Common Variable Immunodeficiency

What is Common Variable Immunodeficiency?

Common variable immunodeficiency (CVID) is a cluster of nearly 150 primary immunodeficiencies or PIDs that are characterized by a common group of features that includes hypogammaglobulinemia but are caused by different underlying factors. It is the most commonly occurring form of primary immunodeficiency, hypogammaglobulinaemia or immunoglobulin deficiency. Nevertheless, the term “common” is relative as its prevalence is still quite low. It causes an increased susceptibility to autoimmune disorders and infections. It is quite likely that CVID includes numerous distinct disorders that are yet to be identified.

The condition is also referred to as Acquired hypogammaglobulinemia.

Common Variable Immunodeficiency Epidemiology

CVID is a rare disorder, occurring only in 1 among 50000 to 200000 individuals. It has a reported incidence of around 1 in every 75000 live births. A CVID patient is typically between the ages of 20 and 40 years. The ratio between male and female patients is more or less equal. Almost 20% of all patients are diagnosed with this disorder during their childhood. No racial predilection in association with this immunodeficiency condition has been found. Females tend to have much more switched memory B-cells than males. Due to this reason, they are normally diagnosed later with the disease and have a longer life.

Common Variable Immunodeficiency Causes

CVID has several probable causing factors, the knowledge of which is limited. While conducting a diagnosis, a medical team should eliminate other possible causes that might lead to immunoglobulin deficiency. Mutations in certain specific genes such as TACI, ICOS and CD19 impair the immune system and leads to the development of CVID. Polymorphism or variation in formation of the genes affects normal functioning of proteins produced by them. This process occurring in a number of genes of immune system is held as a probable factor that creates preconditions favorable for the development of this disorder. It often develops after certain infections.

Although CVID is not hereditary, the polymorphisms are inherited which explains why many families having one individual affected by CVID also have other people suffering from same or some other immunodeficiency having a similar cause. Two of such diseases include:

• IgG subclass deficiency
• Selective immunoglobulin A deficiency.

Due to the defects causes by such immunodeficiencies, a patient does not produce enough number of antibodies when exposed to pathogens. Consequently, the immune system fails to provide protection against common viral and bacterial as well as the occasional protozoan and parasitic infections. This makes an affected individual susceptible to illness.

The B cells get affected in CVID. In another condition known as severe combined immunodeficiency or SCID, both parts of immune system, i.e., the humoral and cellular system gets affected. It is a more critical condition than CVID and is normally diagnosed in infancy.

Due to a genetic predisposition, the immune system can be provoked by a virus or some environmental agents. However, this is still a hypothesis and has not been proven yet.

Common Variable Immunodeficiency Types

CVID appears to be comprised of numerous defects and only some of them have been identified. For most of the conditions, the responsible genetic factors are still unknown. The following are some of the most common types of CVID:

• CVID1
• CVID2
• CVID3
• CVID4
• CVID5
• CVID6

Common Variable Immunodeficiency Symptoms

CVID sufferers may exhibit the following symptoms:

