Common variable immunodeficiency is an autoimmune condition featuring decreased immunoglobulin (Ig) levels in the serum and structurally normal B cells that are able to reproduce but lack the ability to mature into Ig-producing plasma cells. This results in the weakening of the patient's immune system, thus rendering an individual subject to multiple and severe infections and diseases.
Five clinical manifestations have been described for common variable immunodeficiency :
Each and every patient that has a medical history of CVID runs the risk of developing three specific complications: periodic infections, autoimmune diseases and cancer. The recurrent infections usually affect the respiratory tracts (upper/lower); otitis media, diarrhea, pneumonia, and sinusitis are the most commonly occurring infections . Infections caused by rarely encountered organisms, such as prototheca algae, may also be seen . Giardia lamblia infections are common amongst CVID patients, causing diarrhea and malabsorption.
CVID patients are also subject to severe chronic diarrhea due to both infectious and autoimmune causes, rather than GI malignancies. Young children may especially experience hindered growth because of the recurrent infections or GI tract conditions. In cases where the bronchi are often affected, bronchiectasis may occur, with permanent damage being an expected complication. Patients are most frequently infected with h.influenzae, s.pneumoniae, m.catarrhalis and s.aureus.
Approximately 1/4 of the patients with CVID suffer complications of the autoimmune spectrum, including rheumatoid arthritis, vitiligo, hemolytic anemia, thrombocytopenia and neutropenia  . As far as malignancy is concerned, patients also run the risk of B-cell lymphomas, which has been linked to the Epstein-Barr virus.
Patients usually exhibit decreased plasma levels of immunoglobulin A and G and, at some points, equally diminished IgM levels, without any other known cause for this phenomenon. T and B lymphocytes in the serum can be evaluated with the aid of monoclonal antibodies for immunofluorescence staining, with the help of CD19 and CD20 (B cells), CD3 (T cells), CD4 (helper T cells), and CD8 (suppressor T cells). Natural killer cells (also known as NK cells) and T cells can also be enumerated with the use of monoclonal antibodies against CD16, CD56 and CD57.
A high-resolution thoracic computed tomography (CT) scan can prove useful for the diagnosis of pulmonary abnormalities; the information it provides for this specific type of disease is far more useful than that of an x-ray or a test to evaluate lung function. Biopsy samples can be harvested from enlarged lymph nodes in order to rule out malignancy. Bronchoscopy can also be used.
Endoscopy is reserved for patients suspected of suffering from gastrointestinal complications. Lesions and infectious processes can be observed, alongside villous atrophy, infection with cryptosporidium and lambliosis that can be evaluated histologically. Submucosal tissue and lymph nodes are also histologically tested. The former may be infiltrated by plasma cells and the latter may have been subject to the following changes: reactive follicular or atypical hyperplasia and granulomatous inflammation.
Antibody levels are not assessed in patients that have received IV immune globulin (IVIG) during the previous 6 months or earlier, because the antibodies that will be detected are essentially IVIG products. Flow cytometry is also used to determine B- and T-cell count, so as to eliminate the possibility of other conditions causing immunodeficiency, in order to identify CVID versus a multiplicity of other similar conditions: X-linked agammaglobulinemia, multiple myeloma and chronic lymphocytic leukemia. CVID patients usually have a decreased count of class switched memory B cells or CD21+ cells. Protein electrophoresis is used as a screening procedure to exclude monoclonal gammopathies (eg, myeloma), which may be also present with diminished levels of other immunoglobulins.
CVID patients should follow a yearly follow-up plan including spirometry, liver function tests, CBC and a metabolic check up. In cases of impaired lung function, a CT will help investigate the issue appropriately. Screening tests carried out to relatives of the patients are not a recommendation and they are reserved for patients with a given family history of the disease.
In a nutshell, common variable immunodeficiency is diagnosed by observing considerably low levels of IgG and IgA and/or IgM, alongside a decreased antibody production or lack thereof . CVID is fundamentally a condition that is diagnosed upon exclusion of other similar disorders.
Ig replacement therapy (IV or SC) is the most successful and essential treatment plan for CVID. It hinders the recurrence of infections but does come at a certain financial cost.
