Common Variable Immunodeficiency

Common variable immunodeficiency (CVID), the most common clinical primary immunodeficiency in adults, is a disorder that involves the following: (1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent bacterial infections.[12] A diagnosis of CVID is reserved for those with an undefined B-cell dysfunction.[13] Combining DNA sequencing with gene expression, methylation, proteomic, and metabolomics data holds the promise of greatly expanding knowledge about CVID.[14, 15]

CVID is diverse, both in its clinical presentation and in the types of deficiency. Although decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are characteristic, approximately 50% of patients with the deficiency also have diminished serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction. In CVID, the T-cell compartment is strongly impacted, with premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation.[16] About 20% of those with CVID develop an autoimmune disease.[17] In addition, autoinflammatory, granulomatous, and/or lymphoproliferative disorders may become evident.[15]

Also see the article Pediatric Common Variable Immunodeficiency.

In patients with common variable immunodeficiency (CVID), numerous immune-system abnormalities are reported, the most common of which is defective antibody formation. Consequently, both humoral and cell-mediated lymphocytic responses are affected. Some CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help.[18] Innate immunity defects may modify clinical status and findings in these patients.[19]

Changes in the humoral response

The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes. However, evidence shows that this defect in the pathway is not common among patients. One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.

Such cellular deficits have been traced to the second messenger and translocation pathways of B cells. These deficits include problems with protein kinase C activation and tyrosine phosphorylation. Findings from other studies suggest the complete absence of IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA repair, and the presence somatic mutations affecting B-cell regulation.

Changes in the cell-mediated response

A number of factors and cofactors stimulate Ig secretion from B cells harvested from patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 10 (IL-10). Perhaps the most potent stimulant is the CD40 ligand, which is expressed by activated CD4+ cells. In fact, in 40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells. In these patients, decreased IL-2 production after T-cell receptor stimulation is also present.

A common defect is the response to antigens by CD4+ T lymphocytes. After immunization, some patients with CVID have decreased numbers of circulating responsive CD4+ T cells. Other patients have an increased number of CD4+ T cells, but they also have an increased rate of apoptosis of these cells. Signal transduction appears to be the primary defect in these T cells. Rezaei et al report on the meningococcal vaccination response in CVID patients. They suggest it may help define subgroups of patients, which may lead to better monitoring and new therapeutic strategies.[20]

Of all patients with CVID, 25-30% often have increased numbers of CD8+ T cells and a reduced CD4/CD8 ratio (< 1). The cause is an increase in cyclic adenosine monophosphate levels and the increased activation of protein kinase A. On physical examination, patients with this subtype often have splenomegaly and bronchiectasis. In addition, 60% of patients with CVID have a diminished response to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma. However, the T-cell receptors show no evidence of abnormality; in fact, genetic findings indicate normal heterogeneity of the genetic rearrangements. Therefore, most patients with CVID can be said to have antibody deficiency secondary to T-cell signaling abnormalities, as well as defective interactions between T and B lymphocytes. Laino et al report that the prevalence of distinct clinical complications of CVID is higher in patients with B- and T-cell abnormalities.[21]

Both the transient and permanent recovery of Ig production has been reported in both patients with HIV and in patients with hepatitis C infection. This finding may indicate that CVID is associated with potentially reversible defects in humoral and/or cellular immunoregulatory factors.

TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. One series found that 4 of 19 unrelated individuals with CVID and 1 of 16 individuals with IgA deficiency had a missense mutation in 1 allele of TNFRSF13B (encoding TACI).[22] TTACI mutations can result in CVID and IgA deficiency. Four genes have been documented to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19.[23] Heterozygous mutations in TNFRSF13B are also associated with CVID,[13] whereas the other 3 genes are recessive.[24, 25] Those with a mutation in the TNFRSF13B gene may require further investigation.

Autosomal dominant CVID has been linked to chromosome 4q.[26] One study supports the existence of a disease-causing gene for autosomal dominant CVID/IgA deficiency on chromosome 4q. Other possible loci for dominant CVID genes are on chromosomes 5p and 16q.

