Common variable immunodeficiency

Common Variable
Immunodeficiency
24th April 2020
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit, King Chulalongkorn Memorial Hospital

Outline
• Definition
• Epidemiology
• Pathogenesis
• Genetics
• Clinical Manifestation
• Management
• Immunization

Definition
Common variable immunodeficiency (CVID) is a heterogeneous disorder
characterized by hypogammaglobulinemia, poor response to vaccination
and increased susceptibility to recurrent bacterial infections.
It is the most frequent symptomatic antibody deficiency, with a wide variety
of infectious and noninfectious complications.
J Investig Allergol Clin Immunol 2020 Vol. 30(1)

Definition CVID by WHO
“less well-defined antibody
deficiency syndromes”
Francisco A. Bonilla et. al. JACI in practice. 201
History
2016
ICON
1971
The International Union of
Immunological Societies Expert
Primary Immunodeficiency
Committee 2009 :
heterogeneous nature of these
hypogammaglobulinemic states
2009
1999
Conley ME et al,
Diagnosis criteria,PAGID & ESID
Immunoglobulin level <-2SD
(IgG,IgA,IgM)
2013
Ameratunga et al,
Age ≥ 4 years
Clinical and immunological criteria
Histologic markers
2014 2019
ESID registry,
Age ≥ 4 years
Clinical &immunological
criteria
ESID reclassified ,
Age ≥ 4 years
Clinical & immunological
criteria

R. Ameratunga. Clinical and Experimental Immunology,2013, 174: 203–211
ABC or ABD : Probable CVID ,
long term IVIG/scIG
A, AB,AC,AD : possible CVID
Not A : hypogammaglobulinemia of
uncertain significance
≥1
≥3

Bonilla et. al. JACI in practice. 2016
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.
1.Hypogammaglobulinemia should be defined according to the age adjusted
The IgG level must be repeatedly < 2SD more than 3 weeks apart.
if IgG level is very low (<100-300 mg/dL depending on age).
2.IgA or IgM level must also be low.
Note that some experts prefer a more narrow definition requiring low IgA level
in all patients
3.Impairment of response to at least 1 type of antigen
(T-dependent and T-independent ) ; esp IgG level of more than 100 mg/dL
International consensus
Document 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.
International consensus
Document of CVID
4.Other causes of hypogammaglobulinemia must be excluded (Table I).
5.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

Differential diagnosis of hypogammaglobulinemia
Drug induced
Infectious disease
Single gene defect
Chromosomal anomalies
Malignancy
Excessive loss

2016 2013

Disease Clinical criteria for a probable diagnosis
(= clinical diagnosis classification)
Suggestions for alternative
diagnosis
(i.e. if these criteria are not
completely fulfilled)
Common variable
immunodeficiency
disorders (CVID)
At least one of the following:
• increased susceptibility to infection
• autoimmune manifestations
• granulomatous disease
• unexplained polyclonal lymphoproliferation
• affected family member with antibody deficiency
AND marked decrease of IgG and marked decrease of IgA with or without
low IgM levels (measured at least twice; <2SD of normal levels for age)
AND at least one of the following:
• poor antibody response to vaccines (and/or absent isohemagglutinins );
i.e., absence of protective levels despite vaccination where defined
• low switched memory B cells (<70% of age-related normal value)
AND secondary causes of hypogammaglobulinemia have been excluded
(e.g., infection, protein loss, medication, malignancy)
AND diagnosis is established after 4th year of life (symptoms may be present before)
AND no evidence of profound T-cell deficiency, defined as 2 out of the following
• CD4 numbers/microliter: 2-6y <300, 6-12y <250, >12y <200
• % naive of CD4: 2-6y <25%, 6-16y <20%, >16y <10%
• T cell proliferation absent
For patients <4 years old or
patients with incomplete
criteria please consider
“Unclassified antibody
deficiency”.
For patients with evidence of
profound T-cell deficiency, pl
ease consider Combined
immunodeficiency.
ESID Registry - Working definitions for clinical diagnosis of IEI January 22, 2019

