Common variable immunodeficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mohsen Basiri M.D. Syed Hassan A. Kazmi BSc, MD [2]

Synonyms and Keywords: CVID; common variable hypogammaglobulinaemia; non-familial hypogammaglobulinaemia; acquired hypogammaglobulinemia; immunodeficiency, common variable; late-onset immunoglobulin deficiency

Overview

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder. CVID is the most common antibody deficiency affecting both children and adults. The characteristic immunological defect in CVID is impaired B cell differentiation with defective production of immunoglobulin. Impaired B cell differentiation leads to low serum concentrations of immunoglobulin G (IgG), low immunoglobulin A (IgA) and/or immunoglobulin M (IgM), as well poor or absent response to immunization. The majority of patients are diagnosed between the ages of 20 and 40 years. Recurrent bacterial infections of the sino-pulmonary tract (sinusitis and pneumonia) are most common manifestations of patients with CVID. Opportunistic and unusual infections are uncommon, but may occur. In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to autoimmunity. Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations, lymphoid hyperplasia, splenomegaly, or malignancy. Various forms of primary and secondary hypogammaglobulinemia must be excluded before the diagnosis of CVID. The diagnosis of CVID requires a suggestive clinical history, a reduced total serum concentration of IgG, plus low IgA or IgM, and poor responses to both protein- and polysaccharide-based vaccines.

Historical Perspective

  • In 1953, Charles Janeway was the first to describe CVID as a separate entity.
  • In 1990, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) determined the diagnostic criteria, including minimum age of diagnosis and the need to rule out other diseases, to determine CVID.[1]

Classification

Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent sinopulmonary infections, autoimmune diseases, and granulomatous disease. A phenotypic approach to classify CVID has been suggested, based upon the type of complications the patient demonstrates. Five phenotypic categories were proposed:[2]

Pathophysiology

Type Gene Immunoglobulin Deficiency Phenotype
ICOS deficiency ICOS Low IgG and IgA Recurrent infections, autoimmunity, gastroenteritis.
CD19 deficiency CD19 Low IgG and IgA Recurrent infections.

May be associated with glomerulonephritis.

CD81 deficiency CD81 Low IgG, low or normal IgA and IgM Recurrent infections.

May be associated with glomerulonephritis.

CD20 deficiency CD20 Low IgG, normal or elevated IgM, and IgA Recurrent infections.
CD21 deficiency CD21 Low IgG; impaired antipneumococcal response Recurrent infections.
TACI deficiency TNFRSF13B Low IgG and IgA and/or IgM Variable clinical expression
BAFF-receptor

deficiency

TNFRSF13C Low IgG and IgM Variable clinical expression
TWEAK deficiency TWEAK Low IgM and IgA; lack of antipneumococcal antibody Recurrent infections such as Pneumonia, bacterial infections, warts;

and thrombocytopenia; neutropenia

NF-kappa-B2

deficiency

NFKB2 Low IgG and IgA and IgM; very low B cells in some Recurrent infections; adrenal insufficiency;

ACTH deficiency; alopecia

NF-kappa-B1

deficiency

NFKB1 Low IgG and IgA and IgM; low B cells in some Recurrent infections
IKAROS IKZF1 Low IgG and IgA and IgM, very low B cells Recurrent infections

Causes

The cause of common variable immunodeficiency has not been identified. Genetic mutations may be recognized as the cause of CVID in about 10% of patients, and familial inheritance accounts for 10-25% of the affected population. Rather than arising from a single genetic mutation, CVID is due to numerous mutations that all are associated with dysfunction in antibody regulation and production.[7]

Differentiating Common Variable Immunodeficiency from other Diseases

Common variable immunodeficiency should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][31][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]

Disorder Defect (Mechanism of Development) Characteristic Features Clinical Presentation Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job's Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
Hyper IgM Syndrome
Wiskott-Aldrich Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.[58]
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.[59]
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.[60]
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Epidemiology and Demographics

Prevalence

CVID has an estimated prevalence ranging from a low of 2 per 100,000 to a high of 4 per 100,000 with an average of 3 per 100,000.[61]

Age

  • The typical patient is after puberty and between 20 and 40 years age.
  • About 20% of patients are diagnosed in childhood.
  • In an analysis of the CVID data from the ESID about 35 percent of patients were diagnosed before 10 years of age; and in studies from United States centers, 20 percent of patients are diagnosed before the age of 20 years. The majority of patients are diagnosed between the ages of 20 and 45. [62] [63]

Gender

There is no gender predilection to common variable immunodeficiency.

