Common variable immunodeficiency

Common Variable
Immunodeficiency (CVID)
F1 Pongsawat Rodsaward

Outline
•Epidemiology
•Pathogenesis
•Clinical manifestation
•Diagnostic criteria
•Classification
•Management
•Prognosis

Epidemiology
•A study compiling and analyzing various national registries to extrapolate
the worldwide prevalence of PID
• Estimated incidence of PID was highest in children (reaching 21.9/100,000 in the
0-4-year age range)
• Overall 69.4% of all new worldwide PID cases are diagnosed at age over 15
years
• More than 50% are diagnosed at ages over 25 years
J Allergy Clin Immunol Pract. Nov-Dec 2016;4(6):1101-1107.

Epidemiology
•In a Canadian study, of 381 adult patients referred to the Immune
Deficiency Treatment Center of the McGill University Health Center over a
10-year period, more than half (210) of the patients were found to have a
PID.
•In an earlier study, of 237 patients of all ages referred to the Mount Sinai
Immunology Center, 113 were diagnosed with PID, and within this group,
the mean age of diagnosis was 31.5 years.

Epidemiology
•There are no precise data on the prevalence of CVID, but it has been
estimated at between 1:100,000 and 1:10,000 of the population.
•The calculated prevalence of CVID in these European countries ranges
from 0.07 to 0.98 patients per 100,000 inhabitants.
• The reported prevalence in Japan is also within this range (0.25:100,000).
•Discrepancies between these reports are likely a result of different
methodologies and their influences on various forms of ascertainment bias.
J Allergy Clin Immunol Pract. Jan-Feb 2016;4(1):38-59.

Front Immunol. 2021 Mar 23;12:620709.

Pathogenesis
•The exact mechanism of action remains unknown.
•The percentage of patients with monogenic defects associated with CVID
has increased to about 20%-25%.
•Most pathogenetic studies in CVID address disturbed long lived humoral
memory response.
Stiehm's Immune Deficiencies, 2nd Edition

Disturbed long lived humoral memory response
•About 1/3 of CVID patients have a partial block at the preB1 to preB2
transition during central B cell development, possibly suggestive of an
altered (Pre)B-cell receptor (BCR) signaling.
•The inability to produce Ig is a reflection of the deficiency of circulating
isotype-switched memory B cells and plasmablasts.

Middleton's Allergy: Principles and Practice, Ninth Edition

Genetic and molecular defect
• ICOS
• TACI
• BAFF-R
• B cell co-stimulatory receptors
• IKAROS
• IL21, IL21-R
• CD27
• Deficiency in genes linked to immune regulation
• Others

Abbas- Cellular and Molecular Immunology, Tenth Edition

Abbas- Cellular and Molecular Immunology, Tenth Edition
Inducible T cell co-stimulator/ CD278

Monogenic defects- Inducible co-stimulator (ICOS)
• Autosomal recessive mutations
• First monogenic cause of CVID, identified in a German cohort of CVID patients.
• ICOS is expressed on activated T cells and is one of the essential co-stimulatory
molecules on TFH cells during the germinal center response.
• In the absence of ICOS, the germinal center responses are not able to fully mature
and T-dependent antibody responses fail.
• The ICOS disease spectrum has expanded from a pure B-cell to combined B and
T-cell immune deficiency, suggesting genetic and environmental modifiers.

Monogenic defects
•Transmembrane activator and calcium-modulator and cyclophilin ligand
interactor (TACI, TNFRSF13B)
• TACI, as well as the BAFF-R belong to the TNF receptor family
• Involved in B-cell survival, activation and differentiation
• These are autosomal dominant generally with some variants found in
homozygosity but the same mutations have also been observed in relatives of
patients
• Healthy individuals with normal immunoglobulin levels, rendering TACI an
important modifying but not disease-causing gene in CVID.

Monogenic defects- BAFF-R deficiency
•BAFF is the important survival signals are delivered to maturing B cells.
•Maturation of follicular B cells particularly depends on BAFF-BAFFR
signaling.
•AR Inheritance
• Two siblings carrying a homozygous deletion in the BAFF-R gene
• B-cell development is arrested at the stage of transitional B cells and the
numbers of all subsequent B-cell stages are severely reduced

Monogenic defects
•Defects of the B cell co-stimulatory receptors:
• Both CD19 and CD81 deficiency presented with childhood onset recurrent
respiratory infections, and sometimes skin (1/10) or gastrointestinal infections
(3/10).
• CD21 deficient patients have a milder phenotype with mainly respiratory tract
infections in the presence of low IgG and variable IgA and IgM levels.

