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Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults

Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults
Author:
Charlotte Cunningham-Rundles, MD, PhD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Jul 06, 2022.

INTRODUCTION — Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by impaired B cell differentiation with defective immunoglobulin production. It is the most prevalent form of significant antibody deficiency affecting both children and adults. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent infections, chronic lung disease, autoimmune disorders, gastrointestinal disease, and a heightened susceptibility to lymphoma.

The clinical manifestations, epidemiology, evaluation, and diagnosis of CVID will be discussed here, with a focus on presentation in adult patients. Issues that are particularly relevant to children are reviewed separately. The pathogenesis and treatment are also presented separately. (See "Common variable immunodeficiency in children" and "Pathogenesis of common variable immunodeficiency" and "Treatment and prognosis of common variable immunodeficiency".)

DEFINITION — CVID (MIM# 240500) is not a single disease but rather a collection of hypogammaglobulinemia syndromes resulting from many genetic defects. In about 25 percent of cases specific molecular defects have been identified, although in the majority, the causes are unknown. CVID has been defined by the following laboratory criteria [1,2]:

Markedly reduced serum concentrations of immunoglobulin (Ig)G, in combination with low levels of IgA and/or immunoglobulin IgM

Poor or absent response to immunizations

An absence of any other defined immunodeficiency state

Etiologic and genetic factors underlying CVID are discussed elsewhere. (See "Pathogenesis of common variable immunodeficiency".)

EPIDEMIOLOGY — CVID is estimated to affect as many as 1 in 25,000 individuals [3-5]. There is some evidence of higher prevalence among individuals of northern European descent [3,5,6]. Internet-based registries and databases of patients with primary immunodeficiencies have been established by the Immune Deficiency Foundation in the United States (USIDNET) and the European Society for Immunodeficiencies (ESID); in both, CVID is the most common diagnosis, affecting more than 20 percent of registered patients [5,7,8].

CVID is sometimes diagnosed in childhood but more typically after puberty. In an analysis of the CVID data from the ESID registry collected between the years of 2004 and 2012, 34 percent of patients were diagnosed before 10 years of age [5]. In studies from United States centers, approximately 20 percent of patients are diagnosed before the age of 20 years. The majority of patients are diagnosed between the ages of 20 and 45 [9,10].

The clinical manifestations of CVID affect multiple organ systems, and patients often have been evaluated by several specialists by the time they are diagnosed. Perhaps partly for this reason, delayed recognition of this disease is common. In the above study, there was an average of five to seven years between onset of symptoms and diagnosis [5,6,9]. More recent data reported a median diagnostic delay of 4.1 years [5].

CLINICAL MANIFESTATIONS — In addition to recurrent infections, about one-half of patients with CVID also have evidence of immune dysregulation leading to autoimmunity, a variety of inflammatory disorders, and/or malignant disease. Accordingly, CVID can present with disorders in each of these categories. Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations of several organs, lymphoid hyperplasia, splenomegaly, or malignancy [3,4,9-13].

Among 902 patients in the ESID database for whom data were available, the most common reported disorders were pneumonia, autoimmunity, splenomegaly, and bronchiectasis (32, 29, 26, and 23 percent, respectively) [5].

In a series of 473 patients from one center, the following disorders were diagnosed over the course of 40 years [10]:

Infections (94 percent)

Hematologic or organ-specific autoimmunity (29 percent)

Chronic lung disease (29 percent)

Bronchiectasis (11 percent)

Gastrointestinal inflammatory disease (15 percent)

Malabsorption (6 percent)

Granulomatous disease (10 percent)

Liver disease/hepatitis (9 percent)

Lymphoma (8 percent)

Other cancers (7 percent)

Infections — Individuals with CVID may present with recurrent infections affecting different organ systems, especially the upper and lower respiratory tracts and/or gastrointestinal tract (table 1). In a series of 473 patients, 32 percent had infections as their only manifestation of CVID [10].

