should raise suspicion for a combined
immunodeficiency or diagnosis other than CVID

Chronic lung disease
• Sequelae of recurrent acute infections
• Lymphoid interstitial pneumonia or follicular bronchitis/bronchiolitis
• Airway inflammation: Obstructive or restrictive disease and bronchiectatic changes
• Immune-mediated pathology
• Granulomatous lymphocytic interstitial lung disease
• Although not necrotizing, are not perilymphatic as in sarcoidosis
• Mediastinal lymphadenopthy
• Investigation: chest CT scan → gas transfer obtained at the time of
diagnosis , baseline for comparison in the future
• Mortality in CVID was linked to both structural and functional lung
impairment

Nisha Verma. Lancet Respir Med 2015; 3: 651–60

Bronchiectasis
• Definition : permanent abnormal dilatation of the airways in
conjunction with persistent or recurrent bronchial sepsis
• Chronic productive cough, susceptibility to recurrent exacerbations,
and breathlessness
• The prevalence of bronchiectasis in CVID (23% across a European
cohort of 902 patients)

Bronchiectasis
• Management
• Correction of the underlying defect
(IVIg replacement)
• Sputum clearance training from a
respiratory physiotherapist,
• prevention of further infection
• influenza and Pneumococcal vaccines
Radiologic findings
- Increased bronchoarterial ratio (> 1.5)
- Bronchial wall thickening: normally wall of
bronchus should be less than half the width
of the accompanying pulmonary artery
branch
- mucoid impaction
- Signs described on CT include: : tram-track
sign, signet ring sign, string of pearls sign ,
cluster of grapes sign
https://radiopaedia.org/articles/bronchiectasis

Granulomatous lymphocytic interstitial lung
diseases : GLILD
• Associated with autoimmune cytopenia, splenomegaly, enteritis, and
adenopathy
• Cough and breathlessness. Impairment in gas transfer seems to be
the most frequent abnormality on lung function testing
• DDx : infection, other interstitial lung diseases, and lymphoma
• Investigations : bronchoalveolar lavage (BAL) before the biopsy to
exclude infection
• A higher CD4:CD8 ratio was associated with a more favourable
outcome in terms of lung function decline

Granulomatous lymphocytic interstitial lung
diseases : GLILD
• First-line therapy : High-dose
corticosteroids
• Prednisone 1 mg/kg per day until a
maximum improvement in lung
function and radiology
• Combine IVIg + steroid for patient
who not response steroid alone
Radiologic findings
-Irregular ground-glass nodules in a
peribronchovascular distribution
- bulky mediastinal and hilar
Lymphadenopathy
- ﬂuﬀy tree-in- bud “cotton-in-bud” distribution
Basheer et. al.Clin Respir J. 2018;12:337–343

• Optional treatment
• Rituximab plus azathioprine
(targeting T cells) in a small series :
improved spirometry values and
fewer imaging abnormalities
• Ciclosporin and abatacept

Pulmonary assessment in CVID
• Asymptomatic patients and absence of other biological markers
• CT assessment at diagnosis
• Repeat CT assessments (in our practice every 5 years to limit lifetime
radiation exposure with repeated scanning)
• Annual lung function screening)
• Symptomatic patients
• Serial lung function testing every 6–12 months, depending on severity
• Repeat CT imaging, since lung involvement
• Patients whose genetic defect affects DNA recombination and DNA repair,
leading to radio-sensitivity → Prefer MRI than CT

Diffuse granulomatous disease
• Granulomatous disease or atypical sarcoid like lesions occur in 8% to
22%
• Lungs, lymph nodes, and spleen are commonly affected
• Noncaseating, and microbial associations have not been described
• DDx sarcoidosis : Hypergammaglobulinemia, monocytosis

• Methods
• French DEFI cohort, a prospective study on adults with hypogammaglobulinemia.
• The medical charts of.
• Population
• 436 subjects with CVID
• 59 patients (13.5 %) were diagnosed with GD
• 55 patients (93 %) of the GD cohort were reviewed
• Results
• Corticosteroids were the most frequently used drug.
• Other drugs : cyclophosphamide, hydroxychloroquine, rituximab and methotrexate.
Azathioprine, cyclosporine, mycophenolate mofetil
Jean-Nicolas Boursiquot et. al. J Clin Immunol (2013) 33:84–95

GD+ group
- Lower IgG, lower ALC, lower T cell, lower B cell
- 59 patients (13.5 %) were diagnosed with
GD in one or more organs
- Patients from the GD+ group had a more
severe immune deficiency with lower
CD4+CD45RA+naive T cell (13.9 % vs 31.5
%) and lower CD19+CD27+ memory B cells
(9 % vs 18 %)