The levels that doctors wish to achieve in patients' blood are 400-500 mg/dL in adults; therefore, solutions of 3-12% IVIG can be used regularly. Common regimes stipulate that a dose of 400-600 mg/kg per month will achieve the expected result  . Patients with permanent lung damage require greater amounts, 700-800 mg/dL. Doses are usually administered every 1-2 weeks (SC) or 3-4 weeks (IV).
Cyclosporin A has been administered to patients with lymphoid interstitial pneumonitis, which was caused by CVID; the outcome was extremely sucessful. Anti-CD20 monoclonal antibodies have been used against autoimmune thrombocytopenia and neutropenia. Sometimes surgery is bound to be a necessity: chronic sinusitis may be treated with endoscopic surgery, autoimmune thrombocytopenia or hemolytic anemia can be treated with splenectomy.
Biopsy samples ensure that malignancy can be ruled out and an infection can be accurately diagnosed, should the lymph nodes be larger than expected. If an infection is diagnosed, antibiotics and IVIG are promptly administered. Furthermore, drugs like rituximab, TNF-α inhibitors (eg. infliximab), corticosteroids etc., can be used against autoimmune disorders, lymphoid interstitial pneumonia, and granuloma formation.
Male patients maintain a 20-year survival rate of 64% and female patients of 67%. The overall rate for male and female patients is 92% and 94%, respectively.
The prognosis depends on multiple factors: the existence of an acute autoimmune disease, periodic infections from which the patient sustains permanent lung damage and the emerge of cancer. Other factors that play a significant role in the estimation of the prognosis is the degree of organ damage and the extent to which a patient can successfully be protected against future infections. Lymphoid malignancy is a complication feared mostly in cases of polyclonal lymphocytic infiltration . Increased serum IgM and diminished CD8 count may be indicative of polyclonal lymphocytic infiltration, as well as disorders of the autoimmune spectrum .
Despite tremendous effort, 40 years of research have yet to discover the exact primary cause for common variable immunodeficiency. This is partly because of the great diversity of this condition. Approximately 20% of patients suffering from CVID have a parent, sibling or offspring who also exhibits a selective IgA deficiency, leading to the suggestion that the disease may be affected by genetic factors. In cases where multiple family members are affected with CVID, about 5% of the patients display a coexisting IgA deficiency; it has been proposed that the inheritance pattern involved in these cases is that of an autosomal recessive inheritance.
Antirheumatic or antiepileptic medication has also been incriminated for causing CVID. If it is proven later on that such a drug has indeed caused the disorder, genetic factors are perceived as having played the role of predisposition, as opposed to causality.
A common flaw of the B-cell differentiation process is bound to play an important role in the occurrence of the disease, but in the majority of the patients the molecular defect remains unknown. Mutations are also sporadic in more than 90% of the cases. There has only been a sub-category of patients whose molecular abnormalities were identified: most are extremely uncommon, except for mutations in TNFRSF13B, which encodes the transmembrane activator and calcium modulator and cyclophilin ligand (TACI). Mutations in TACI occur in ∼8–10% of patients with CVID  .
From a clinical point of view, CVID resembles X-linked agammaglobulinemia concerning the types of infections that arise, but the former characteristically presents between the ages of 20 and 40, namely at a later stage when compared to X-linked agammaglobulinemia. A definite genetic cause of CVID has been established in less than 10% of the patients. The most common type of the condition involves patients who report no prior medical history of CVID in their family; in these cases it is believed that the disease is caused by a synergy of environmental and genetic factors (aka multifactorial inheritance), with genes controlling the differentiation and function of plasma cells being deemed as the primary cause.
Common variable immunodeficiency affects approximately 1 person per 50,000 population throughout the world, without a definite tendency towards a specific race or gender.
It can occur in various ages, from infants to people aged 40 years or older. Peaks of onset include children of 1-5 years and people of 16-20 years, with more than 2/3 of the patients having surpassed the 2nd decade of their lives when CVID is diagnosed . It affects approximately 1 in 25,000–50,000 individuals   , with report varying according to race. Given its relative prevalence and numbers of cases addressing a physician for medical help, CVID has an indubitable clinical significance  .