Most common pathogens — Nearly all patients develop bacterial infections (specific organisms are discussed below). Other common infections include giardiasis and mycoplasma and more recently, norovirus.

Other pathogens — Unusual or opportunistic infections with viral and fungal pathogens are uncommon. T cell dysfunction is variable in patients with CVID, and in vitro estimates of T cell function may not necessarily correlate with patients' clinical history. Cryptosporidia, Pneumocystis pneumonia, and severe herpes zoster (shingles) have been reported, even in patients who do not have laboratory abnormalities indicative of decreased T cell numbers or depressed T cell function [6,14,15].

Sinopulmonary infections — Sinopulmonary infections, including pneumonia, bronchitis, and sinusitis, as well as otitis and conjunctivitis, are observed in the majority of patients with CVID [5,6,13,15]. These infections may be acute, chronic, or recurrent. Patients are particularly susceptible to infection with the encapsulated bacteria, Streptococcus pneumoniae and Haemophilus influenzae, and with atypical bacteria from the Mycoplasma species [6,7,15-20].

Pneumonia – Over three-quarters of patients have had at least one episode of bacterial pneumonia prior to diagnosis [6,9,16,20,21]

Rhinosinusitis/otitis media – Both acute and chronic rhinosinusitis and otitis media are common, particularly in untreated CVID patients. Patients with longstanding disease may develop hearing loss.

Often multiple pathogens are responsible, including both bacteria and viruses, with rhinovirus being the most common [22]. It is unclear if patients with CVID suffer from more frequent or severe infections with viruses causing common colds.

Conjunctivitis – Chronic or recurrent conjunctivitis in patients with CVID is principally due to nonencapsulated H. influenzae [9,12].

Gastrointestinal infections — Causes of acute diarrhea in patients with CVID include infections with norovirus, Campylobacter jejuni, or Salmonella. (See "Approach to the adult with acute diarrhea in resource-rich settings".)

Chronic giardiasis causing refractory diarrhea, malabsorption, and/or weight loss has been reported in patients with CVID [5,23,24]. Other infections causing chronic diarrhea include cytomegalovirus, or rarely, cryptosporidium or norovirus [9,23-26]. However, many gastrointestinal symptoms cannot be attributed to an infectious etiology. (See 'Gastrointestinal disease' below.)

Other infectious disorders — Other infectious disorders reported in patients with CVID include septic arthritis, meningitis (both bacterial and viral), and sepsis.

Septic arthritis – Streptococci or mycoplasma can cause septic arthritis (as well as respiratory infections) in patients with CVID [4,17,27,28]. The presentation can range from acute monoarthritis that responds rapidly to antibiotic therapy, or for mycoplasma, to erosive, chronic polyarthritis that is resistant to treatment [28]. (See "Septic arthritis in adults".)

Bacterial meningitis/sepsis – Bacterial meningitis and sepsis were reported in CVID patients, mostly before treatment with immunoglobulin therapy became available [4,9,29,30]. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

Pulmonary disease — Chronic lung disease is a common problem in patients with CVID and can lead to recurrent hospitalizations and significant morbidity [4,10,13,31-33]. It has historically been a leading cause of death in these patients [4,9,29].

Approximately one-third have chronic lung disease by the time of diagnosis. For example, in one study of 224 patients, 34 percent had chronic lung disease at the time of diagnosis, which increased to 46 percent during a mean follow-up of 11 years [17]. In another large series of 248 patients, 27 percent had either bronchiectasis, or restrictive or obstructive lung disease [9].

The respiratory manifestations of CVID follow two main mechanisms: injury due to acute or recurrent infections and damage due to poorly understood immune-mediated processes. Because of this, there are two types of chronic lung disease - bronchiectasis and interstitial lung disease, which are best distinguished by chest CT. In retrospective studies, these can be associated with different immune phenotypes. Bronchiectasis is more often found in older subjects (as this may reflect longer term damage) and interstitial lung disease, in younger subjects, who often have a history of autoimmune cytopenias, increased serum IgM levels, and lower CD3 T cell counts [34-37]. In terms of prevalence, bronchiectasis was found in a 54 percent of a large CVID cohort in one study [17]; a subsequent study found it to be present in 61 percent [38].