The primary cause of common variable immunodeficiency (CVID) remains unknown despite 40 years of research. Part of the problem is the heterogeneity of the disease.

Genetic factors may be involved. In approximately 20% of patients with CVID, a first-degree family member has a selective IgA deficiency. This finding may indicate that the genes are linked.

When more than one family member is affected with CVID, approximately 5% of the patients have a concurrent IgA deficiency.

Further results reveal specific localization to the C4A gene and, rarely, to the C2 gene in the class III region of the major histocompatibility complex on chromosome 6.

No clear pattern of inheritance has been observed. Because most patients represent sporadic cases and because they have no family history of immunodeficiency, different modes of inheritance such as autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms have been reported.[27]

An autosomal recessive pattern of inheritance is suggested when more than one family member is affected.

CVID is associated with the use of antirheumatic or antiepileptic drugs. If such an association is later proven to be a causal relationship, the genetic etiology may turn out to be a genetic predisposition to the disease. A common insult to the B-cell differentiation pathway may be involved.

The prevalence of common variable immunodeficiency (CVID) is approximately 1 case per 50,000 population worldwide.

Race-, sex-, and age-related frequency

CVID does not show a predilection for any specific race.

CVID equally affects males and females.

CVID can occur in infants, young children, adolescents, or even those aged 20-40 years or older. CVID can become evident at any time from infancy to after the fourth decade of life. Peaks of onset occur in children aged 1-5 years and in persons aged 16-20 years. More than two thirds of patients are aged 21 years or older when CVID is diagnosed.

The prognosis depends on the presence of severe autoimmune disease, recurrent infections causing structural lung damage, and the development of a malignancy. A 20-year survival rate is 64% for male patients and 67% for female patients. In general, the expected survival rate for male and female patients is 92% and 94%, respectively. Death may result from various causes. In 1 series, neoplasia became a common complication in the elderly during follow-up.[28]

Other major factors in determining the prognosis is the extent of end-organ damage and the success of prophylaxis against future infections.

Polyclonal lymphocytic infiltration is a clinical predictor associated with a 5-fold increased risk of lymphoid malignancy.[29]

Elevated serum IgM and reduced circulating CD8 proportions may be predictive markers for polyclonal lymphocytic infiltration and autoimmunity.[29]

Those who develop granulomatous lymphocytic interstitial lung disease tend to experience early mortality. Clues to this complication may include splenomegaly and a low serum IgA level.[30]

Patients and their families should be educated about the early signs of infection so that aggressive treatment is not delayed.

One helpful organization is the Immune Deficiency Foundation, which provides a wealth of information to health care providers and patients and their families.

Five distinct clinical phenotypes have been delineated for common variable immunodeficiency (CVID): no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy.[29] In any patient with a past medical history of CVID, 3 complications must be considered: recurrent infections, autoimmune phenomena, and malignancy (see Physical).

Patients with CVID often have a history of recurrent infections.

The recurrent infections commonly affect the upper and lower respiratory tracts. Patients come to medical attention due to infectious diseases at the time of onset, the most common being otitis media, diarrhea, pneumonia, and sinusitis.[31] Almost all have acute and recurrent infections. Infections with unusual organisms, including Prototheca algae infection, may be seen.[32]

Persistent diarrhea and malabsorption caused by Giardia lamblia infection occur in patients with CVID. Symptoms generally resolve after treatment with metronidazole. Infectious and autoimmune etiologies are the most likely causes for severe chronic diarrhea. Diarrhea is not a common symptom of gastrointestinal malignancy.

Young children may fail to thrive because of the frequent infections or gastrointestinal tract disease.

Generally, the physical examination findings are correlated to the history, and they depend on the clinical presentation and specific organs involved.

Splenomegaly and generalized lymphadenopathy are present in many patients with common variable immunodeficiency (CVID).

Recurrent infections

Permanent damage to the bronchi may occur, resulting in bronchiectasis.