Immunol Rev. 2021 Mar;300(1):82-99.

Monogenic defects- IKAROS Deficiency
• IKAROS proteins are lymphoid-restricted zinc finger transcription factors,
considered as master regulators of hematopoiesis.
• Somatic and germline mutations have been linked to the occurrence of acute
lymphoblastic leukemia.
• The patients identified had moderate to profound hypogammaglobulinemia, loss
of antibody production and often severe B cell deficiency.
• Most patients have had early onset recurrent bacterial infections, some have
autoimmunity or organ inflammation; a few have had disturbed hematopoiesis or
acute lymphoblastic leukemia (ALL).

Monogenic defects- IL21
•Autosomal recessive mutation
•Early onset inflammatory bowel disease with pathology similar to Crohn’s
disease, with oral aphthous ulcers.
•Recurrent infections due to hypogammaglobulinemia (IgG deficiency) in
the only currently identified child.
•Reduced B cell numbers and dramatically reduced class-switched memory
B-cells, but increased serum IgE.

Monogenic defects- IL21R
•Autosomal recessive IL21R gene defects were found in five children of
three kindreds.
•Four patients had cryptosporidiosis associated with chronic cholangitis and
severe liver disease affecting survival and transplantation outcome, while
the only child without cryptosporidiosis did well after transplant.
•Reduced class-switched CD27+ memory B cells and impaired specific
antibody responses to immunization antigens.
•Increased serum IgE

Monogenic defects- CD27
•CD27 is the surface marker of memory B cells
• is an essential costimulatory molecule that regulates the function and survival of
T-cells and NK cells.
•Homozygous mutations lead to a combined immune deficiency
• Decreased numbers of switched memory B cells
• Hypogammaglobulinemia
• Severe T cell and NK defects leading to persistent EBV viremia.

Monogenic defects
•Deficiency in genes linked to immune regulation
• PIK3CD and PIK3R1
• Lipopolysaccharide-responsive beige-like anchor protein (LRBA)
• Cytotoxic T lymphocyte antigen-4 (CTLA4)
• Phospholipase Cg2eAssociated Antibody De ficiency and Immune Dysregulation
(PLCG2)
• Protein Kinase C delta deficiency
• Nuclear factor Kappa-B (NFkB)

Monogenic defects- PIK3CD and PIK3R1
• Activated Phosphoinositide 3-kinase delta syndrome (APDS) is due to autosomal
dominant mutations in the catalytic subunit of 110 kDa (PIK3CD) or the 85 kDa
regulatory subunit (PIK3R1).
• Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-
trisphosphate and phosphorylated AKT protein and were prone to activation-
induced cell death.
• Some of the APDS patients present as CVID.
• Laboratory clues may be an elevated IgM.
• Targeted therapies with mTOR inhibitors and selective PI3Kd inhibitors.
OMIM

Monogenic defects- Cytotoxic T lymphocyte antigen-4 (CTLA4)
•Patients typically present with an immune dysregulation syndrome
characterized by extended lymphocytic activation and organ infiltration
manifesting in most cases with autoimmune cytopenias, enteropathy and
granulomatous infiltrative lung, even inflammatory CNS lymphoma.

Monogenic defects- Cytotoxic T lymphocyte antigen-4 (CTLA4)
•Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte
antigen 4-insufficient subjects
• In total, 14 affected mutation carriers received the CTLA-4 fusion proteins
abatacept or belatacept, 11 of whom responded with an improvement in their
clinical symptoms.
J Allergy Clin Immunol. 2018 Dec;142(6):1932-1946.

Monogenic defects- Lipopolysaccharide-responsive beige-like
anchor protein (LRBA)
• LRBA (lipopolysaccharide inducible cytosolic protein) localized in the vesicles
and endoplasmic reticulum of almost all cell types.
• protect CTLA-4 in T cells from lysosomal degradation
• Usually present early in life, a combined immune deficiency, resembling complex
forms of CVID.
• LRBA deficient patients commonly suffer from early onset autoimmunity
(commonly hemolytic anemia or ITP), enteropathy, interstitial lung disease,
splenomegaly and in some cases opportunistic infections.
• Patients may benefit from treatment with targeted immunosuppressive.