Race

Race is not associated with an increased risk of common variable immunodeficiency. However, there is some evidence of higher prevalence among individuals of northern European descent.[64]

Natural History, Complications and Prognosis

Natural History

  • All patients have several histories of acute and recurrent infections.
  • The majority of patients with CVID have evidence of immune dysregulation leading to autoimmunity, inflammatory disorders, and malignant disease.
  • Accordingly, CVID Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations of several organs, lymphoid hyperplasia, splenomegaly, or malignancy.[65]
  • The clinical manifestations of CVID affect multiple organ systems, and patients often have the history of several specialists visits by the time they are recognized. It may be partly for this reason, delayed diagnosis of this condition is common. in the European Society for Immunodeficiencies (ESID) database, and other studies, there was an average of five to seven years between the beginning of symptoms and diagnosis[66][67]

Complications

Numerous complications are possible in CVID. They include:[68][69][70]

Prognosis

  • The prognosis with the advent of immune globulin treatment is generally good, and the incidence of death associated with acute bacterial infection in CVID decreased dramatically.[71]
  • Afterwards, the leading causes of death are owing to complications of chronic lung disease and malignancies.
  • In the several large series of following patients with CVID, the leading causes of death were respiratory failure due to bronchiectasis, lymphoma, and liver disease.[72][73]

Diagnosis

History and Symptoms

Symptoms of CVID are:[74][75]

Physical Examination

Physical examination of patients with longstanding immune defects may be remarkable for:

Laboratory Findings

Patients with CVID do not usually present abnormalities in routine laboratories, such as complete blood counts, serum chemistries, and electrolytes. In the presence of infection and associated condition some abnormalities which may develop include:

Laboratory findings consistent with the diagnosis of CVID are reduced concentrations of serum immunoglobulins levels and include:[76]

  • IgG of 258 mg/dL
  • IgA of 28 mg/dL
  • IgM of 40 mg/dL

Evaluation of vaccine response to both protein and polysaccharide-based vaccines is part of the diagnosis and should be evaluated. IgG responsiveness to tetanus and diphtheria and polysaccharide pneumococcal vaccine provide an estimate of the patient's responsiveness.[77]

Diagnosis is often delayed,and diagnosis is often made in the second or third decade of life after referral to an immunologist. As with several other immune cell disorders, CVID may predispose to lymphoma or possibly stomach cancer. There also appears to be a predilection for autoimmune diseases, with a risk of up to 25%. Autoimmune destruction of platelets or red blood cells are the commonest of these.

Treatment

Medical Therapy

The mainstay of treatment for CVID is immune globulin replacement therapy. In addition, management also includes monitoring and screening for other associated conditions, such as sinopulmonary, granulomatous, gastrointestinal, and autoimmune diseases, and malignancy.

Immune Globulin Replacement Therapy

  • Human antibodies harvested from blood donations are administered either intravenously or subcutaneously.
  • Immune globulin replacement therapy reduces the number of infections and decreases antibiotic use and hospitalizations.[78]
  • This therapy is not a cure, but it strengthens immunity in hypogammaglobulinemic patients, which helps to prevent recurrent upper respiratory infections, and fewer serious infections and days of hospitalization among patients with primary immunodeficiency . However, immune globulin therapy does not completely eliminate infections in most patients, and the sinopulmonary and gastrointestinal systems, in particular, remain susceptible.[79]
  • IG therapy should not be used if the patient has anti-IgA antibodies but in these cases, products low in IgA can be used; subcutaneous delivery also is a means of permitting such patients to have adequate antibody replacement.
  • IVIG treatment can be received by patients with a complete IgA deficiency if the IgA is completely removed from the treatment.
  • Preferred regimen : Intravenous immunoglobulin 300 to 600 mg/kg every three to four weeks.
  • Alternative regimen (1) :Subcutaneous immunoglobulin G administered weekly or every other week. Dose depends on body weight and immune globulin requirements.
  • Alternative regimen (2) : Intramuscular immunoglobulin (IMIG, less effective, painful).

Adverse reactions

Some CVID patients may experience reactions to immune globulin replacement therapies; reactions may include:

Reactions can be minimized by taking an antihistamine and/or hydrocortisone and some paracetamol/acetaminophen/anti-inflammatory (naproxen, advil, aspirin) prior to treatment; patients should also be thoroughly hydrated and continue to drink water before, after and during treatment (if possible).

Antimicrobial Therapy

Antibiotics may be administered prophylactically, as well as for the treatment of acute infections or exacerbations of chronic infections.

  • Prophylactic antibiotics do not routinely administer to all patients with CVID. In CVID patients with ongoing lung disease, and with recurrent sinopulmonary infections, this approach is helpful. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.[80]
  • Antibiotics are required for management of acute infections among patients with immunodeficiency. CVID patients typically do not clear common infections without the use of proper antibiotics. Thus, immediate recognition and treatment with antibiotics can help prevent chronic infections and infectious complications. It is important to ensure that the infection has treated completely at the end of a course of antibiotics, as patients with immunodeficiency sometimes necessitate longer duration of therapy. Antibiotic resistance does not seem to be a serious problem in patients with CVID, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.[81]

Prevention

  • There are no primary preventive measures available for common variable immunodeficiency.
  • Secondary and tertiary prevention strategies following CVID include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy, and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended.
    • Avoidance to reduce exposure to others with potentially contagious illnesses: proper hand-washing and use of alcohol-based disinfectants should be provided to patients and their families; Co-sleeping among family members should be minimized, and immunization of family members and close contacts is required.
    • Careful attention should be paid to patient's oral hygiene and dental health.
    • The efficiency of killed or inactivated vaccines in patients with CVID is not fully understood because of the impaired responses to of patients to vaccination due to dysregulated , however, vaccination might augment T cell immunity to viral agents, in addition to inducing the formation of specific antibodies. Certain live vaccines i.e. oral polio, smallpox, live-attenuated influenza vaccine, yellow fever, or live oral typhoid vaccines should not be given to patients with CVID , particularly those with significantly impaired T cell function.[82]

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