Issues related to pulmonary diseases in patients with primary immunodeficiency are reviewed separately. (See "Pulmonary complications of primary immunodeficiencies".)

Obstructive diseases — An obstructive pattern on spirometry in patients with CVID can accompany asthma, bronchiectasis, or other lung processes. Therefore, additional evaluation, such as bronchodilator challenge to demonstrate reversibility or bronchial provocation testing, may be needed to diagnose asthma conclusively [37,39]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults" and "Bronchiectasis in adults: Treatment of acute exacerbations and advanced disease".)

Restrictive diseases — Restrictive changes on pulmonary function testing may indicate the presence of an inflammatory lung disease. Restrictive defects may result from lymphocytic or granulomatous infiltrates or both. Other causes of restrictive changes include mucous plugging or postsurgery restriction. On pulmonary imaging, features of interstitial lung disease in patients with CVID include reticular, nodular, or ground glass opacities.

Interstitial lung disease — The prevalence of interstitial lung disease (ILD) is increased in patients with CVID. This may include lymphocytic infiltrates with or without granulomata. In one retrospective study, 2 of 18 patients with biopsy proven granuloma in one or more tissue sites had ILD on high resolution computed tomography. Thirteen patients had diffuse reticulation, which varied from fine to coarse with features of fibrosis, while eight had nodules [40,41]. In another study, lung tissues of four of six patients with ILD contained ill-poorly formed granulomata, variable T/B ratios, and several had B cell follicles with the characteristics of ectopic germinal centers [42].

Granulomatous lung disease — When both lymphocytic ILD and granuloma are present on a lung biopsy, the term "granulomatous-lymphocytic interstitial lung disease" (GLILD) has been used [43,44]. GLILD was defined as "a distinct clinico-radio-pathologic interstitial lung disease occurring in patients with CVID, associated with a lymphocytic infiltrate and/or granuloma of the lung, and in whom other conditions have been considered and were possibly excluded" in a 2017 British consensus statement [45]. GLILD is a common cause of diffuse parenchymal lung disease in patients with CVID. It typically presents in patients between the ages of 20 and 50 years with the gradual development of dyspnea on exertion with new or altered cough, although some patients are asymptomatic when characteristic findings are first detected on chest imaging. GLILD is more common in CVID subjects with history of autoimmune cytopenia, hypersplenism, polyarthritis, lower marginal zone and switched memory B cells, and restrictive lung function [46,47]. (See "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)

Extrapulmonary granulomas — Patients with CVID, with or without granulomatous lung disease may also have or develop noncaseating granulomas in the lymphoid or solid organs, including the lymph nodes, spleen, liver, intestine, brain, eyes, or skin [40,48-50]. It is estimated that 8 to 20 percent of CVID patients have some form of granulomatous disease, although the prevalence is probably underappreciated since most tissues are not biopsied [5,13,50]. Common presentations besides pulmonary symptoms are lymphadenopathy and splenomegaly. In the United States, patients with granulomatous disease in CVID appear to have higher rates of autoimmune disorders as well, such as ITP and AIHA [40,48].

When granuloma are found in tissues, clinicians may have diagnosed this as "sarcoid," but the current view is that the immune defect is the underlying cause of these tissue changes; there are also significant differences between "sarcoidosis" and the granulomatous disease that may accompany CVID. These commonly include hyperglobulinemia in sarcoidosis, for example. Some patients may have variable elevations in angiotensin-converting enzyme (ACE) levels, but this is not diagnostic [40,48,51], as these are found in other immunodeficient subjects with no history of granuloma, as well as approximately 75 percent of patients with sarcoidosis. One series found 8 cases of CVID among 80 patients with sarcoidosis, with 22 other cases reported in the literature [51]. Therefore, patients with apparent sarcoidosis who are hypogammaglobulinemic and have recurrent infections should be evaluated for CVID [52].