Disease Clinical criteria for a probable diagnosis
(= clinical diagnosis classification)
Suggestions for
alternative
diagnosis
Unclassified
antibody
deficiency
At least one of the following:
• Recurrent or severe bacterial infections
• Autoimmune phenomena (especially cytopenias)
• Polyclonal lymphoproliferation
• Affected family member
AND at least one of the following:
• marked decrease of at least one of total IgG, IgG1, IgG2, IgG3, IgA or IgM levels
• failure of IgG antibody response(s) to vaccines
AND
secondary causes of hypogammaglobulinemia have been excluded (e.g., infection,
protein loss, medication, malignancy)
AND
no clinical signs of T-cell related disease AND does not fit any of the other working
definitions (excluding ‘unclassified immunodeficiencies’)
ESID Registry - Working definitions for clinical diagnosis of IEI January 22, 2019

J Clin Immunol (2020) 40:66–81

Epidemiology
Antibody deficiencies are the most common defect among PIDs and affect
30%-70% of all patients identified with a specific defect.
Prevalence of 1:25,000-1:50,000 affecting male and female equally
CVID is the most frequent symptomatic antibody deficiency diagnosed in adulthood
Geographic disparities in the prevalence of CVID, as follows:
North America (n=6443) Europe (n=4279) Asia (n=459),
Australia (n=657) Africa (n=156).
The highest prevalence of CVID in the USA (40.2% of all PID patients),
The lowest rates were observed in the Middle East (2.6%) and Africa (1.3%) .
Yazdani R, et al.J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-
34

P. Benjasupattanan et al. J Clin Immunol. 2009; 29:357-364.
Incidence in Thailand
Primary Immunodeficiency Diseases; A 20 Years
Experience in a Tertiary University Hospital at Ramathibodi
O. Luecha et al. J Allergy Clin Immunol. 2012.

Pathogenesis
Yazdani R, et al.J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-
34
Surface molecular defect
CVID
monogenetic
Complex disease
Cytosolic defect
Nuclear defect

• Most cases of CVID are sporadic.
• 5% to 25% are familial, with an AD pattern
• CVID/IgA deficiency 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
Jordan K. Abbott. Immunol Allergy Clin N Am 35 (2015) 637–658

Estimated share of each disease gene within the common variable immunodeﬁciency population based on published cases
Delfien J A Bogaert et. al. J Med Genet 2016;53:575–590

Surface molecule defect
• 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 bet
ween TACI and its ligands
• APRIL [a proliferation-inducing ligand]
• BAFF [B cell activating factor]
Mutation in TNFRSF13B or TACI occur 10% of CVID
Autosomal dominant
Increase risk of lymphoproliferation and
autoimmunity

Surface molecular defect
1
2
3
4

Cytosolic defect

Nuclear defect

Monogenetic defects associated with CVID
Picard Cet al. Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol 2018;
J Clin Immunol (2020) 40:24–6442

• Molecular genetic analysis of patients is not 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.
- Genetic work up in monogenic CVID
- patients with severe complication ,
- patients recurrent infection without complication
- early disease onset (present infancy or early childhood)
- positive family history or consanguinity
Genetics

Pathogenesis
Yazdani R, et al.J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-34
Immune cell
abnormality
B cell subsets
T cell subsets
Dendritic cell
Innate lymphoid cell
Monocyte/Macrophage
NKT cell
• Decrease
isotype-switched B cells ,IgM memory B cell
Plasma cell
• Decreased plasmacytoid and myeloid DCs
• No quantitative abnormality of DC precursors
in bone marrow and tissue
• Decreases number of naive CD4 cells, Treg
in peripheral blood
• Defective generation of T-cell precursors in BM
• no difference
• increase IL-12 monocyte

B cell defect

• Decrease T cells, invariant 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
• Anti-inflammatory effects
Chronic immune activation

Infections
• Infections are the most typical clinical manifestations of CVID and involve the
respiratory and gastrointestinal tracts.
• upper and lower respiratory tract are the most common sites of infection.
• Encapsulated bacterial pathogen :
Streptococcus species, Haemophilus species,
Moraxella catarrhalis, Neisseria meningitides,
Staphylococcus species and Mycoplasma species
• Viral pathogens : Rhinovirus and Herpes zoster (HHV8) , EBV
• Opportunistic infections by Pneumocystis jiroveci and Cytomegalovirus are
CVID with low CD4 T cell

Infections
Major lung complication : Bronchiectasis and interstitial lung disease
Immunoglobulin replacement : decrease frequency sinusitis ,
bronchitis ,otitis media
- GI infection : present chronic or acute diarrhea
Common pathogen : Giardia lamblia , Campylobacter jejuni and
Salmonella species.