Common infective organisms include Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.

In some patients with CVID, uncommon infectious agents such as Pneumocystis carinii and Mycoplasma pneumoniae may be detected first.

In addition to pulmonary infection, M pneumoniae can also cause primary infection in the urinary tract and joints.

Infection with G lamblia may cause persistent diarrhea and malabsorption.

Recurrent infections with herpes simplex virus are reported. Herpes zoster infection may develop in as many as 20% of patients with CVID.

Enterovirus infection has been reported in association with CVID.[33]

Autoimmune phenomena

As many as 20% of patients with CVID develop autoimmune complications.[1]

Rheumatoid arthritis, vitiligo, hemolytic anemia, thrombocytopenia, pyoderma gangrenosum,[2] and neutropenia have all been associated with CVID.[4]

Gastrointestinal diseases include pernicious anemia, a spruelike malabsorption disorder, autoimmune hepatitis, primary biliary cirrhosis, intestinal nodular lymphoid hyperplasia, atrophic gastritis, aphthous stomatitis, and inflammatory bowel disease.[34]

Malignancy

In patients with CVID, the risk of certain malignancies is high.

Lymphomas of a B-cell phenotype are of particular concern.

Malignancy is most likely associated with the Epstein-Barr virus.

The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.

Malignant melanomas are reported.

Dermatologic manifestations[35]

Alopecia areata and alopecia universalis may occur.[36] Any time a person presents with recurrent infections and alopecia, CVID should be considered in the differential diagnosis. In one case study from the Hacettepe University in Turkey, Kiliç et al[37] reported a 12-year-old boy who had recurrent respiratory tract infections and chronic diarrhea since age 2 years. At age 2.5 years, he had a bandlike localized loss of hair (alopecia areata), and 1 year later, he had lost all body hair. His sister had similar findings and died from a pulmonary infection at the age of 7 years. On further studies, the patient was found to have decreased serum levels of IgG, IgA, and IgM and an increased number of CD8 cells. In addition, a skin biopsy specimen showed a perifollicular infiltrate of mononuclear cells.

Cutaneous infections may be serious too, with necrotizing fasciitis described in one patient.[38]

In patients with CVID, both non-necrotizing granulomas (sarcoidlike) and necrotizing granulomas (tuberculoid) have been observed.[5, 6, 8, 7]

In one case report by Pujol et al,[39] histopathologic biopsy showed perivascular lymphoid infiltrates in the upper and mid dermis, with central necrosis and a palisading granuloma.

A syndrome similar to sarcoidosis can affect patients with CVID.[10] This syndrome is characterized by noninfectious cutaneous granulomas, with underlying visceral granulomas of the lungs, liver, spleen, or conjunctiva in most patients. These cutaneous granulomas are nonspecific in patients with CVID and can appear as a maculopapular rash; as infiltrated erythematous papules, plaques, excoriated papules, and ulcers; or as nodules with ulcerations. On histologic analysis, such granulomas are noncaseating and involve the dermis or subcutaneous fat. These nonsarcoidal, nontuberculoid asymptomatic cutaneous granulomas often appear as multiple, nontender subcutaneous nodules, predominantly juxta-articular, and the skin overlying the nodules was either normal or slightly erythematous.[11]

Lesions frequently appear on the face and extremities and are always sterile. They often resolve with treatment of the underlying disease.

Residual hyperpigmentation may be observed.

The increased incidence of malignancy in patients with CVID is well known. In 1992, Green and Moschella[40] reported the first known case of a patient with CVID who developed multiple squamous cell carcinomas. Many other cases have been published since then. Patients with CVID have an increased risk for actinic keratosis and squamous cell carcinoma. This risk is not surprising given the increased incidence of skin cancer with prolonged iatrogenic immunosuppression, as in transplant recipients.

Other dermatologic manifestations of CVID include atopic dermatitis, cutaneous vasculitis including polyarteritis nodosa,[9] and polymorphic light eruption.[41] However, these are not specific markers of CVID, and they are not indications for a workup for CVID unless other implicating factors (eg, recurrent infections) are present.