Monogenic defects
Defect Clinical other than CVID
PTEN deficiency Cowden’s syndrome
TRNT1 deficiency Congenital sideroblastic anemia
PLCG2 deficiency PLCG2 associated antibody deficiency
and immune dysregulation (PLAID)
- cold urticaria

Epigenetic Changes
•Epigenetic mechanisms can influence gene expression without altering the
germline DNA gene sequences and play an important role in the normal
developmental program of immune cells.
•The mechanisms described to date include DNA methylation, chromatin
modulation, histone modification, transcription factor expression, and
noncoding RNAs (ncRNAs).
J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-34

Epigenetic Changes
•A study of monozygotic twins who were discordant for a diagnosis of CVID
revealed a higher degree of DNA methylation in the switched and
nonswitched memory B cells of the patient when compared with the healthy
sibling.
J Investig Allergol Clin Immunol 2020; Vol. 30(1): 14-34

Clinical manifestation
•Infection
•Autoimmune disease
•Malignancy

Oman Med J. 2020 Jul 30;35(4):e157

Infection (Respiratory System)
•The upper and lower respiratory tract are the most common sites of
infection.
•Bronchiectasis and interstitial lung disease are major lung complications
that manifest after recurrent and severe lung infections.
•Organism
• Streptococcus pneumoniae, H. influenzae, Moraxella catarrhalis, Mycoplasma
J Investig Allergol Clin Immunol. 2020;30(1):14-34

Infection (Gastrointestinal System)
•Gastrointestinal tract infections manifest in form of chronic or acute
diarrhea.
•Organism
• Giardia lamblia
• is the most commonly identified pathogen
• Campylobacter jejuni
• Salmonella species
J Investig Allergol Clin Immunol. 2020;30(1):14-34

Late-Onset Combined Immune Deficiency (LOCID)
•A Subset of Common Variable Immunodeficiency with Severe T Cell Defect
•Severe T Cell Defect
• Experienced OIs AND/OR had a CD4 T cell count <200 cells/L
Clin Infect Dis. 2009 Nov 1;49(9):1329-38.

LOCID

Differential diagnosis
• Recurrent sinopulmonary infection
• Anatomy and physiologic defect
• Immotile cilia syndrome
• Cystic fibrosis
• Immune cell defect
• Asplenia
• B cell deficiency
• Secondary immunodeficiency
• Infection mimic
• Pulmonary vasculitis or bronchiolitis obliterans organizing pneumonia (BOOP)

Autoimmune disease
•Autoimmune Hematologic Disease
•Autoimmune Pulmonary Disease
•Autoimmune Gastrointestinal Disease
•Autoimmune Rheumatologic Disease
•Autoimmune Dermatologic Disease
Ann Allergy Asthma Immunol 123 (2019) 454-460

Front Immunol 2021 Jul 5;12:652487.

Autoimmune Hematologic Disease
•Autoimmune cytopenia, occurring in 4% to 20% of patients, usually with
immune thrombocytopenic purpura (ITP), sometimes autoimmune
hemolytic anemia (AIHA).
•Autoimmunity may be the first manifestation of the immune defect in an
occasional patient who has never had a significant infection.
•The treatment strategies used for cytopenias in CVID are essentially the
same as applied for immune-competent patients.

Autoimmune Pulmonary Disease
•Interstitial lung disease
• Incidence is unclear
• Associated with evidence of systemic immune dysregulation, including previous
cytopenias, lymphadenopathy, and splenomegaly
• Requires biopsy to diagnose
• Follicular bronchiolitis, lymphocytic interstitial pneumonitis, and nodular lymphoid
hyperplasia
• Granulomatous inflammation -> Granulomatous and lymphocytic interstitial lung
disease (GLILD)

Autoimmune Pulmonary Disease
•Low doses of corticosteroids may be used acutely but have limited benefit
long term.
•Therapy targeting both T and B cells concurrently, such as
cyclophosphamide, cyclosporine, or azathioprine combined with rituximab,
is required.