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
dermatomyositis- like syndrome
• Opportunistic infections should raise suspicion for combined
immunodeficiency or diagnosis other than CVID

Complication Chronic lung disease
• Sequelae of recurrent acute infections
• Lymphoid interstitial pneumonia or follicular bronchitis/bronchiolitis
• Airway inflammation: Obstructive or restrictive disease and bronchiectasis changes
• Immune-mediated pathology
• Granulomatous lymphocytic interstitial lung disease
• Although not necrotizing, are not peri-lymphatic as in sarcoidosis
• Mediastinal lymphadenopathy
• Investigation: HRCT scan → gas transfer obtained at the time of diagnosis
, baseline for comparison in the future
• Mortality in CVID was linked to structural and functional lung impairment
CINETTO ET AL.PRIMARY ANTIBODY DEFICIENCIES.Eur Respiratory review 2018;27

CINETTO ET AL.PRIMARY ANTIBODY DEFICIENCIE
S.Eur Respiratory review 2018;27
Pathogenesis of bronchiectasis & COPD
in primary antibody deficiencies (PAD).

• Permanent abnormal dilatation of the airways in conjunction with
persistent or recurrent bronchial infection
• Clinical : chronic productive cough, susceptibility to recurrent exacerbations,
and breathlessness
• Prevalence of bronchiectasis in CVID (23% across a European cohort of 902 pt)
• Radiologic findings : Increased bronchoarterial ratio (> 1.5) , Bronchial wall thickening
mucoid impaction , tram-track sign, string of pearls sign on HRCT
• Management
- Correction of the underlying defect (IVIg replacement) for decrease risk infection
- Sputum clearance training from a respiratory physiotherapist
- Prevention of further infection , influenza and Pneumococcal vaccines
Complication : Bronchiectasis
Nisha Verma. Lancet Respir Med 2015; 3: 651–60

SCHUSSLER ET AL.ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2016
Complication : Bronchiectasis
Treatment algorithm for management of
bronchiectasis in patients with PAD
Bronchiectasis : irreversible dilation
of the bronchial airways
caused by inflammatory destruction
of airway walls.
- Bronchiectasis were significantly
have CD4 T-cell < 700 cells/mL
-Indicated for patient surveillance imaging
with CVID
- low CD4 T-cell counts
- history of pneumonia
- low serum IgM levels

Interstitial Lung Disease
- ILD occurs in at least 10% to 20% of patients with CVID
-symptoms : chronic cough and shortness of breath and are hence quite
nonspecific. Biopsies may be necessary for diagnosis of ILD in PAD
-Radiologic findings of ILD in CVID are pulmonary nodules, ground glass
opacities, and mediastinal lymphadenopathy
-PFT : restrictive lung disease resulting in reductions in FVC and/or
decrease DLCO
-Lung biopsy : granulomatous lymphocytic ILD is a term used exclusively
for CVID

Interstitial Lung Disease

SCHUSSLER ET AL.ALLERGY CLIN IMMUNOL
PRACT NOVEMBER/DECEMBER 2016
Treatment algorithm for
management of ILD in
patients with PAD.