• Fatigue
• Asthma
• Nausea
• Bloating
• Diarrhea
• Diabetes
• Vomiting
• Giardiasis
• Weight loss
• Granulomas
• Malabsorption
• Alopecia areata
• Abdominal pain
• Enlarged spleen
• Cryptosporidiosis
• Alopecia universalis
• Aphthous stomatitis
• Rheumatoid arthritis
• Pulmonary infections
• Maculopapular rashes
• Enlarged lymph nodes
• Nodules with ulcerations
• Hypogammaglobulinemia
• Helicobacter pylori disease
• Inflammatory bowel disease
• Risks of pulmonary damage
• Inflammatory intestinal diseases
• Increased intestinal permeability
• Enlargement of the thyroid gland
• Small intestinal bacterial overgrowth
• Low levels of immunoglobulin A (IgA)
• Low levels of immunoglobulin G (IgG)
• Low levels of immunoglobulin M (IgM)
• Nodular lymphoid hyperplasia of GI tract
• A pulmonary infection known as Candida
• Viral infections that generally respond to antivirals
• Atrophic gastritis with achlorhydria and pernicious anemia
• Villous atrophy of small intestine that might resemble celiac disease
• Bronchiectasis might occur due to recurrent and severe lung infections
• Depression and anxiety usually caused by dealing with other symptoms
• Infiltrated erythematous papules, excoriated papules, plaques, and ulcers
• Immunological thrombocytopenia (i.e., autoimmune blood platelet deficiency)
• Autoimmune haematolytic anemia (i.e., anemia that occurs due to autoimmune destruction of the red blood cells)
• Children might fail to thrive properly; they might be underdeveloped and underweight compared with their normal peers
• Poorer titer response to vaccinations with polysaccharide and/or protein antigens (e.g. tetanus, pneumococci and diphtheria)
• Joint pain or polyarthritis that is spread across most of the joints, but mostly fingers, elbows, wrists, ankles, toes and knees. In certain cases, the pains can be caused by Mycoplasma.
• Recurring infections of the eyes, ears, nose, sinuses, lungs, bronchi, skin, bones, joints, GI tract, parotid glands, central nervous system, etc which respond positively to antibiotics but nevertheless recur upon discontinuation of the medicines.

Common Variable Immunodeficiency Diagnosis

Diagnosis of this disorder is generally made by detecting lower levels of immunoglobulins within the serum. Although the diagnosis can be made quickly, it is often delayed and made after being referred to an immunologist only during the 2nd or 3rd decade of life. The diagnostic process of CVID mostly involves the exclusion of other possible disorders that may lead to an immune deficiency.

Diagnoses to exclude other problems might include a loss of protein from kidneys or a reduced antibody production that is secondary to multiple myeloma or chronic lymphocytic leukemia. Although the symptoms presented are similar to that of X-linked agammaglobulinemia, CVID can be easily distinguished by flow cytometry.

The various other diagnostic procedures, used to check whether or not an individual is having CVID, include:

• Biopsies
• Endoscopy
• Enteroscopy
• Bronchoscopy
• Autoantibody testing
• Complete blood count
• Radial immunodiffusion
• High resolution CT scans of the chest
• Evaluation of the functions of T-cell and B-cell lymphocytes
• Measurement of the proliferation of T-cell and B-cell lymphocytes
• Measurement of the levels of cytokines, mediators, antigens and activators
• Measurement of the levels of secreted immunoglobulin in culture supernatant

Common Variable Immunodeficiency Differential Diagnosis

There are certain health conditions whose symptoms overlap with those of CVID. Hence while determining the diagnosis of CVID; it should be differentiated from these similar appearing diseases. The differential diagnoses of CVID include telling its symptoms apart from conditions such as:

• Allergies
• Trisomy 8
• Thymoma
• Trisomy 21
• Cystic fibrosis
• Celiac disease
• IgA deficiency
• Tropical sprue
• Monosomy 22
• Crohn’s disease
• Down syndrome
• B cell malignancy
• Kabuki syndrome
• DiGeorge anomaly
• Tufting enteropathy
• Netherton syndrome
• Ataxia Telangiectasia
• Hyper IgM syndromes
• Selective IgA Deficiency
• Immotile cilia syndromes
• Chromosomal anomalies
• Complement deficiencies
• Food protein enteropathy
• Graft versus host disease
• Non Hodgkin’s lymphoma
• Protein-losing enteropathy
• CHARGE syndrome (CHD7)
• 22q11.2 deletion syndrome
• Microvillus inclusion disease
• Chromosome 18q- Syndrome
• Bruton’s agammaglobulinemia
• Chronic Lymphocytic Leukemia
• Wiskott-Aldrich syndrome (WAS)
• Selective IgG subclass deficiency
• Immunodeficiency with Thymoma
• X-linked agammaglobulinemia (XLA)
• Severe combined immunodeficiency
• Chronic granulomatous disease (CGD)
• Leukocyte adhesion deficiencies (LAD)
• X-linked lymphoproliferative disease (XLP)
• Autosomal recessive agammaglobulinemias
• X-linked severe combined immunodeficiency
• Autoimmune lymphoproliferative syndrome (ALPS)
• Autoimmune enteropathies, such as IPEX syndrome
• Autosomal forms of severe combined immunodeficiency
• Intestinal lymphangiectasia and lymphatic malformations
• Transcobalamin II deficiency and hypogammaglobulinemia
• Transient hypogammaglobulinaemia secondary to infections
• Selective deficiency in response to the polysaccharide antigens
• Immunodeficiency associated with an excess loss of immunoglobulins
• Immunodeficiency associated with hypercatabolism of immunoglobulin
• Warts/hypogammaglobulinemia/infection/myelokathexis (WHIM) syndrome
• Lymphoid neoplasias, such as multiple myeloma and chronic lymphocytic leukemia
• Congenital neutropenias such as ELA2-related neutropenia and X-linked severe congenital neutropenia
• Combined immune deficiencies, such as adenosine deaminase deficiency (ADA), ataxia-telangiectasia (ATM) or polynucleotide phosphorylase (NP)