Autoimmune Gastrointestinal Disease
•Stomach
• Autoimmune gastritis
• à Pernicious anemia
•Small Bowel and Colon
• Inflammatory bowel disease (IBD) resembling Crohn’s or ulcerative colitis

• IBD-like disease
• Investigation
• Stool fecal calprotectin
• Stool alpha-1 antitrypsin
• Absence of detectable serum antibodies against gliadin, reticulin, tissue transglutaminase, and
endomysium
• Endoscopic features
• Longitudinal ulcers and cobblestone appearance
• Histopathology
• Intraepithelial lymphocytosis, lymphoid aggregates, granulomas, and crypt distortion
• Lack of plasma cells

•IBD-like disease
• Treatment
• Difficult to control and unresponsive to standard IBD therapies
• Immunoglobulin replacement does not ameliorate the IBD-like disease.
• Low-dose corticosteroids can be used, although higher doses can lead to a significant
risk of infections.

•IBD-like disease
• Treatment
• Antibiotics to eliminate bacterial overgrowth.
• Oral budesonide, and immunosuppressants, including 5-aminosalicylate agents, 6-MP,
and AZA
• Targeted biological therapies in gastrointestinal inflammation, such as anti-TNF alpha,
IL-12, and IL- 23 antagonist, have been used with some benefit in severe cases

•Liver
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Nodular regenerative hyperplasia
• Treatment for autoimmune liver disease in CVID includes corticosteroids or
immunomodulators and ursodeoxycholic acid if biliary damage is present.

Autoimmune Rheumatologic Disease
• Adult and juvenile forms of chronic inflammatory arthritis (most common)
• Less frequently reported
• SLE
• Raynaud’s syndrome vasculitis
• Mixed connective tissue disorder
• Inflammatorymyositis
• Behcet’s disease
• Sjogren’s syndrome
• Treated in the same fashion as for patients without CVID

Autoimmune Dermatologic Disease
•Less reported in CVID
•Alopecia totalis
•Lichen planus
•Psoriasis
•Vitiligo
•Granuloma

Other systems
•Autoimmune encephalitis
•Autoimmune thyroiditis
Ann Allergy Asthma Immunol 127 (2021) 131−151

Malignancy
•Meta-analysis from 48 studies including 8123 CVID patients
• Overall prevalence of malignancy was 8.6%
• The prevalence of lymphoma, gastric cancer and breast cancer in CVID patients
were 4.1%, 1.5%, and 1.3%, respectively.
Expert Rev Clin Immunol. 2019 Oct;15(10):1105-1113.

Expert Rev Clin Immunol. 2019 Oct;15(10):1105-1113.

Diagnostic criteria
•The ESID/ PAGID diagnostic criteria 1999
•Revised ESID diagnostic criteria 2014
•The diagnostic criteria of Ameratunga 2013
•ICON criteria 2016

The ESID/ PAGID diagnostic criteria 1999
•Probable CVID
• 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 fulfils all of the following criteria:
• Onset of immunodeficiency at >2 years of age
• Absent isohemagglutinins and/or poor response to vaccines
• Defined causes of hypogammaglobulinemia have been excluded
Clin Immunol. 1999;93(3):190-7.

The ESID/ PAGID diagnostic criteria 1999
•Possible CVID
• Male or female patient who has a marked decrease (at least 2 SD below the
mean for age) in at least one of the major isotypes (IgM, IgG, and IgA) and fulfils
all of the following criteria:
• Onset of immunodeficiency at >2 years of age
• Absent isohemagglutinins and/or poor response to vaccines
• Defined causes of hypogammaglobulinemia have been excluded
Clin Immunol. 1999;93(3):190-7.

Defined causes of hypogammaglobulinemia
•Drug induced
•Single gene and other defects
•Chromosomal anomalies
•Infectious diseases
•Malignancy
•Other systemic disorders

•Drug induced
• Antimalarial agents
• Captopril
• Carbamazepine
• Glucocorticoids
• Fenclofenac
• Gold salts
• Penicillamine
• Phenytoin
• Sulfasalazine Anti-CD20 mAbs
• (rituximab)

• Single gene and other defects
• Ataxia telangiectasia
• Autosomal-recessive forms of SCID and
other forms of combined
immunodeficiency
• Hyper-IgM syndromes
• Transcobalamin II deficiency
• 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