• 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
• Investigations : bronchoalveolar lavage (BAL) before the biopsy to exclude infection
• A higher CD4:CD8 ratio was associated with a more favorable outcome in terms of
lung function decline
• Treatment : 1st line therapy High dose corticosteroid
combine IVIg + steroid for who not response steroid alone
Granulomatous lymphocytic interstitial lung diseases : GLILD
• Radiologic finding : Irregular ground-glass nodules
in a peri-bronchovascular distribution
- bulky mediastinal and hilar Lymphadenopathy
-fluffy tree-in- bud “cotton-in-bud” distribution

Routine monitoring
- Putative extrapulmonary predictors of GLILD (splenomegaly, autoimmunity, liver
disease, B-cell flow-cytometric) are routinely assessed in all PAD patients
- Spirometry before & after bronchodilator at diagnosis and annually
- DLCO measurement annually
- Blood gas analysis as conventionally indicated
- HRCT: at diagnosis (if not recently performed) and every 5 years. HRCT is part
of the initial evaluation aimed to a tailored therapeutic approach that includes
the choice of Ig replacement therapy dosage, route and frequency, adjunct of
antibiotic prophylaxis and/or need pulmonary rehabilitation & exercise training
- Lung MRI: currently under evaluation as radiation-sparing imaging technique
monitor and manage lung disease in primary antibody deficiencies

• Asymptomatic patients and absence
of other biological markers
- CT assessment at diagnosis
- Repeat CT assessments (in our practice
q 5 years to limit lifetime radiation exposure
with repeated scanning)
- Annual lung function screening
Pulmonary assessment in CVID
• Symptomatic patients
- Serial lung function testing q 6–12 mo,
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

Monitor & manage lung disease in primary antibody deficiencies
ILD suspicion (cough, dyspnea on exertion, DLCO reduction, restrictive PFT pattern)
Investigation
- 6MWT as first choice exercise testing
- HRCT scan repetition
- Bronchoscopy is in most cases the first invasive step, both for microbiology and
BALF cytology, with lymphocytes sub-population analysis
- A trans-bronchial biopsy or mediastinoscopy (lymphoproliferative disease)
Treatment:
asymptomatic : IgG replacement level (higher trough levels),
concomitant bronchiectasis : prophylactic azithromycin
symptomatic : steroid treatment (20–40 mg of prednisone)

• 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
Treatment
- Systemic oral steroids were the most frequently used drug and most of the complete
responses
- Cyclophosphamide, hydroxychloroquine, rituximab and methotrexate have also led to
complete responses in a few cases
- Complete response was the most commonly seen in lymph nodes
Diffuse granulomatous disease
Jean-Nicolas Boursiquot et. al. J Clin Immunol (2013) 33:84–95

Autoimmunity
-Autoimmunity is present in 21% to 42% of the patients
-Presentation : autoimmune cytopenia (ITP, AIHA and Evans syndrome)
rheumatologic autoimmune
-Other autoimmune diseases : enteropathy, granulomatous disease,
splenomegaly and splenectomy, low IgA level, and later age of onset

Resnick ES.,et.al. Blood. 2012;119(7):1650-1657
CVID: Clinical phenotype
Autoimmune diseases (20% )

• 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
• Complication : granulomatous disease and lymphopenia
Gastrointestinal disease : Enteropathy

GI manifestations in CVID
GI symptoms GI Infection
GI complition
Barmettler et al. J ALLERGY CLIN IMMUNOL PRACT .APRIL 2020

• Incidence of malignancy : 2.5% in children , 8.5% in adult
• Cervical, mediastinal, and abdominal lymphoid hyperplasia and/or
splenomegaly are found in at least 20%
• Lymph nodes biopsy : atypical lymphoid hyperplasia, reactive lymphoid
hyperplasia, or granulomatous inflammation
• polyclonal lymphadenopathy increase risk non-Hodgkin B-cell lymphoma
being 2-10% for CVID patients.
• Splenomegaly can be massive and yet not cause clinical symptoms
• CVID patients are prone to develop malignant gastric cancers (EBV and H pylori)
Lymphoid hyperplasia and Malignancy

• United States and in Europe have suggested that IgG levels of < 4.5 g/L are
found in most patients with CVID (85%-94%)
• IgA levels are low or undetectable in CVID, with 70%
• 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 patients with CVID may have very low levels or absence of all immuno
globulin isotypes at presentation
• IgM levels are variable
• Antigen-specific IgG levels or vaccine responses : within normal limits at initial
presentation, but may decrease over time , normal isohemagglutinin titers
• Absent responses to pneumococcal polysaccharide antigens was noted in 71%
of children
Laboratory manifestations