In any patient with a medical history of common variable immunodeficiency (CVID), the three following complications must be considered (see Physical):

• Recurrent infections

• Autoimmune phenomena

• Malignancy

Death may result. A common cause of death in patients with CVID is lymphoma. Other causes include cor pulmonale secondary to chronic pulmonary infection, liver failure caused by viral or autoimmune hepatitis, malnutrition resulting from gastrointestinal tract disease, and other viral infections. Factors associated with mortality include low levels of IgG, poor T-cell responses to antigens, and a low percentage of peripheral B cells.

Other complications include chronic sinusitis, severe autoimmune thrombocytopenia, and hemolytic anemia.

Common variable immunodeficiency (CVID) can be diagnosed after defective functional antibody formation is obtained. Usually, patients have decreased (not absent) serum IgA and IgG levels and, occasionally, decreased serum IgM levels in the absence of other known causes of antibody deficiency. Low serum IgE is a sensitive and specific marker for CVID. Accordingly, routine serum IgE levels should be used in evaluating patients with hypogammaglobulinemia.[44]

Compared with patients with X-linked agammaglobulinemia, patients with CVID generally have higher serum Ig levels; however, the levels are consistently depressed. The reference range for serum Ig varies with the patient's age, and the Ig results must be evaluated on the basis of these age-dependent ranges.

Although electrophoresis and immunoelectrophoresis are not acceptable techniques for the quantification of Ig levels, radial immunodiffusion or immunoturbidimetric methods remain valuable.

An assessment of functional antibody production in response to natural antigens or antigens to which the population is commonly exposed may be helpful. Similarly, an evaluation of the antibody response after active immunization with polysaccharide or protein antigens is possible.

However, because the nonresponse rate to hepatitis B is so high, especially among persons older than 40 years, these antigens remain unreliable in the testing of immune competence.

Circulating T and B lymphocytes can be assessed by using monoclonal antibodies for immunofluorescence staining. CD19 and CD20 (B cells), CD3 (T cells), CD4 (helper T cells), and CD8 (suppressor T cells) are all commonly used.

Natural killer (NK) cells also express CD3 and CD8 surface proteins. Therefore, NK cells and T cells can be further enumerated by using monoclonal antibodies against CD16, CD56, and CD57, though they are not lineage specific.

The in vivo measurement of T-cell function is possible by using an anergy panel to assess localized immunologic skin responses.

The antigens most commonly used include mumps (1 mg/mL), although availability of this antigen has varied; trichophytin (1:30 dilution); purified protein derivative (PPD) (2-10 IU); Candida antigen (1:100 dilution); and tetanus fluid toxoid (1:1000 dilution). An intradermal injection of 0.1 mL of antigen is necessary to perform the test.

The results should be read 48-72 hours after the injection to ensure an induration of maximal diameter. A positive test result indicates intact delayed-type hypersensitivity. A negative test result to all antigens suggests impaired type IV immunity. Erythema around the injection site does not indicate a positive result.

To assess the functional activity of the lymphocytes in vitro, they must be isolated and stimulated with a variety of agents. One class of activators is the mitogens, which includes phytohemagglutinin and concanavalin A, both of which stimulate T cells. Pokeweed mitogen promotes proliferation of both T and B lymphocytes.

Another class of stimulators includes antigens. PPD, streptokinase, Candida antigen, and tetanus toxoid all activate lymphocytes, if the patient has had a prior exposure to the antigen or superantigen.

Allogeneic cells can also act as activators. They stimulate T-cell proliferation in mixed lymphocyte cultures. The proliferation of lymphocytes can be activated by in vitro antibodies to T-cell surface molecules that are important in signal transduction. These molecules include CD3, CD2, CD28, and CD43.

T-cell activity can be directly studied. T lymphocytes express certain antigens after activation. These antigens include CD69, IL-2 receptor (CD25), transferring receptors (CD71), and major histocompatibility complex class II molecules (human leukocyte antigen DR).