• Infectious diseases
• HIV
• Congenital infection with rubella virus
• Congenital infection with cytomegalovirus
• Congenital infection with Toxoplasma
gondii
• EBV
• Malignancy
• Chronic lymphocytic leukemia
• Immunodeficiency with thymoma
• Non-Hodgkin lymphoma
• Monoclonal gammopathy (mutiple
myeloma, Waldenstrom
macroglobulinemia)
• Other systemic disorders
• Immunodeficiency caused by excessive
loss of immunoglobulins (nephrosis,
severe burns, lymphangiectasia, protein-
losing enteropathy)

The diagnostic criteria of Ameratunga 2013
A. Must meet all major criteria
• Hypogammaglobulinaemia: IgG below 5 g/l for adults
• No other cause identified for immune defect
• Age > 4 years
B. Clinical sequelae directly attributable to in-vivo failure of the immune system (one
or more criteria)
C. Supportive laboratory evidence (three or more criteria)
D. Presence of any one of relatively specific histological markers of CVID (not
required for diagnosis but presence increases diagnostic certainty)
Clin Exp Immunol. 2013 Nov;174(2):203-11.

B. Clinical sequelae directly attributable to in-vivo failure of the immune
system (one or more criteria)
• Recurrent, severe or unusual infections
• Poor response to antibiotics
• Breakthrough bacterial infections in spite of prophylactic antibiotics
• Infections in spite of immunization with the appropriate vaccine, e.g. HPV
disease
• Bronchiectasis and/or chronic sinus disease
• Inflammatory disorders or autoimmunity

• Concomitant deficiency or reduction of IgA (<0.8 g/l) and/or IgM (<0.4 g/l)
• Presence of B cells but reduced memory B cell subsets and/or increased CD21 low
subsets by flow cytometry
• IgG3 deficiency (<0.2 g/l)
• Impaired vaccine responses compared to age-matched controls
• Transient responses to vaccines compared to age-matched controls
• Absent isohaemagglutinins (if not blood group AB)
• Serological support for autoimmunity in section B, e.g. positive Coombs’ test
• Sequence variations of genes predisposing to CVID, e.g. TACI, BAFFR, MSH5, etc.

D. Presence of any one of relatively specific histological markers of CVID
(not required for diagnosis but presence increases diagnostic certainty)
• Lymphoid interstitial pneumonitis
• Granulomatous disorder
• Nodular regenerative hyperplasia of the liver
• Nodular lymphoid hyperplasia of the gut
• Absence of plasma cells on gut biopsy

A. Must meet all major criteria
• Hypogammaglobulinaemia: IgG below 5 g/l for adults
• No other cause identified for immune defect
• Age > 4 years
B. Clinical sequelae directly attributable to in-vivo failure of the immune system (one
or more criteria)
D. Presence of any one of relatively specific histological markers of CVID (not
required for diagnosis but presence increases diagnostic certainty)
Probable CVID - ABC or ABD
(should be treated with IVIG/scIG)
Possible CVID- A alone, AB or AC or AD

Revised ESID diagnostic criteria 2014
•At least one of the following:
• Increased susceptibility to infection
• Autoimmune manifestations
• Granulomatous disease
• Unexplained polyclonal lymphoproliferation
• Affected family member with antibody deficiency
http://esid.org/Working-Parties/Registry/Diagnosis-criteria

Revised ESID diagnostic criteria 2014
• Marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured
at least twice)
• 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)
• Secondary causes of hypogammaglobulinemia have been excluded
• Diagnosis is established after the fourth year of life (but symptoms may be present before)
• No evidence of profound T-cell deficiency, defined as two out of the following
• CD4 numbers/microliter: 2–6 y < 300, 6–12 y < 250, >12 y < 200
• % Naive CD4: 2–6 y < 25%, 6–16 y < 20%, >16 y < 10%
• T-cell proliferation absent
http://esid.org/Working-Parties/Registry/Diagnosis-criteria

ICON criteria 2016
1. At least 1 of the characteristic clinical manifestations
2. Hypogammaglobulinemia
3. IgA or IgM level must also be low.
(some experts prefer a more narrow definition requiring low IgA level in all patients.)
4. 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.
5. Other causes of hypogammaglobulinemia must be exclude

ICON criteria 2016
1. At least 1 of the characteristic clinical manifestations
• Infection
• Autoimmunity
• Lymphoproliferation
However, a diagnosis of CVID may be conferred on asymptomatic individuals who
fulfill criteria 2 to 5, especially in familial cases

ICON criteria 2016
2. Hypogammaglobulinemia
•should be defined according to the age adjusted reference range
•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

ICON criteria 2016
4. 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
• There must be a demonstrable impairment of response to at least 1 type of
antigen (TD or TI).