Laboratory manifestations
• normal levels of total circulating T cells and NK 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
• CD27+IgM-IgD- associated with splenomegaly, granulomatous disease, p
ossibly chronic lung disease, and autoimmunity
• Transitional B cells (CD38hi IgM hi ) and CD21low B cells associated with
lymphadenopathy and splenomegaly
Flow cytometry

• 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)
Late-onset combined immune deficiency (LOCID)
• Low IgG and low IgA or low IgM
• Elevate IgE is unusual in this setting : immune dysregulation
• Diagnosis : persistently low serum immunoglobulin levels
• Quantitation of IgG subclasses is not relevant to the diagnosis
Serum immunoglobulins

• Vaccine responses should be determined in all patients except those
who present with very low or undetectable IgG levels
• Tetanus and diphtheria toxoids, H. influenza type B, and
pneumococcal vaccine
• If antigen-specific antibody levels are low on initial measurement,
immunization followed by repeat of specific antibody levels
3 - 6 wks later (4 wk is often considered standard)
• Evaluation of functional antibody responses to T-independent antigens
Postimmunization specific IgG level, in adults and children > 2 yrs
Assessment of vaccine responses

Treatment
1. Immunoglobulin replacement therapy
2. Immunization
3. Treatment of complications
4. Special considerations

Management
• The required IgG dose for an individual patient is unknown
• Dosage : 0.4 to 0.5 g/kg/month for IVIG, Interval q 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 preexisting bronchiectasis, there is evidence for using 0.6 g/kg/dose
• Higher doses (0.6-0.8 g/kg) for patients with enteropathy or splenomegaly
Immunoglobulin replacement therapy

Management : Immunization
A. Bonilla et al. J Allergy Clin Immunol. 2015; 136(5), 1186–1205.
Diagnosis IgG
replacement
HSCT Gene therapy other
CVID Yes Rare no Avoid all live vaccines
Antibiotic prophylaxis
Splenectomy
Immunomodulation
Chemotherapy
Inactivated influenza vaccine is recommended in patients with
antibody deficiency receiving IVIG

Cunningham-Rundles. Non-infectious Complications in CVID.Frontiers in Immunology .1 February 2020 . Volume 11 , Article 149.
Non-infectious complications
CVID is reflected clinically
in broad spectrum of
non-infectious manifestation,
which can lead to further
sequelae with disease
progression and increased
mortality

• Chronic lung disease was the most common organ-specific complication
• interstitial disease and bronchiectasis were the most common findings,
with lymphoma at this site being a rare (n = 6), but serious, manifestation
Chronic lung disease and associated complications
Interstitial lung disease pathology

Cunningham-Rundles. Non-infectious Complications in CVID.Frontiers in Immunology .1 February 2020 . Volume 11 , Article 149.
Non-infectious complications
Autoimmunity
Immune thrombocytopenic purpura (ITP),
AIHA were common (16.2%,7.7%)
Gastrointestinal disease and malabsorption in
CVID are associated with increased mortality
intraepithelial lymphocytosis (64.7%, n = 22)
villous atrophy/blunting (32.4%, n = 11),
nodular lymphoid hyperplasia (8.8%, n = 3)

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 PFT are essential
• Physiotherapy and sometimes prophylactic anti
biotics : Azithromycin
• 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, Inflixi
mab

Enteropathy
• Biopsies of the intestinal mucosa for diagnosis
• CVID is not responsive to gluten withdrawal
• prednisolone , azathioprine or 6-mercaptopurine,
can be used safe
• Infliximab : severe enteropathy
Interstitial lung
disease
• At least annually with spirometry
• azathioprine and rituximab  pt with granulomatous/
lymphocytic infiltrates
• Corticosteroids + cyclosporine prominent T cell infiltrate
• Anti-TNF antibody complex interstitial lung disease
• High mortality
• All patients should have at least 1 HRCT scan at diagnosis

B-cell and T-cell dysregulation and immunophenotypic
characteristics of autoimmunity in CVID.
Gereige and Maglione Current Understanding of CVID Autoimmunity. Frontiers in Immunology.December 2019.Volume 10