A number of infectious diseases may lead to immunodeficiencies whose signs overlap with that of CVID. Among these are:

• HIV/AIDS
• Epstein-Barr virus
• Congenital Rubella
• Congenital infection with Cytomegalovirus
• Congenital infection with Toxoplasma gondii

There are also certain drugs and medications which can lead to immunodeficiencies mimicking the symptoms of CVID. These include:

• Captopril
• Gold salts
• Phenytoin
• Fenclofenac
• Sulfasalazine
• Penicillamine
• Carbamazepine
• Glucocorticoids
• Antimalarial agents

Common Variable Immunodeficiency Associated Disorders

As is the case with various other immune cell conditions, CVID can predispose an individual to lymphoma or even possible stomach cancer. A predilection for certain other autoimmune disorders can also be noticed, with an increased risk of around 25%. The most prevalent of these are the autoimmune destruction of red blood cells or platelets.

Common Variable Immunodeficiency Treatment

The main goal of treatment is to minimize the chances of infections, thereby preventing the onset of chronic pulmonary disease or other infections that are damaging to the organs. Treatment primarily consists of:

• Intravenous immunoglobulin
• Intramuscular immunoglobulin
• Subcutaneous immunoglobulin

The above mentioned modes of treatment are sometimes backed up by additional preventative medications like prophylactic antibiotics. When CVID has been identified and proper treatment has been administered, there is a good chance that an affected individual would feel less fatigued and lead a healthier life.

People having CVID should be treated lifelong with gamma globulin. Appropriate doses of gamma globulin are going to reduce the frequency of bacterial infections as well as the risks of associated organ damage. Gamma globulins are concentrate of antibodies that are obtained from plasma of numerous blood donors. Blood obtained from each donor is carefully screened for infections like HIV and hepatitis. It is then treated to minimize the risks from bacteria and viruses. It is a liquid that contains purified IgG antibodies along with small portions of IgM and IgA antibodies. Although it is not possible to make gamma globulin entirely free from the agents of infection (as it is a type of blood product), the current production methods along with latest developments in medical technologies guarantee very high levels of safety.

The antibodies that are introduced in the body get broken down successively. The treatment is then repeated after every 1 to 3 week intervals. The period of interval depends on the quantity of medication administered every time. In case of intravenous administration, larger doses are generally given every 3rd week. On the other hand, subcutaneous doses should be carried out more frequently in smaller quantities.

Treatment for all signs of infections should begin early and antibiotic medications should be administered to manage such conditions. Prophylactic antibiotics might be required before certain surgical operations for preventing infection of the wounds or spreading of bacterial infections through blood stream. Individuals having CVID should not be given live vaccines without a complete medical evaluation. Vaccines with inactivated or live pathogens normally serve to trigger production of antibodies which help to create immunity against CVID. As the people having this disorder are generally unable to produce enough numbers of antibodies, some live vaccines might cause chronic infections. However, some individuals have shown positive response when they were vaccinated against influenza, Hemophilus influenzae and Streptococcus pneumoniae. Granulomas should be treated with cortisones as well as other anti-inflammatory medications.