Patients suffering from CVID exhibit multiple immune-system defects; usually the predominant flaw concerns an impaired antibody production. Humoral and cell-mediated lymphocytic reactions are irregular; the basic pathophysiologic mechanism in CVID is a failure in the process of B lymphocyte maturation. However, studies have shown that this type of abnormality is not frequently observed in patients. One study used pokeweed mitogen to stimulate B cells in vitro and proved that they did not posess the capability to differentiate into plasma cells, something that strongly suggests that surface molecules are expressed in B-cells in an abnormal way.
Cellular irregularities such as these are believed to be caused by defects of the second messenger and translocation pathways of B cells: defective protein kinase C activation and tyrosine phosphorylation. Further studies suggested that the complete lack of IgG and IgA, an increased rate of spontaneous apoptosis, insufficient DNA repair and somatic mutations all impair the functionality of B-cells.
Various factors and cofactors trigger the production of Ig from B cells acquired from patients with CVID: B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, IL-2, IL-4 and IL-10. Among patients suffering from the condition, 25-30% also present with augmented levels of CD8+ T cells and a diminished CD4/CD8 ratio (less than 1). It is believed that increased cyclic adenosine monophosphate levels and the activation of protein kinase A constitute the cause for this phenomenon. Moreover, 60% of patients with CVID display a flawed reaction to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma. CVID carrying an autosomal dominant inheritance pattern has been associated with the chromosome 4q , with one study supporting the validity of a certain gene, thought to be responsible for the development of autosomal dominant CVID/IgA deficiency. This gene's location is believed to be on chromosome 4q. Other potential locations for dominant CVID genes include chromosomes 5p and 16q.
There are not many preventive measures against CVID, since its causes still remain unknown. The only existing recommendation advises patients to receive a polysaccharide vaccine , because some of them are capable of producing sufficient antibodies, therefore rendering the immunization a success.
Common variable immunodeficiency is a condition otherwise known as acquired or adult-onset hypogammaglobulinemia. Its typical characteristic is insufficient immunoglobulin (Ig) levels in the plasma, accompanied by morphologically normal B cells that are able to multiply in number but exhibit an inability to turn into Ig-producing plasma cells, which is the last stage of their maturation process. Amongst the primary immunodeficiencies causing clinical manifestations, CVID is by far the most common and can include a broad range of symptoms and fluctuating degrees of severity. It is deemed as a group of conditions with no known cause, primarily due to the multiple immune system defects that have been found to cause this disorder. Low immunoglobulin levels result in a diminished ability to attack foreign substances (bacteria, viruses etc.) and protect the organism. Immunoglobulins are naturally produced by white blood B-type cells once they differentiate into plasma cells.
Common variable immunodeficiency features are decreased levels of most or all of the immunoglobulin classes (IgA, IgG, IgM, IgD, IgE). A diagnosis of CVID is based upon exclusion of other disorders causing immunodeficiency and is mainly established in cases of a B-cell dysfunction that cannot be traced to any other causes .
Lastly, CVID can present with a fluctuating clinical presentation and variable types of deficiency. Despite of decreased plasma concentration of immunoglobulin G (IgG) and immunoglobulin A (IgA) being typical of CVID, nearly 50% of patients with this disorder also exhibit low plasma levels of IgM and T-lymphocyte dysfunction. It has been estimated that about 20% of CVID patients will eventually be affected by an autoimmune disease .
People affected by common variable immunodeficiency have very low antibody levels and a normal number of B cells (lymphocytes). B cells follow a certain maturation pattern, and when they develop into the so-called plasma cells, they start producing antibodies. In cases of CVID, B cells fail to do so, resulting in less natural protection from microorganisms and other conditions.
Patients usually suffer from periodic infections, including pneumonia, sinusitis, diarrhea. Diarrhea in particular can also result from autoimmune causes; CVID patients are also at a greater risk of developing an autoimmune disease at a percentage of 25%. Antibiotics are administered in cases of infections and other types of treatment (corticosteroids, rituximab) are reserved for autoimmune phenomena.
Doctors suspect CVID by evaluating the symptomatology. Blood tests can measure antibody levels and observe how well the body responds to vaccines. Patients receive "supplementary antibodies" throughout their lives to compensate for those that cannot be naturally produced, namely sera containing antibodies of people with normally functioning immune systems. The majority of the patients have a normal life span, except for cases of a coexisting complication, such as a lymphoma which does not respond to treatment.