Treatment of autoimmunity in CVID

Pecoraro et al.Clin Mol Allergy. 2019; 17: 9.
Rituximab
(antiCD20 monoclonal antibody)
- B-cell depletion
- ADCC
- CMC
- Induction of apoptosis
- T cell
- decrease Th1 cells
- increase Th2 and Treg cells

Abatacept, CTLA-4 immunoglobulin fusion protein, considered CTLA-4 replacement
precision therapy dose of 500-750mg X2 as monthly intravenous infusions
for these patients, has been used to treat autoimmune manifestations.
Uzel G, et al. Management of cytopenias in CTLA4 haploinsufficiency using abatacept and sirolimus. Blood. (2018)

STAT3 GOF mutations,
IL-6 emerged as a potential target for treatment.
Tocilizumab, an IL-6 receptor antagonist, was trialed successfully
Flanagan SE et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. (2014) 46:812–4.

Forbes LR, et al. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator
of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. (2018) 142:1665–9.
Jakinibs, inhibitors of Janus kinases (JAKs)
involved in the activation cascade of STAT3,
have been used adjunctly with tocilizumab .
the combination of IL-6 blockade and
Jakinibs may be the most effective
treatment strategy for patients with
STAT3 GOF mutations

PIK3CD mutations have focused on the mTOR pathway inhibitor,
- Rapamycin. A cohort of 26 APDS patients from the ESID registry were treated
excellent effects on the lymphoproliferative aspect of the disease,
but less promising results on autoimmune cytopenia and enteropathy
- Leniolisib: early results of the clinical trial published in 2017 showed
improvement in lymphoproliferation as well as cytopenia . (phase3 trial)
Rao VK, et al. Effective “activated PI3Kd syndrome”-targeted therapy with the PI3Kd inhibitor leniolisib key points. Blood. (2017)130:2307–16.

PIK3CD mutations have focused on the
mTOR pathway inhibitor,
- Rapamycin. A cohort of 26 APDS patients
from the ESID registry were treated
excellent effects on the lymphoproliferative
aspect of the disease, but less promising results
on autoimmune cytopenia and enteropathy
- Leniolisib: early results of the clinical trial published in
2017 showed improvement in lymphoproliferation as well
as cytopenia .
Rao VK, et al. Effective “activated PI3Kd syndrome”-targeted therapy with the PI3Kd inhibitor leniolisib key points. Blood. (2017)130:2307–16.

• - Hematologic malignancy : Lymphoma
• - refractory to conventional therapies: autoimmune cytopenia, respiratory
or gastrointestinal infections, interstitial/granulomatous lung disease,
and/or autoimmune enteropathy
Chemotherapy
persistent hypertrophy of lymph nodes
 lymphoma or autoimmune
lymphoproliferative syndrome Rx  Corticosteroid
An acute increase in adenopathy or splenomegaly
 possible malignant transformation.
Lympho
proliferation
HSCT
Survived 33%
lymphoma

• 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 → Survival rate 83%
• Other conditions : refractory to conventional therapies:
autoimmune cytopenia , respiratory or gastrointestinal infections,
interstitial/granulomatous lung → Survival rate 33 %
HSCT
• HSCT in CVID might improve PID-related complications and
cure hypogammaglobulinemia
• high mortality and high GvHD incidence.
• Cure of chronic disease is possible (selection & transplant refinement)
Claudia Wehr et. al. JACI. 2012

CVID: Surveillance
• Lifetime surveillance for cancer and autoimmunity
– no standardized specific recommendations for routine or testing or imaging
– Routine monitoring studies related to IgG replacement
( CBC, LFT, BUN, Cr: minimal of q 6-12 months)
• For those patients who remain healthy on replacement immunoglobulin
– At a minimum, age-appropriate cancer screening as general healthy population
– Colonoscopy, prostate examination, pap smears, mammograms
Park MA,et.al. Lancet 2008; 372: 489–502
Francisco A, et al. Practice parameter, JACI 2015

Special consideration
Children
• main goal of treatment: decrease morbidity and mortality associated with
recurrent infections
•Treatment : 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 replacement IgG dose during this time and for delivery

Common variable immunodeficiency

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