The pathogenesis of noncaseating granulomas in CVID is not known. An unusual tumor necrosis factor (TNF) polymorphism was found in some increased numbers, but effects on serum TNF levels were not examined [53]. An abnormal CD8+ T cell response to cytomegalovirus has also been detected in patients with CVID and inflammatory disease [54].

Gastrointestinal disease — Gastrointestinal disease is identified in approximately 10 to 20 percent of CVID patients and may be the presenting disorder in some [9,12,23,24,26,55,56]. Diarrhea is the most common symptom, with malabsorption and weight loss also reported. Vitamin and electrolyte deficiencies may result in severe cases. Specific disorders include (in decreasing order of prevalence):

Inflammatory bowel-like disease, which may resemble ulcerative colitis, ulcerative proctitis, Crohn-like disease, or microscopic colitis

Sprue-like illness with flat villi

Nodular lymphoid hyperplasia (picture 1) [57,58]

Pernicious anemia

Bacterial overgrowth

Protein-losing enteropathy

Nonspecific malabsorption

Gastrointestinal lymphoma

The gastrointestinal manifestations of primary immunodeficiency are reviewed separately. (See "Gastrointestinal manifestations in primary immunodeficiency".)

Specific disorders are discussed in detail elsewhere. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Predisposing conditions' and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

The pathophysiology of many of these gastrointestinal disorders is not understood, although defects in cellular immunity, rather than antibody deficiency alone, may predispose patients to such illnesses [56,59,60]. In the data from the ESID registry, enteropathy was associated with autoimmunity and with low serum IgM but not with low serum IgA [5]. Patients with very low total memory B cells and low switched memory B cells appear more likely to develop malabsorption or chronic diarrhea than patients with normal memory B cells [61]. (See 'Additional testing' below.)

Autoimmune disease — Autoimmune conditions are diagnosed in 25 to 30 percent of CVID patients and can be the presenting disorder [62-64]. For unclear reasons, these patients seem to be less likely to have a history of repeated infections [10] and may be more likely to have enteropathy [5]. Autoimmunity is a manifestation of immune dysregulation, although the specific mechanisms for this heightened susceptibility in CVID are not known. The most frequently diagnosed disorders are (table 2) [9,10,63,64]:

Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) [63,65,66] (see "Diagnosis of hemolytic anemia in adults")

Rheumatoid arthritis and rheumatoid-like arthritis [67] (see "Clinical manifestations of rheumatoid arthritis")

Pernicious anemia [9,12] (see "Treatment of vitamin B12 and folate deficiencies")

Autoimmune thyroiditis [63] (see "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)")

Vitiligo [68] (see "Vitiligo: Pathogenesis, clinical features, and diagnosis")

Autoimmune hematologic disorders are the most common autoimmune conditions in these patients. A review of 326 CVID patients found that 11 percent had a history of ITP, AIHA, or Evans syndrome [65]. Approximately one-half of these developed hematologic autoimmune disease before or concurrent with the diagnosis of CVID. A small case control study suggested that patients presenting with AIHA initially may represent a distinct phenotype, with lower rates of recurrent infections, but higher rates of splenomegaly, other autoimmune conditions, and lymphoma [66]. Autoimmune disorders in children with CVID are discussed in more detail separately. (See "Common variable immunodeficiency in children", section on 'Autoimmune disease'.)

CVID may also be identified in rare patients who were previously diagnosed with systemic lupus erythematosus (SLE) [69]. In most cases, the SLE appeared to precede the CVID, and it remains unclear if immunosuppressive or glucocorticoid therapy in SLE patients could cause the development of hypogammaglobulinemia and immune defects, or if the two conditions are arising from a common underlying defect.

Other autoimmune conditions that have been reported in CVID patients include inflammatory bowel disease, juvenile idiopathic arthritis, Sjögren disease, vitiligo, reactive arthritis (formerly Reiter syndrome), autoimmune hepatitis, and autoimmune neutropenia [63].