Measuring the levels of mediators and cytokines such as IL-2, IL-4, IL-5, interleukin 6 (IL-6), interferon gamma, and tumor necrosis factor in the culture supernatant is another useful tool.

Another method is the measurement of levels of secreted Ig in the culture supernatant. The complete blood count and autoantibody testing may be helpful as well. Anemia secondary to an autoimmune process may be detected. Severe lymphopenia may indicate that the patient has severe combined immunodeficiency disease or other primary T-cell defects.

For the detection of pulmonary abnormalities in patients with common variable immunodeficiency (CVID), high-resolution computed tomography of the chest may be more useful than plain chest radiography or pulmonary function testing.

Excluding an infectious etiology is important. The periodic monitoring of pulmonary function is crucial in any patient who is able to perform the forced expiratory maneuvers.

Biopsy should be considered to exclude infection or malignancy in enlarging lymph nodes.

Bronchoscopy or endoscopy can provide information regarding specific lesions or infectious processes.

Villous atrophy or infection with cryptosporidia or G lamblia can be reflected in the histologic changes of the intestine. Submucosal tissue can be examined for the presence of plasma cells.

Histologic changes may be observed in the lymph nodes of patients with CVID. The findings may include reactive follicular hyperplasia, atypical hyperplasia, and granulomatous inflammation.

Nonsarcoidal, nontuberculoid asymptomatic cutaneous granulomas seen in CVID show well-demarcated areas of fibrinoid degeneration of collagen that stain homogeneously and are surrounded by histiocytes in a palisading arrangement, suggestive of granuloma annulare; no microorganisms could be detected.[11]

Any malignancies complicating CVID are staged by using conventional guidelines.

Common variable immunodeficiency (CVID) patients were divided into four distinct clusters correlating to perceived health, a potentially important factor in providing care.[45]

The mainstay of treatment for common variable immunodeficiency (CVID) is Ig replacement therapy. Although expensive, Ig replacement therapy stops the cycle of recurrent infections. See the image below.

Intravenous immunoglobulin infusion. Courtesy of Wikimedia Commons (Steve Brew, own work).

Ig may be administered intravenously or subcutaneously. Solutions of 3-12% intravenous immunoglobulin (IVIG) can be used on a regular basis to maintain a trough level of 400-500 mg/dL in adults. A dose of 400-600 mg/kg every 2-4 weeks is usually required. In patients with structural lung damage, a trough level of 700-800 mg/dL is required.

A solution of 16% subcutaneous injection of IV immunoglobulin (SCIG) is also an effective treatment in patients with poor intravenous access. As expected, the volume required to achieve adequate trough levels is much higher with SCIG than with IVIG. A dose of 160 mg/kg/wk is comparable to an IVIG dose of 400 mg/kg/mo.

Adverse reactions to Ig administration must be monitored during therapy. The most common reactions include backache, nausea, vomiting, chills, low-grade fever, myalgias, and fatigue. Adverse effects occur within 30 minutes of the infusion and usually last for several hours. Slowing the rate of infusion or interrupting the infusion for a few minutes greatly helps in preventing symptoms. The effects can be treated with antipyretics, diphenhydramine, and/or corticosteroids. Although anaphylactic reactions to IVIG are uncommon, patients with IgA deficiency have an increased risk for these effects. Long-term intravenous access is not recommended because it can increase the risk of infection.

The transmission of infectious agents during infusion has caused problems in the past. Although no cases of HIV infection have been linked to Ig therapy, the transmission of hepatitis C virus has been reported. Current methods of viral inactivation help prevent transmission. These methods include treatment with organic solvents and detergents, pasteurization, and storage at a low pH. In the United States, Ig products are derived from pooled human plasma, which undergoes a manufacturing process that includes cold ethanol fractionation and viral inactivation steps.

