Common variable immunodeficiency

Common variable immunodeficiency
ICD-10	D83
ICD-9	279.06
OMIM	240500
DiseasesDB	3274
MeSH	D017074

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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. It is the most common form of severe antibody deficiency affecting both children and adults. The characteristic immune defect in CVID is impaired B cell differentiation with defective production of immunoglobulin. CVID is defined by low total serum concentrations of immunoglobulin G (IgG), as well as low immunoglobulin A (IgA) and/or immunoglobulin M (IgM), poor or absent response to immunization, and the absence of any other defined immunodeficiency state.

Most patients are diagnosed between the ages of 20 and 40 years. Delayed recognition is common.

Bacterial infections of the sinopulmonary tract, particularly sinusitis and pneumonia, are experienced by most patients with CVID. Opportunistic and unusual infections are uncommon, but do occur.

In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to autoimmunity, a variety of inflammatory disorders, and malignant disease. 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 can be assigned.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

Charles Janeway et al (1953) is generally credited with the description of the first case of CVID.

Classification

Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent sinopulmonary infections, autoimmune disorders, granulomatous disease, and an enhanced risk of malignancy

A phenotypic approach to categorizing CVID has been proposed, based upon the type of complications the patient develops. This arose from an analysis of the European Common Variable Immunodeficiency Disorders registry, in which 334 patients with CVID were followed for an average of 26 years . Five phenotypic categories were proposed:

1. Patients with no complications
2. Patients with autoimmune disease
3. Patients with lymphocytic organ infiltration (ie, lymphocytic enteropathy, granulomas, unexplained hepatomegaly, persistent lymphadenopathy, splenomegaly, and/or lymphoid interstitial pneumonitis)
4. Patients with predominant enteropathy
5. Patients with lymphoid malignancy

Pathophysiology

The exact pathophysiology of CVID is not fully understood. CVID is a group of disorders with a common endpoint of defective immunoglobulin secretion and dysregulated immune functions. The clinical dissimilarity of CVID proposes that multiple immunoregulatory dysfunctions can result in the final common pathway of hypogammaglobulinemia.

The immune defect in CVID is due to defective B cell differentiation into plasma cells, with the inability to produce immunoglobulin. 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 with variable penetrance. 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

Differentiating Common Variable Immunodeficiency from other Diseases

CVID should be differentiated from the following diseases:

• Bruton agammaglobulinemia(X-linked agammaglobulinaemia)
• Severe combined immunodeficiency(SCID)

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
• Inflammatory bowel disease

Prognosis

The incidence of death associated with acute bacterial infection in CVID decreased dramatically with the advent of immune globulintreatment. Thereafter, the major causes of death have been complications of chronic lung disease and malignancies [16,17,46,59,60]:

The largest series of 473 patients reported long-term data for 411 individuals, followed over a period of 40 years [16]. During this time, 19.6 percent died, with a median age at death of 44 and 42 for females and males, respectively. The leading causes of death were respiratory failure due to chronic lung disease (36 percent), lymphoid and other malignancies (29 percent), and liver disease (9 percent). Reduced survival was seen in patients with gastrointestinal disease, chronic lung disease, hepatic disease, and lymphoma, although not in those with other complications, such as autoimmune disorders, granuloma, or bronchiectasis without other lung disease. Long-term survival was excellent in patients with only infectious complications, but significantly lower in those with one or more noninfectious complications (95 versus 42 percent at 40 years, respectively). Immunologic parameters associated with higher mortality were lower levels of serum immunoglobulin G (IgG), increased serum immunoglobulin M (IgM), and lower percentages of circulating B cells.

Another center reported on the 353 patients diagnosed as adults also followed over a 40-year period [60]. Mortality in this group was very similar at 19.5 percent, with a median age at death of 54 and 53 from females and males, respectively. The leading cause of death was chronic lung disease (30 percent). A similar percentage of patients succumbed to lymphoma, while a higher percentage died from other types of malignancies.

In a third series of 334 patients, mortality was highest in patients with bronchiectasis, enteropathy, polyclonal lymphocytic infiltration, and autoimmunity [17]. In this series, there were no associations between survival and gender or initial serum IgG, immunoglobulin A (IgA), or IgM levels.

Diagnosis

History and Symptoms

Symptoms of CVID are:

• Polyarthritis, or joint pain, spread across most joints, but specifically fingers, wrists, elbows, toes, ankles and knees
• 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)
• 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

Head

• Swelling of the lymph glands - lymphadenopathy

Abdomen

• Enlarged spleen

Laboratory Findings

• Complete blood count and differential count - lymphocytopenia
• Blood culture
• Hypogammaglobulinemia, or low levels of immunoglobulin G (IgG), IgA and/or IgM. Lack of normal levels of antibody in the serum is part of the diagnosis
• Poor titer levels in response to vaccination. Responsiveness may be tested after administration of polysaccharide and non-polysaccharide coated pathogens (e.g. streptococci and tetanus respectively)

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 requires precise monitoring for associated conditions, such as sinopulmonary, granulomatous, gastrointestinal, and autoimmune diseases, and malignancy.

Immune globulin replacement therapy is an injection of human antibodies harvested from blood donations which may be administered either intravenously or subcutaneously:

• Intravenous immunoglobulin (IVIG, most common treatment)
• Subcutaneous immunoglobulin G (SCIG, relatively new therapy)
• Intramuscular immunglobulin (IMIG, less effective, painful).

This is not a cure, but it strengthens immunity by ensuring that the patient has "normal" levels of antibodies, which helps to prevent recurrent upper respiratory infections.

IG therapy can't be used if the patient has anti-IgA antibodies but in this case, 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.

Some CVID patients may experience reactions to IG 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)

Patients should not receive therapy if they are fighting an active infection as this increases the risk of reaction. Also, patients changing from one brand of product to another may be at higher risk of reaction for the first couple of treatments on the new brand.

Reactions can be minimised 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).

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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