Preschools are not suitable for children having CVID. Adults having this disease should not work with preschool children either, as children between 2 to 4 years of age have the highest vulnerability to infections. Even children who seem to be healthy frequently carry bacteria which can lead to respiratory tract infections in throat and nose, thereby posing as a major threat to adults and children having immunodeficiency disorders.

Along with antimicrobial therapy, specific therapy is also often required to heal a particular target organ system. Patients having chronic lung disease frequently develop conditions like airway obstructive disease. This can be treated with inhaled corticosteroids or other asthma medications.

Headaches can be treated with antihistamines, acetaminophen or paracetamol, or some anti-inflammatory agents, such as advil, naproxen and aspirin.

Surgery

The following surgical operations are commonly held in association with CVID:

• Endoscopic sinus surgery, which may be required to treat chronic sinusitis.
• Hemolytic anemia or severe autoimmune thrombocytopenia, which can be managed by splenectomy.

Physical exercise

Patients should follow a regular physical exercise regimen. Maintaining a basic standard of physical fitness can help in combating infections as well as other forms of physical stress. Suitable activities can be recommended by a physiotherapist, who can also set up an exercise program for people suffering from inflammations of the muscles and joints. However, it is always advisable to stay away from strenuous exercises during infections as it can work against the healing process.

Continuous or recurrent infections may damage the tissue of the lungs. Development of phlegm and severe long-lasting infections can be prevented by breathing exercises as well as with the use of expectorants and bronchodilating inhalers. Spontaneous coughing and deep breathing can be stimulated by various forms of physical activities.

Dental care

Some patients of CVID may develop mucous membrane abnormalities and oral infections, thus requiring specialist dental care. Good oral hygiene and regular dental care can help in the prevention of gingivitis and periodontitis. If bleeding occurs, antibiotic medications should be administered prior to dental procedures such as tooth extraction or removal of plaque.

Common Variable Immunodeficiency Complications

Some CVID patients might have adverse reactions to immunoglobulin therapies which may include:

• Chills
• Joint pains
• Hives (rare)
• Headaches
• Muscle pains or aches
• Difficulty in breathing
• Thrombotic events (rare)
• Nausea (common with IVIG)
• Anaphylactic shock (quite rare)
• Severe fatigue (very common with IVIG)
• Fever (rare in SCIG and common with IVIG)
• Swelling at the site of insertion (common in SCIG)
• Aseptic meningitis (rare but more frequent in patients having SLE)

Other complications reported in patients of CVID include:

• Sepsis
• Diabetes
• Meningitis
• Lymphoma
• Osteomyelitis
• Viral infections
• Chronic sinusitis
• Hemolytic anemia
• Pulmonary damage
• Rheumatoid arthritis
• Recurrent infections
• Enlarged thyroid gland
• Autoimmune phenomena
• Low count of peripheral B-cells
• Inflammatory intestinal diseases
• Severe autoimmune thrombocytopenia
• Malnutrition as a result of gastrointestinal tract disease
• Cor pulmonale secondary to chronic pulmonary infection
• Liver failure occurring due to viral and/or autoimmune hepatitis

Common Variable Immunodeficiency Prognosis

The outcome depends on presence of recurrent infections that cause structural lung damage, severe autoimmune disease as well as development of some malignancy. Other factors that influence the prognosis include extent of end organ damage and success of prophylactic medications against future infections. A clinical predictor of a lymphoid malignancy is polyclonal lymphocytic infiltration. Reduced proportions of circulating CD8 and elevated serum IgM may indicate autoimmunity and polyclonal lymphocytic infiltration.

Common Variable Immunodeficiency Prevention

Polysaccharide vaccine on an immunization program needs to be considered for the CVID patients who can produce the protective antibody titers, as this can minimize the risks associated with the condition.