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.

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), as well as 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 can 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.

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:

• CVID patients with no complications.
• CVID patients with autoimmune disease.
• CVID patients with lymphocytic organ infiltration i.e. lymphocytic enteropathy, granulomas, hepatomegaly, lymphadenopathy, and splenomegaly.
• CVID patients with predominant enteropathy.
• CVID patients with lymphoid malignancy.

Pathophysiology

• The exact pathophysiology of CVID is not fully understood.
• Defective immunoglobulin secretion leading to dysregulated immune function is believed to be main pathophysiological mechanism of CVID.
  • Defective B cell differentiation into plasma cells, results in inability to produce specific immunoglobulins.
• Multiple immuno-regulatory dysfunction leads to hypogammaglobulinemia.
• CVID is associated with a high occurrence of autoimmune, inflammatory, and malignant disorders, whereas these conditions are not observed in X-linked agammaglobulinemia (XLA), a disease that affects early B cell development.

• CVID appears to result from a number of gene defects. which may be either recessive in inheritance or autosomal dominant. Some of these are due to defects of B cell signalling molecules but additional genes affecting immune regulation may also lead to the CVID phenotype.

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 can 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.

Differentiating Common Variable Immunodeficiency from other Diseases

CVID should be differentiated from diseases which hypogammaglobulinemia is their primary laboratory feature include:

• Bruton agammaglobulinemia (X-linked agammaglobulinaemia)
• Transient hypogammaglobulinemia of infancy
• Severe combined immunodeficiency (SCID)
• IgG subclass deficiency
• Hyperimmunoglobulin M syndrome

In addition to primary causes of hypogammaglobulinemia a large number of conditions are associated with secondary hypogammaglobulinemia and should be excluded:

• Malignancy: Such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, or Waldenström's macroglobulinemia cause the reduction in the immunoglobulin production.

• Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with hypogammaglobulinemia.

• 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.

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.

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.

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.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

Complications

Numerous complications are possible in CVID. They include:

• Recurrent infections in the sinopulmonary, gastrointestinal, septic arthritis, bacterial meningitis/sepsis
• Autoimmune phenomena - Vitiligo, autoimmune hepatitis, primary biliary cirrhosis, hemolytic anemia
• Malignancy - Lymphomas, gastric cancer, malignant melanoma
• Rheumatoid arthritis
• Vitiligo
• Thrombocytopenia
• Neutropenia
• Hemolytic anemia
• Pernicious anemia
• Malabsorption
• Autoimmune hepatitis
• Primary biliary cirrhosis
• Atrophic gastritis
• The mainstay of treatment for Inflammatory bowel disease

Prognosis

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. 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.

Diagnosis

History and Symptoms

Symptoms of CVID are:

• Chronic infections (most common symptom) specifically upper respiratory tract infection e.g. bronchitis, sinusitis which respond to antibiotics but return or reoccur. Common infective organisms include:
  • Haemophilus influenzae
  • Streptococcus pneumoniae
  • Moraxella catarrhalis
  • Staphylococcus aureus
• Viral infections that usually respond to antivirals, (URTIs), sinusitis, tonsilitis, epiglottitis, dermatological abscesses/boils (often, but not exclusively, facial and axillary), pneumonia, bronchitis, pleurisy, stomach/intestinal infections, colds, influenza, shingles, conjunctivitis
• Tiredness
• Shortness of breath - due to bronchiectasis (lung tissue damage as a result of repeated chest infections)
• Polyarthritis, or joint pain, spread across most joints, but specifically fingers, wrists, elbows, toes, ankles and knees
• Patients may lose weight
• Children may show a "failure to thrive" - they may be underweight and underdeveloped compared with "normal" peers
• Diarrhoea and malabsorption - due to villous atrophy in the small intestine, which can resemble coeliac disease, intestinal infections, including protozoan and parasitic infections, bacterial overgrowth of the intestine
• Increased incidence of inflammatory bowel disease
• Abdominal pain, bloating, nausea, vomiting, diarrhea, weight loss.

Physical Examination

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

• Low body mass index
• Scarring of tympanic membranes or skin
• Signs of chronic lung disease such as chronic cough, absent gag reflex, clubbing, crackles, or wheezing to suggest bronchiectasis
• Ongoing infection signs of chronic sinusitis, oral thrush, warts, or dermatophyte infections

• Swelling of the lymph glands - lymphadenopathy

• Enlarged spleen

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:

• lymphocytopenia
• Hypoalbuminemia
• Elevated C-reactive protein
• Elevated liver transaminases
• Positive Blood culture and/or urine culture

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

• 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.

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.
• 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.
• 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:

• Anaphylactic shock (very rare)
• Hives (rare)
• Difficulty breathing
• Headache (relatively common, may be relieved by an antihistamine, paracetamol / acetaminophen, or an anti-inflammatory (naproxen, advil, aspirin)
• Nausea (common)
• Fever (common)
• Aseptic meningitis (rare)
• Severe fatigue
• Muscle aches and pain, or joint pain
• Thrombotic events (rare)

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.
• 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.

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.

External links

• Primary Immunodeficiency Association (UK)
• Immune Deficiency Foundation (US)
• Immune Deficiencies Foundation of Australia
• Immune Deficiencies Foundation of New Zealand
• IPOPI (International Patient Organisation for Patients with Primary Immunodeficiency)
• Canadian Immunodeficiencies Patient Organization (Canada)

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