ICON criteria 2016
Unspecified IgG deficiency
• Or unspecified hypogammaglobulinemia
• Patients with a low IgG level and impaired vaccine responses but IgA or IgM level
is not low
• IgG and IgA levels may be low, but vaccine responses may appear normal by
standard criteria
• Many patients with abnormal immunoglobulin levels and/or functional antibody
responses not meeting criteria for CVID may have a significant burden of
infections and should be assessed for benefit from IgG replacement.

J Allergy Clin Immunol Pract. 2019 Apr;7(4):1277-1284.

Classification
•Freiburg Classification
•Paris Classification
•EUROclass Classification
•B-Cell Pattern Classification
•Chapel Classification

EUROclass Classification (2008)
•based on their percentage of CD19 B cells
•B– - ≤1% CD19 B cells
•B+ - >1% CD19 B cells
• smB– - ≤2% switched memory B cells
• smB– Trhi - ≥9% transitional B cells (CD21intCD38++IgM++)
• smB– Trnorm - <9% transitional B cells
• smB+ - >2% switched memory B cells
Blood. 2008 Jan 1;111(1):77-85.

Blood. 2008 Jan 1;111(1):77-85.

B-Cell Pattern Classification (2011)
• Divided into 5 distinct groups based on their B-cell subsets
• Group 1- decreased numbers of transitional B cells along with a reduction in
memory B cells
• Group 2 - reduced number of transitional B cells, as well as naive, marginal zone–
like, and memory B cells
• Group 3 - reduced marginal zone–like and memory B cells
• Group 4 - only decreased memory B cells
• Group 5 - normal marginal zone–like and memory B cells in combination with a
reduced plasmablast count
Blood. 2011 Dec 22;118(26):6814-23.

Chapel Classification
•According to this classification, patients are divided into 5 distinct clinical
phenotypes including
• No complications
• Autoimmunity
• Polyclonal lymphocytic infiltration
• Enteropathy
• Lymphoid malignancy
Blood. 2008 Jul 15;112(2):277-86.

Management
•Immunoglobulin replacement therapy
•Immunization
•Treatment of complications

Immunoglobulin replacement therapy
•Dose
• Starting dose of 0.4 to 0.5 g/kg/month for both intravenous immunoglobulin(IVIG)
and 0.4 to 0.6 g/kg/month for subcutaneous immunoglobulin (SCIG)
• Preexisting bronchiectasis à 0.6 g/kg/month
• Enteropathy or splenomegaly à 0.6-0.8 g/kg/month

Immunoglobulin replacement therapy
•Adverse events
• Acute reactions
• Headaches, nausea and vomiting, flushing, hives, chills, myalgia, arthralgia, or
abdominal and/or back pain
• Severe, life-threatening anaphylactoid reactions are very rare
• Delayed reactions
• can occur up to 72 hours after the infusion
• Fatigue, headache, myalgias

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 to
the most commonly used live viral vaccines
• such as measles, mumps, rubella, polio, and varicella
•Less commonly used inactivated vaccines do not pose any risk to patients,
but efficacy is unknown.

Immunization
•Live attenuated polio vaccine, may cause disease in patients with CVID.
•Efficacy and safety of less frequently used live-agent vaccines have not
been studied in patients with CVID, and they are usually considered to be
contraindicated.

J Allergy Clin Immunol. 2014 Apr;133(4):961-6.

Treatment of complications
•Rhinosinusitis
•Bronchiectasis

Treatment of complications-Rhinosinusitis
•Routine saline nasal rinses may be used to aid in mucus clearance.
•Antibiotic prophylaxis for chronic or recurrent rhinosinusitis and/or otitis
media
• no controlled trials have been conducted

Treatment of complications- Bronchiectasis
Hill AT, et al. Thorax 2019;74(Suppl 1):1–69.

Hill AT, et al. Thorax 2019;74(Suppl 1):1–69.

Prognosis

Common variable immunodeficiency

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