Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency in adults. It is often diagnosed late when there is less scope to prevent complications. A recent BMJ article details a patients experience of the condition.¹ This account and the accompanying medical view highlights important issues for better diagnosis and management.

Common variable immunodeficiency is an umbrella diagnosis in that it encompasses a group of genetic disorders that result primarily in hypogammaglobulinaemia or failure of antibody production.¹ Often specific genetic defects cannot be identified, unlike with some of the other immunodeficiency disorders. Patients typically present with recurrent infections, particularly of the respiratory tract. Gastrointestinal disease, autoimmune and inflammatory features, and lymphoma are also more commom in CVID.

In CVID there are, as implied in the name, many and varied immune-system abnormalities. To understand these some understanding of immunology is helpful. The most common defect is in antibody formation but there are related defects in both humoral and cell-mediated lymphocytic responses.

• Defective humoral responses:
  • Failure in differentiation of B lymphocytes.
  • Variety of defects at a cellular level have been described including defects in surface molecules, absence of IgA and IgG production, increased rates of apoptosis, impaired DNA repair and others.
• Defective cell-mediated responses. These are complex but can be summarised as:
  • Defective T-cell signalling.
  • Defective interactions between T and B lymphocytes.

CVID is characterised by:

• Low levels of most or all of the immunoglobulin classes.
• Lack of B lymphocytes or plasma cells capable of producing antibodies.
• Frequent bacterial infections.

• There are defects in both the innate and adaptive immune systems but the cause is unknown²
• Genetic factors:
  • Recently evidence of a disease-causing gene for an autosomal dominant CVID/IgA deficiency has been found on chromosome 4q³
  • 20% of patients with CVID have first-degree family member with IgA deficiency
  • No clear pattern of inheritance has been identified
• There is a possible association with use of antirheumatic or antiepileptic drugs

• It is found in about 1 in 25,000 to 50,000 adults
• It affects male and females equally
• There is no predilection for a particular race

CVID can present in infants, young children, adolescents and adults.

• It is diagnosed often in children with peaks in onset between 1 and 5 years and 16-20 years
• It can present later in adults up to age 40 years
• More than two thirds of patients are aged 21 years or older when CVID is diagnosed
• CVID presents often with recurrent bacterial infection:
  • The most common are sinusitis, pneumonia, bronchitis, otitis, conjunctivitis and gastrointestinal infection.⁴
  • Septicaemia and central nervous system infections can also occur.
  • Persistent diarrhoea and malabsorption (causing failure to thrive in children) from gastrointestinal infections. These include giardia lamblia (the most common), salmonella, shigella and campylobacter.
• Some patients present with mycobacterial or fungal infection
• Some present with Pneumocystis jiroveci (carinii)
• Viral infection is uncommon although some 20% of patients suffer from recurrent herpes zoster infection
• There may be associated diseases particularly:
  • Autoimmune diseases
  • Malignancies
  • Granulomatous disease
  • Dermatological manifestations

Other diseases which may need to be excluded are:

• Cystic fibrosis
• Immotile cilia syndromes
• Allergy
• Other primary immune deficiencies including:
  • Selective IgG subclass deficiency
  • IgA deficiency
  • Selective deficiency in the response to polysaccharide antigens
  • Bruton Agammaglobulinaemia
  • Severe Combined Immunodeficiency
• Protein losing enteropathy
• Thymoma
• Transient hypogammaglobulinemia secondary to infection

Greater awareness of the primary immunodeficiency disorders among generalists is still needed to avert late diagnosis and subsequent chronic ill health in patients.¹ Detailed investigation is complex and beyond the scope of general practice. Basic investigations may give some general clues with the history but referral for diagnosis is needed.

Generally serum immunoglobulins are reduced. Serum hypogammaglobulinemia is the key finding present in all patients with CVID, but tests of immune function should also be used.⁵ Further investigation is required to exclude other causes of antibody deficiency, especially in the over 50 age group. Investigation to exclude:B cell lymphoproliferative disease, protein losing diseases, iatrogenic or drug related causes. The possible investigations can be summarised as:

• Laboratory studies:
  • Full blood count
  • Autoantibody testing
  • Serum electrophoresis
  • Immunoelectrophoresis
  • Radial immunodiffusion methods
  • Immunoturbidimetric methods
  • Assessment of antibody response
  • Assessment of T and B lymphocytes by use of monoclonal antibodies for immunofluorescence staining
  • In vivo measures of T-cell function by assessing localised immunologic skin responses
  • Other measures of T-cell activity
• Imaging. This is likely to be required and may have to be extensive including different modalities (CT scanning, MRI) according to the clinical manifestations of disease.
• Further investigations such as pulmonary function tests, bronchoscopy, microbiological and histological testing may be required to diagnose associated diseases.

Patients with CVID may have:

• Bronchiectasis, particularly if presenting later, is common
• Autoimmune diseases occur more often than in the general population, including:
  • Idiopathic thrombocytopenic purpura
  • Thyroid disease
  • Pernicious anaemia
  • Haemolytic anaemias
  • Autoimmune neutropenias
  • Vitiligo
  • Autoimmune hepatitis
  • Primary biliary cirrhosis
  • Atrophic gastritis
  • Aphthous stomatitis
  • Inflammatory bowel disease
• Granulomatous disease affecting:
  • Lungs
  • Spleen
  • Liver
  • Skin
  Granulomatous diseases affect 15% of patients at presentation
• Malignancy:
  • B cell lymphomas occur more commonly
  • The risk of gastric carcinoma is 50 times greater in CVID
  • Malignant melanomas occur in CVID
• Dermatological diseases:
  • Alopecia areata
  • Skin granulomas both sarcoid-like (non-necrotising) and tuberculoid (necrotising)
  • More widespread granulomatous disease
  • Increased risk of squamous cell carcinomas and actinic keratosis
  • Increased risk of polymorphic light eruption and atopic dermatitis
  Such dermatological diseases are not markers for the disease and CVID should only be considered if there are other manifestations which might implicate CVID as the cause (for example recurrent infections).

It is likely that referral will be required to establish the diagnosis and plan treatment of the disease, the varied associated diseases and complications. It is an uncommon and complicated disease requiring both a multidisciplinary approach to care and the employment of good shared care arrangements. This involves sharing information with patients and their GPs. Information for patients and GPs about the disease and the management of the disease is essential for good care of patients.

• Antibiotics for bacterial infection, usually chest or sinus infection
• Postural drainage where bronchiectasis has developed
• Immunoglobulin replacement therapy:
  • This can be given intravenously (most commonly) or subcutaneously
  • Patients may require lifelong 3 weekly infusions to maintain IgG levels above 7-8g/L (immunoglobulins have a 3 week half-life)
  • Infusions may delay progression to bronchiectasis by reducing the number of infections
  • They may improve life expectancy and quality of life
  • Unfortunately infusions have no effect on the autoimmune or granulomatous disease which accompanies CVID
  • Infusions carry a risk of acquiring transmissible infections, particularly hepatitis C
• Corticosteroids
• TNF-alpha antagonists have also been used^{6 7}

There are many and varied complications of the disease as can be appreciated from the account above.

This depends on the extent of respiratory disease at presentation. There is an increased risk of B cell lymphoma and gastric carcinoma. The 20 year survival is 64% for men and 67% for women.