In most patients, CVID responds well to Ig therapy. The recurrence of infections, arthritic symptoms, and the severity and/or incidence of the autoimmune disease are reduced. Gastrointestinal disease shows little improvement with IVIG. In some patients with severe autoimmune disease, the concurrent use of steroids or other immunosuppressive drugs may be needed.

Cyclosporin A has been successfully used in patients with CVID and lymphoid interstitial pneumonitis. The administration of anti-CD20 monoclonal antibody has been used to treat autoimmune thrombocytopenia and neutropenia. Studies are underway to evaluate the efficacy of IL-2 administration in conjunction with polyethylene glycol. Results of early in vitro studies show an increase in Ig production by B lymphocytes.

Antimicrobial therapy should be initiated at the first sign of infection. A narrow spectrum of drugs should be used when culture and sensitivity results are available. The prophylactic use of antibiotics should be avoided because of an increased risk of infection with fungi or other resistant organisms.

Specific therapy is often necessary to target the organ system involved. For instance, patients with chronic lung disease often develop airway obstructive disease that requires treatment with inhaled corticosteroids and other asthma medications.

Patients with CVID at risk of coronavirus disease 2019 (COVID-19) represent a challenge.[46]  Use of convalescent plasma and intravenous immunoglobin may be considered, with efficacy not yet determined. A small sampling of ten CVID patients in New York City developed COVID-19, only one of whom was hospitalized and all recovered.[47]

In pregnant patients with CVID and lung disease, the pulmonary deficit is often exacerbated in the third trimester. If the mother receives adequate IVIG replacement therapy during pregnancy, her neonate (with CVID) has IgG levels in the reference range because the antibody is actively transported across the placenta.

Patients and their families may benefit from a periodical health-related quality-of-life assessment, highlighting the value of psychological support.[48]

Inpatient care may be necessary, depending on the severity of the clinical manifestations secondary to CVID.

Surgery is required to treat the complications of common variable immunodeficiency (CVID). Chronic sinusitis may require endoscopic sinus surgery. Severe autoimmune thrombocytopenia or hemolytic anemia can be treated with splenectomy. Biopsy should be considered to exclude infection or malignancy in enlarging lymph nodes.

A specialist should be consulted whenever necessary.

Because at least some CVID patients can produce protective antibody titers, one should consider the inclusion of polysaccharide vaccine in an immunization program for them.[49] Most CVID patients would benefit from seasonal influenza vaccination.[50]

The mainstay of outpatient care is the prevention of secondary medical conditions. IVIG should be administered every 2-4 weeks to keep the level of serum antibodies in the reference range.

Although long-term intravenous access is often required for IVIG therapy, it is not recommended. The use of a plastic cannula should be avoided because it can increase the risk of venous sclerosis. Butterfly needles should be used in their place. Alternatives to implantable venous access devices should be sought, although such devices have been used for long periods without problems.

Patients should see their physicians annually, unless they develop associated infections, which warrant immediate treatment. Physicians should obtain a thorough history and perform a thorough physical examination. Patients should be evaluated for associated conditions such infection, autoimmune disease, and malignancy.

The goals of pharmacotherapy for common variable immunodeficiency (CVID) are to reduce morbidity and prevent complications. Treatment with rapamycin has been suggested, but this therapy awaits proper evaluation.[51] Rituximab has been used to treat associated hemolytic anemia and thrombocytopenia.[52] Additionally, Lin et al reported on the treatment of CVID-associated cutaneous granuloma using etanercept.[53]

Class Summary

Ig passively supplies recipients with a broad spectrum of IgG antibodies against bacteria, viruses, and parasites.

Immune globulin intravenous (Gamimune, Gammar-P, Sandoglobulin, Gammagard S/D)

Intravenous immune globulin neutralizes circulating myelin antibodies with anti-idiotypic antibodies. It down-regulates proinflammatory cytokines, including interferon-gamma. It blocks Fc receptors on macrophages and blocks the complement cascade. It suppresses inducer T and B cells and augments suppressor T cells. It also promotes remyelination and may increase CSF IgG levels by 10%.