- Systemic oral steroids were the most frequently used
drug (54 TR in 31 patients) and most of the complete
responses were achieved with this medication
- Cyclophosphamide, hydroxychloroquine, rituximab
and methotrexate have also led to complete
responses in a few cases
- Complete response was most commonly seen in
lymph nodes

Autoimmunity
• 25% to 30% of the patients
• The most common : ITP, AIHA, Evans syndrome
• Other autoimmune diseases : enteropathy, granulomatous disease,
splenomegaly and splenectomy, low IgA level, and later age of onset

Gastrointestinal disease
• Some form of enteropathy was found in 9% of the patients
• High rate of nonmalignant mortality, possibly due to malabsorption
• Unexplained persistent chronic diarrhea, weight loss, steatorrhea,
and malabsorption with loss of both minerals and fat soluble vitamins
• Bacterial overgrowth is common and can lead to bloating and
worsening diarrhea

Lymphoid hyperplasia
• Cervical, mediastinal, and abdominal lymphoid hyperplasia and/or
splenomegaly are found in at least 20%
• splenomegaly was reported in 26%
• Lymph nodes biopsy : atypical lymphoid hyperplasia, reactive
lymphoid hyperplasia, or granulomatous inflammation
• Clonal lymphocytes is not diagnostic of lymphoma because these can
be found in CVID lymphoid tissue showing reactive hyperplasia
• Splenomegaly can be massive and yet not cause clinical symptoms

Malignancy
• Possibly 6% to 9% of the patients
• Lymphomas are the most common
• Ratio for lymphoma in CVID : normal population was 12:1 and for
stomach cancer was 10:3

Laboratory manifestations
• United States and in Europe have suggested that IgG levels of less
than 4.5 g/L are found in most patients with CVID (85%-94%)
• IgM levels are variable
• IgA levels are low or undetectable in CVID, with 70%
• There are several reported cases of patients with selective IgA deficiency with
normal IgG level at initial evaluation in whom IgG levels slowly decline until
they fulfill laboratory criteria for CVID
• 21% of the patients with CVID may have very low levels or absence of
all immunoglobulin isotypes at presentation

Specific antibody production
• Antigen-specific IgG levels or vaccine responses : within normal limits
at initial presentation, but may decrease over time
• Large proportion of children (73%) retained normal isohemagglutinin
titers and specific antibody responses to protein antigens
• Absent responses to pneumococcal polysaccharide antigens was
noted in 71% of children

Flow cytometry
• Most patients with CVID will have normal levels of total circulating T
cells and natural killer cells in peripheral blood
• B-cell numbers are variable
• 54% of the patients had normal levels (6%-16%)
• 19% had increased levels (>17%)
• 12% had reduced levels (1%-6%)
• 12% had undetectable levels

Flow cytometry
• CD27+IgM-IgD- associated with splenomegaly, granulomatous
disease, possibly chronic lung disease, and autoimmunity
• Transitional B cells (CD38hi IgM hi ) and CD21low B cells associated with
lymphadenopathy and splenomegaly

Late-onset combined immune deficiency
(LOCID)
• 9% of CVID patients
• Decrease in the naive CD4 population (CD45RA+CCR7+CD4+)
• CD4 T-cell count of less than 200 cells/mL
• Opportunistic infection
• Intestinal disease, splenomegaly, lymphomas, and granulomas
• Similar to Good syndrome (without thymoma)

Serum immunoglobulins
• Low IgG and low IgA or low IgM
• Diagnosis merits demonstration of persistently low serum
immunoglobulin levels (as discussed previously) before starting IgG
therapy
• IVIg therapy should not be unduly delayed if harmful condition
• Quantitation of IgG subclasses is not relevant to the diagnosis
• Elevate IgE is unusual in this setting : immune dysregulation

Assessment of vaccine responses
• Vaccine responses should be determined in all patients except those
who present with very low or undetectable IgG levels
• Tetanus and diphtheria toxoids, Haemophilus influenza type B, and
pneumococcal vaccine
• Meningococcus (both protein-conjugate and polysaccharide
preparations) and pure polysaccharide salmonella vaccine
• Other routine childhood vaccines such as measles, mumps, rubella,
polio, hepatitis B, and varicella may sometimes be helpful

Assessment of vaccine responses
• If antigen-specific antibody levels are low on initial measurement,
immunization followed by repeat measurement of specific antibody
levels 3 to 6 weeks later (4 weeks is often considered standard)
• Evaluation of functional antibody responses to T-independent
antigens
• Postimmunization specific IgG level
• May be used reliably in adults and in children older than 12 months

