Common variable immunodeficiency

Common variable immunodeficiency (CVID) is a disorder that involves low levels of most or all of the immunoglobulin (Ig) classes.

Lack of B lymphocytes or plasma cells that are capable of producing antibodies.

Frequent bacterial infections.

A diagnosis of CVID is reserved for persons with an undefined B-cell dysfunction.

Genetic factors may be involved, as approximately 20% of patients with CVID, a first-degree family member has a selective IgA deficiency.

When multiple family members are affected, approximately 5% of the patients have a concurrent IgA deficiency.

Studies suggest specific localization to the C4A gene and, rarely, to the C2 gene in the class III region of the major histocompatibility complex on chromosome 6.

In most patients it is a sporadic process.

An autosomal recessive pattern of inheritance is suggested when more than one family member is affected.

Lymphoma of the B cell phenotype is a common cause of death in patients with CVID.

Recurrent infections are common and damage to the bronchi may occur, resulting in bronchiectasis.

As many as 20% of patients with CVID develop autoimmune complications and include rheumatoid arthritis, vitiligo, hemolytic anemia, thrombocytopenia, neutropenia, and gastrointestinal diseases.

Can occur at any age.

A syndrome similar to sarcoidosis characterized by noninfectious cutaneous granulomas, with underlying visceral granulomas of the lungs, liver, spleen, or conjunctiva can affect patients with CVID,

Laboratory studies can reveal decreased serum IgA and IgG levels commonly and occasionally decreased serum IgM levels.

Approximately 50% of patients with the deficiency also have diminished serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction.

Histologic changes in the lymph nodes of patients with CVID may have reactive follicular hyperplasia, and ganulomatous inflammation.

Primary treatment for CVID is immunoglobulin replacement therapy, which reduces arthritic symptoms, infection recurrence, and the severity and/or incidence of the autoimmune disease.

Immunoglobulin may be administered intravenously or subcutaneously.

About 20% of those with CVID develop an autoimmune disease.

The most common abnormality is defective antibody formation, affecting both humoral and cell-mediated lymphocytic responses.

Some CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help.

Basic abnormality is a failure in the differentiation of B lymphocytes, with a defect in B-cell expression in surface molecules.

Deficits have in the second messenger and translocation pathways of B cells, including abnormalities with protein kinase C activation and tyrosine phosphorylation.

Associated with impaired production or complete absence of IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA repair, and the presence somatic mutations affecting B-cell regulation.

Changes in the cell-mediated response A number of factors and cofactors stimulate Ig secretion from B cells harvested from patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 10 (IL-10).

One of the most potent stimulants of Ig secretion is the CD40 ligand, which is expressed by activated CD4+ cells.

n 40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells.

Commonly a defect in the response to antigens by CD4+ T lymphocytes is present.

After immunization, some patients have decreased numbers of circulating responsive CD4+ T cells, while others have an increased number of CD4+ T cells, but also have an increased rate of apoptosis of such cells.

Signal transduction appears to be the primary defect in T cells.

25-30% of patients with CVID have increased number of CD8+T cells and a reduced CD4/CD8 ratio of <1, due to an increase in cyclic adenosine monophosphate levels and the increased activation of protein kinase A.

These patients often have splenomegaly and bronchiectasis.

60% of patients with CVID have a diminished response to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma.

Most patients with CVID can be said to have antibody deficiency secondary to T-cell signaling abnormalities, as well as defective interactions between T and B lymphocytes.

CVID is associated with potentially reversible defects in humoral and/or cellular immunoregulatory factors.

Four genes mutated in CVID patients: ICOS, TNFRSF13B, TNFRSF13C, and CD19.

Autosomal dominant CVID has been linked to chromosome 4q and other possible loci for dominant CVID genes are on chromosomes 5p and 16q.

The prevalence of common variable immunodeficiency (CVID) is approximately 1 case per 50,000 population.

A 20-year survival rate is 64% for male patients and 67% for female patients.

No racial predilection.

Affects males and females equally.

Can become evident at any time from infancy to after the fourth decade of life, but peak levels occur in children aged 1-5 years and in persons aged 16-20 years.

More than two thirds of patients are on. adulthood when diagnosed.

Associated with 5 clinical phenotypes: no clinical complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy.

Complications include recurrent infections, autoimmune phenomena, and malignancy.

Patients with CVID often have a history of recurrent infections commonly affecting the upper and lower respiratory tracts.

Patients come to medical attention due to infectious diseases.

The most common infections are otitis media, diarrhea, pneumonia, and sinusitis.

Almost all patients experience acute and recurrent infections.

Persistent diarrhea and malabsorption caused by Giardia lamblia infection may occur in patients with CVID.

Young children may fail to thrive secondary to frequent infections or gastrointestinal tract disease.

Many patients have splenomegaly and generalized lymphadenopathy.

Recurrent infections may cause permanent damage to the bronchi, resulting in bronchiectasis.