The spectrum of autoimmune disease associated with primary immunodeficiency disorders is discussed elsewhere. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Allergic disease — Patients with CVID can have signs and symptoms consistent with allergic diseases, especially allergic rhinitis and asthma, although allergic disease is less common than in people without CVID. Diagnosis may not be straightforward, because despite a consistent clinical presentation, most patients have low or undetectable levels of serum IgE and negative skin test results. In fact, one study noted that the presence of IgE was an indicator that CVID was not the diagnosis [70]. Another study demonstrated that some patients with CVID and symptoms suggestive of allergic asthma had low or undetectable total IgE and negative in vitro tests for allergen-specific IgE, and yet still developed symptoms to bronchoprovocation tests with allergen [39].

Lymphadenopathy/splenomegaly — Splenomegaly and lymphadenopathy are common in CVID patients, although the pathogenesis of this finding is not known. One report of 224 CVID patients showed 26 percent had an enlarged spleen by ultrasound [17]. Splenomegaly was most closely associated with granulomatous disease (of various organs) in the ESID registry analysis [5].

Liver disease — Approximately 10 percent of patients have significant liver dysfunction, with elevations in alkaline phosphatase being common [71]. The most common liver pathology in CVID appears to be nodular regenerative hyperplasia, a poorly understood cause of both cirrhosis and portal hypertension [72,73]. Patients typically present with anicteric cholestasis and/or portal hypertension. In a series of CVID patients with evidence of liver dysfunction, biopsies revealed idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia) in many [72,73]. These patients appeared to have higher rates of autoimmune disease and nonceliac enteropathy, compared with CVID patients without liver disease. Hepatitis B and C virus infection, primary biliary cholangitis, and granulomatous liver disease have also been reported [10]. (See "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease'.)

Malignancies — An increased risk of malignancies is reported in CVID. In a large European study, the relative risk of cancer at all sites was 1.8, with an absence of an increased risk among relatives, suggesting that the effect was due to CVID [74]. Non-Hodgkin lymphomas (NHL) are most common. In another large European collaborative study of 334 CVID patients, having a form of polyclonal lymphocytic infiltration was associated with a fivefold increased risk of lymphoid malignancy [12]. In addition, there was a correlation between higher serum IgM levels and the eventual development of either polyclonal lymphocytic infiltration or lymphoid malignancy.

Non-Hodgkin lymphomas — NHLs occur at a markedly increased rate among patients with CVID, although the precise incidence is difficult to determine [75-77]. In a large clinical study of 248 patients with CVID, 8 percent of patients developed NHL over variable periods of time [10]. Another study estimated that females had a 438-fold increased risk of developing NHL compared with the age-adjusted expected incidence [78]. An update of this single-center study of 647 CVID subjects reported 45 patients (15 males and 30 females, 7 percent) with 49 lymphoid malignancies. The mean age at CVID diagnosis was 42.6 years, and at lymphoma diagnosis, 48.8 years [79]. Clusters of NHL within families affected by CVID have also been reported [80]. In clinical practice, it is important to tell patients that the risk of lymphoma is elevated (possibly 2 to 8 percent lifetime risk [9]) and review with them common signs and symptoms, such as fever, weight loss, night sweats, and persistent swellings of the lymph nodes or abdomen (due to hepatomegaly or splenomegaly).

The NHLs that occur in patients with CVID are mostly extranodal in origin, well-differentiated, and of B cell origin [9,79,80]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

An association exists between NHL and other congenital immunodeficiency diseases, although principally those with prominent T cell defects. These include ataxia-telangiectasia, Wiskott-Aldrich syndrome, X-linked lymphoproliferative disease, and severe combined immunodeficiency [74]. (See "Ataxia-telangiectasia" and "Wiskott-Aldrich syndrome" and "Severe combined immunodeficiency (SCID): An overview".)

