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 BMJ article details a patient's experience of the condition. This account and the accompanying medical view highlights important issues for better diagnosis and management.

CVID is an umbrella diagnosis in that it encompasses a group of genetic disorders which result primarily in hypogammaglobulinaemia or failure of antibody production.  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 common in CVID.

 

Pathophysiology

 

In common variable immunodeficiency (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.

  • A 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.

  • There is a deficiency of isotype switched memory B cells in peripheral blood. This is associated with problematic clinical complications and outcomes such as inflammatory and autoimmune conditions.

• 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.

CVID is diverse in clinical presentation, the types of deficiency and the presence of associated diseases.The sequelae of this antibody deficiency syndrome include:

• Impaired terminal B-cell differentiation which leads to varying degrees of hypogammaglobulinaemia:

  • Reduced levels of IgG and IgA, which are characteristic.

  • 50% of patients also having reduced IgM levels.

• 50% of patients have T-lymphocyte dysfunction as well.

• Susceptibility to recurrent infection by encapsulated bacteria (mainly Streptococcus pneumoniae and Haemophilus influenzae).

However, CVID, like other immunodeficiency disorders, is further complicated by a plethora of systemic immunopathology, such as autoimmune disease, lymphoproliferative disease, malignancy and sarcoid-like granulomas.

 

 

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Aetiology

• There are defects in both the innate and adaptive immune systems but the cause is unknown.

• Genetic factors:

  • A disease-causing gene for an autosomal dominant common variable immunodeficiency (CVID)/IgA deficiency has been found on chromosome 4q.

  • 20% of patients with CVID have a 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 anti-epileptic drugs.

Epidemiology

• It is found in one per 50,000 to one per 200,000 with a reported incidence of one per 75,000 live births.

• It affects male and females, and differing races equally.

• Females have more switched memory B cells and tend to be diagnosed later and live longer.

Presentation

Common variable immunodeficiency (CVID) can present in infants, young children, adolescents and adults.

• It is often diagnosed in children aged between 10 and 20 years.

• The majority 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.

  • 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 jirovecii.

• Viral infection is uncommon although some may suffer from recurrent herpes zoster infection.

• There may be associated diseases particularly:

  • Autoimmune diseases

  • Malignancies

  • Granulomatous disease

  • Dermatological manifestations

 

 

 

Investigations

 

Greater awareness of the primary immunodeficiency disorders among generalists is still needed to avert late diagnosis and subsequent chronic ill health in patients.  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 hypogammaglobulinaemia is the key finding present in all patients with common variable immunodeficiency (CVID), but tests of immune function should also be used.[8] 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:

  • FBC.

  • Autoantibody testing.

  • Serum electrophoresis.

  • Immunoelectrophoresis.

  • Radial immunodiffusion methods.

  • Immunoturbidimetric methods.

  • Assessment of antibody response.

  • Assessment of T and B lymphocytes by flow cytometry.

  • In vivo measures of T-cell function by assessing localised immunological 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.

Associated diseases

Patients with common variable immunodeficiency (CVID) may have:

• Bronchiectasis (particularly if presenting later), which is common

• Autoimmune diseases occurring 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).

 

Management

 

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 7-8 g/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 common variable immunodeficiency (CVID).

  • Infusions carry a risk of acquiring transmissible infections, particularly hepatitis C.

• Corticosteroids

• TNF-alpha antagonists have also been used.

Immunisations

• The measles, mumps and rubella (MMR) and varicella vaccines are not recommended in patients receiving replacement immunoglobulin therapy, because the vaccines may be inactivated.

• Inactivated vaccines can be given to patients with CVID but these may not be effective because of the underlying antibody deficiency.

• The influenza vaccine is commonly recommended annually.

•  

Complications

 

There are many potential complications due to the wide-ranging nature of the disease.

 

Prognosis

 

This depends on the extent of lung damage as a consequence of infection, severity of autoimmune disease and the development of a malignancy.

Numbers of switched memory B cells may also play an important role.  Women tend to be diagnosed later and live longer.