Common infective organisms in CVID include Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus, and uncommon infectious agents such as Pneumocystis carinii and Mycoplasma pneumoniae may occur.

M pneumoniae can also cause primary infection of the lung, urinary tract and joints.

Recurrent infections with herpes simplex virus may occur, and Enterovirus infection has been reported.

Herpes zoster infection may develop in as many as 20% of patients.

As many as 20% of patients with CVID develop autoimmune complications, and rheumatoid arthritis, vitiligo, hemolytic anemia, thrombocytopenia, and neutropenia have all been reported associations.

CVID associated with gastrointestinal diseases, pernicious anemia, a spruelike malabsorption disorder, autoimmune hepatitis, primary biliary cirrhosis, intestinal nodular lymphoid hyperplasia, atrophic gastritis, aphthous stomatitis, and inflammatory bowel disease.

The risk of lymphomas of a B-cell phenotype are high.

Malignancy is most likely associated with the Epstein-Barr virus.

The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.

Malignant melanomas have been reported in association with CVID.

May be associated with alopecia areata and alopecia universalis.

A syndrome similar to sarcoidosis can occur characterized by noninfectious cutaneous granulomas, visceral granulomas of the lungs, liver, spleen, or conjunctiva.

Cutaneous granulomas often appear as multiple, nontender subcutaneous nodules, predominantly juxta-articular, and the skin overlying the nodules was either normal or slightly erythematous.

These sterile cutaneous lesions frequently appear on the face and extremities, and they resolve with treatment of the underlying disease.

Cutaneous lesions may leave residual hyperpigmentation.

Associated with increased incidence of malignancy.

Patients experience an increased risk for actinic keratosis and squamous cell carcinoma, atopic dermatitis and polymorphic light eruption.

Associated with the use of antirheumatic or antiepileptic drugs.

An insult to the B-cell differentiation pathway may be involved.

Patients usually have decreased serum IgA, IgG and occasional IgM levels

Usually have higher serum immunoglobulin levels compared with patients with X-linked agammaglobulinemia.

The periodic monitoring of pulmonary function is essential in following CVID.

Histologic changes in the lymph nodes include reactive follicular hyperplasia, atypical hyperplasia, and granulomatous inflammation.

Treatment for common variable immunodeficiency (CVID) is Ig replacement therapy, which stops recurrent infections.

IgG may be administered intravenously or subcutaneously.

Intravenous immunoglobulin (IVIG) can be used to maintain a trough level of 400-500 mg/dL in adults.

A dose of 400-600 mg/kg every 2-4 weeks is usual therapy.

In patients with structural lung damage and CVID, a trough level of 700-800 mg/dL is required.

A solution of 16% subcutaneous injection of IV immunoglobulin (SCIG) is also an effective treatment, and a dose of 160 mg/kg/wk is comparable to an IVIG dose of 400 mg/kg/mo.

Adverse reactions to IgG administration can occur within 30 minutes of the infusion and usually last for several hours and include: backache, nausea, vomiting, chills, low-grade fever, myalgias, and fatigue.

Slowing the rate of infusion helps in preventing symptoms, and can be treated with antipyretics, diphenhydramine, and/or corticosteroids.

Anaphylactic reactions to IVIG are uncommon, but patients with IgA deficiency have an increased risk.

IgG products are derived from pooled human plasma, which undergoes a manufacturing process that includes cold ethanol fractionation and viral inactivation steps.

Utilizing IV IgG reduces infections, arthritic symptoms, and the severity and/or incidence of the autoimmune disease.

Antimicrobial therapy should be initiated at the first sign of infection.

IV IgG supplies broad spectrum of IgG antibodies against bacteria, viruses, and parasites.

IV IgG neutralizes circulating myelin antibodies with anti-idiotypic antibodies.

IV IgG down-regulates proinflammatory cytokines, including interferon-gamma.

IV IgG blocks Fc receptors on macrophages.

IV IgG blocks the complement cascade.

IV IgG Suppresses inducer T and B cells and augments suppressor T cells.

IV IgG promotes remyelination.

IV IgG may increase CSF IgG levels by 10%.

Treatment goal is the prevention of secondary infections by administering IV IgG.

IVIG should be administered every 2-4 weeks to keep the level of serum antibodies in the normal range.

Complications of common variable immunodeficiency include:

Recurrent infections

Autoimmune phenomena

Malignancy, and a common cause of death is lymphoma.

Other complications include cor pulmonale secondary to chronic pulmonary infection, liver failure caused by viral or autoimmune hepatitis, malnutrition resulting from gastrointestinal tract disease, and viral infections.

Low levels of IgG, poor T-cell responses to antigens, and a low percentage of peripheral B cells are associated with risk of mortality.

Patients may experience chronic sinusitis, autoimmune thrombocytopenia, and hemolytic anemia.

Prognosis depends on the presence of severe autoimmune disease, recurrent infections manifesting in lung damage, the development of a malignancy, the extent of end-organ damage and the ability to prevent future infections.

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