Gastric cancers — An increased risk of gastric cancer has been reported in some studies of CVID patients [4,17,81-83]. This may have been related to the increased frequency of pernicious anemia or Helicobacter pylori infection, as a study of 34 CVID patients with dyspepsia found that 41 percent had biopsy-proven H. pylori [83]. In these patients, the infection was significantly associated with multifocal atrophic gastritis, which is associated with gastric carcinoma. Common presenting symptoms of gastric cancer include abdominal pain, weight loss, and dyspepsia. However, the incidence of this cancer may be decreasing, as suggested by a 2010 study of 476 patients with CVID, in which gastric cancer was diagnosed in only 0.6 percent of patients, whereas NHL developed in 6.7 percent [84]. (See "Clinical features, diagnosis, and staging of gastric cancer".)

PHYSICAL EXAMINATION — Physical examination of patients with CVID may be normal, or there may be signs and symptoms of chronic illness (eg, failure to thrive or growth retardation in children, weight loss in adults) [30,85]. Other common abnormalities include nasal discharge or congestion signifying chronic sinusitis, scarring of the tympanic membranes, and/or digital clubbing signifying chronic pulmonary disease. Additional findings that may be noted in some patients include lymphadenopathy, splenomegaly, arthritis, conjunctivitis, and skin findings associated with autoimmune disease. Oral thrush is uncommon.

EVALUATION — The initial laboratory evaluation of patients with CVID involves the measurement of immunoglobulin levels, the demonstration of impaired responses to vaccinations, and exclusion of other causes of these abnormalities.

Routine laboratories — Patients with CVID may not generally have abnormalities in routine laboratories, such as complete blood counts, serum chemistries, electrolytes, or urinalysis, in the absence of a specific associated condition. Reductions in albumin or total protein level may be seen, and lymphopenia may develop over time, but these are not reliable abnormalities. Elevations in C-reactive protein are seen with infection. Liver transaminases and alkaline phosphatase may be variably elevated and should be monitored if increased, as elevations may signal the development of nodular regenerative hyperplasia. (See 'Liver disease' above.)

Immunoglobulin levels — By definition, serum immunoglobulin levels are markedly abnormal in patients with CVID. Serum IgG is generally below the lower limit of normal and generally under 400 mg/dL. Most laboratories define the normal reference range as two standard deviations above and below the age-adjusted mean. In addition, IgA and/or IgM should be below the lower limit of normal. One-half of patients have no detectable IgA. IgE is also useful because many patients with CVID have undetectable levels, although IgE levels are not currently part of the formal diagnostic criteria [70].

A study of 224 CVID patients reported the following mean immunoglobulin levels at diagnosis [17]:

IgG of 258 mg/dL (with a normal reference range of 768 to 1728 mg/dL)

IgA of 28 mg/dL (with a normal reference range of 99 to 396 mg/dL)

IgM of 40 mg/dL (with a normal reference range of 38 to 266 mg/dL)

Immunoglobulin levels should be repeated to confirm that the values are persistently low and that a laboratory error has not occurred. Repeating levels once is sufficient if patients are in their usual state of health. If there is a concomitant illness that could cause secondarily low immunoglobulin levels (eg, nephrotic syndrome or protein-losing enteropathy), then the measurement should be repeated approximately three months after resolution of the illness. In contrast, neither acute infection, such as pneumonia, nor short-term administration of systemic glucocorticoids, should significantly reduce or increase immunoglobulin levels. However, chronic systemic glucocorticoids may reduce serum IgG levels, as reviewed separately. (See "Glucocorticoid effects on the immune system".)

A few patients with marginally low levels of IgG, borderline or low levels of IgA, and retained antibody function, may over time progress to CVID with more complete losses of IgG, IgA, and IgM, and loss of functional antibody.

Patients with CVID may have low, normal, or (rarely) increased levels of IgM. However, significantly elevated levels of IgM should prompt consideration of alternative diagnoses. (See "Hyperimmunoglobulin M syndromes".)