Pneumococcal vaccine Serotype
1 3 4 5 6B 7F 9V 14 18
C
19
F
19
A
23
F
1 2 3 4 5 6B 7F 8 9N 9V 10
A
11
A
12
F
14 15
B
17
F
18
C
19
F
19
A
20 22
F
23
F
33
F
1 4 6B 14 15
B
18
C
23
F
33
F
PCV13
PCV23
LAB
https://www.merckvaccines.com/products/pneumovax23
https://www.prevnar13.com/
6A

Immunoglobulin replacement therapy
• The required IgG dose for an individual patient is unknown
• Dose
• 0.4 to 0.5 g/kg/month for IVIG, Interval every 3-4 weeks
• 0.4 to 0.6 g/kg/month for SCIG
• SCIG in adult 100 to 200 mg/kg/week and dosing intervals from daily to twice
weekly (Vary dose)
• If there is preexisting bronchiectasis, there is evidence for using 0.6
g/kg/month
• Higher doses (0.6-0.8 g/kg/month) for patients with enteropathy or
splenomegaly

Immunoglobulin replacement therapy
• It is possible to use SCIG in patients who previously had severe
adverse effects with IVIG and in those with high titers of IgG anti-IgA
antibodies
• Complication
• Hepatitis B or hepatitis C, are now extremely rare → check AST, ALT annully
• AKI : associated with sucrose-containing products and in patients with
preexisting kidney disease
• Hemolysis and thromboembolic phenomena

Immunization
• Routine boosters of tetanus or diphtheria toxoids or pneumococcus
are probably not necessary for individuals receiving IgG replacement
therapy
• Therapeutic IgG contains significant amounts of neutralizing
antibodies : measles, mumps, rubella, polio, and varicella
• Live attenuated polio, may cause disease in patients with CVID if they
have not yet been diagnosed or if IgG therapy has not been initiated

Treatment of complications
• Rhinosinusitis
• Adequate replacement immunoglobulin therapy
• Adequate antibiotics and/or surgery
• antibiotic prophylaxis CRS, AOM : no controlled trials, expert opinion
• Bronchiectasis
• Baseline chest CT and lung function tests are essential
• Physiotherapy and sometimes prophylactic antibiotics : Azithomycin
• 7% hypertonic saline in conjunction with pulmonary hygiene has been found
to be useful

• Unusual infections (Ureaplasma or Mycoplasma infections)
• Macrolide antibiotic to which the organism is sensitive
• High-dose IVIG with measurable titer antibody to the infecting serotype may
be helpful
• Granulomatous disease
• Corticosteroids, in low doses for long periods
• Steroid sparing drugs: azathioprine, cyclosporine, Infliximab

• Enteropathy
• Biopsies of the intestinal mucosa for diagnosis
• CVID is not responsive to gluten withdrawal
• azathioprine or 6-mercaptopurine, can be used safely
• Infliximab : severe enteropathy
• Interstitial lung disease → High mortality
• All patients should have at least 1 high-resolution CT scan at diagnosis
• at least annually with spirometry

HSCT
• HSCT have not been considered to have an important role in the
treatment of CVID
• Significant procedure-related mortality in those receiving HSCT
• The indication for HSCT
• Hematologic malignancy → Survivial rate 83%
• Other conditions : refractory to conventional therapies: autoimmune
cytopenias, respiratory or gastrointestinal infections,
interstitial/granulomatous lung → Survival rate 33 %

• Objective:
• We sought to define the outcomes of HSCT for patients with CVID
• Methods:
• Retrospective data were collected from 14 centers worldwide on patients
with CVID receiving HSCT between 1993 and 2012
Claudia Wehr et. al. JACI. 2015

Summary
• HSCT in patients with CVID might improve PID-related complications
and cure hypogammaglobulinemia
• but is associated with high mortality and high GvHD incidence.
• Cure of this chronic disease is possible, but patient selection and
transplant refinement are critical.

Children
• The main goal of treatment: decrease the morbidity and mortality
associated with recurrent infections
• Higher doses of IgG replacement therapy (800 mg/kg IVIG every 4
weeks) result in fewer infections
• Complications in children are common
• Recurrent infection effect growth
• Bronchial hyperreactivity

Pregnancy
• Plasma dilution in the third trimester of pregnancy results in a modest
reduction in serum IgG trough levels
• It is advisable to increase the replacement IgG dose during this time
and for delivery

Common variable immunodeficiency

Common variable immunodeficiency

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Common variable immunodeficiency

Similar to Common variable immunodeficiency (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Common variable immunodeficiency