Serum total IgE levels were undetectable in 76 percent of a large cohort of 354 patients with CVID, and allergen-specific IgE was undetectable in over 96 percent. Less than 1 percent of patients had an elevated total IgE (>180 IU/mL) [70].

Absence or very low levels of natural antibodies, such as isohemagglutinins, is common. Isohemagglutinins are discussed separately. (See "Laboratory evaluation of the immune system" and "Assessing antibody function as part of an immunologic evaluation".)

Indications for referral — If the patient's history and physical examination raise concern about a possible diagnosis of CVID, immunoglobulin levels should be evaluated initially, as just described. Referral to a clinical immunologist is indicated, whenever possible, to assess vaccine responsiveness and exclude other causes of hypogammaglobulinemia. Immunology specialists can also determine the most appropriate therapies (such as prophylactic antibiotics and immune globulin replacement) and help monitor the patient for associated disorders.

Further immunologic evaluation — Once hypogammaglobulinemia has been demonstrated, the patient's ability to respond to vaccines should be assessed.

Vaccine response — The patient's response to both protein- and polysaccharide-based vaccines should be assessed in most cases, unless antibody levels are very low (eg, IgG <200 mg/dL) or undetectable, in which case vaccine response can be assumed to be deficient. Acute illness does not generally affect vaccine responsiveness, nor does systemic glucocorticoid therapy, particularly if the daily dose is lower than about 40 mg of prednisone. (See "Glucocorticoid effects on the immune system", section on 'Impact on vaccination'.)

In adults who received routine vaccinations, the following should be assessed:

IgG antibodies to tetanus and diphtheria, which provide an estimate of the patient's response to protein-based antigens.

A panel of IgG antibodies to 14 or 23 serotypes of the polysaccharides in the polysaccharide pneumococcal vaccine, which provide an estimate of the patient's response to polysaccharide-based antigens.

Patients with CVID usually have impaired responses to both protein and polysaccharide-based vaccines. Evaluation of vaccine response is part of the diagnosis of many immunodeficiencies and is reviewed in detail separately. (See "Assessing antibody function as part of an immunologic evaluation".)

Additional testing — Additional testing may include flow cytometry of leukocytes and molecular analysis. However, neither test is required for diagnosis.

Flow cytometry – Although flow cytometry of leukocytes is not required for diagnosis, patients with CVID may show abnormalities. Most patients with CVID have normal numbers of circulating T and B lymphocytes. However, most can be shown to have somewhat reduced levels of circulating memory B cells (CD27+ B cells) and especially low levels of isotype switched memory B cells (CD27+ IgD- IgM-) [86,87]. Some have impaired T cell function. Abnormal cytokine levels have also been described. These findings are not used in diagnosis and are discussed separately. (See "Pathogenesis of common variable immunodeficiency" and "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'Common variable immunodeficiency'.)

Molecular analysis – Molecular analysis is not required for the diagnosis of CVID but these studies may be helpful for management. Genome-wide association previously identified diverse associations with CVID [88]. Increasing numbers of genetic defects have been described in subjects with CVID, and 25 to 30 percent of patients, will be found to have such gene changes [89-95]. The molecular defects that have been reported in patients with CVID are discussed separately. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

For these reasons, molecular testing might be considered for cases with early onset (before the age of 15) or with autoimmune or inflammatory complications, or in those with other affected family members, making detection of a discrete defect somewhat more likely [94]. It is also sometimes useful for excluding other immunodeficiencies that arise from known genetic defects, such as some of the causes of hyperimmunoglobulin M syndromes (HIGM) or agammaglobulinemias. (See 'Differential diagnosis' below.)

B cell maturation antigen – Serum B cell maturation antigen (BCMA) is an investigational test in the diagnosis of severe antibody defects. BCMA correlates with the presence of plasma cells in various tissues and was found to be low in patients with CVID and X-linked agammaglobulinemia who had serum IgG levels below 600 mg/dL, indicating that BCMA could be used to identify the more severe disorders of antibody production [96]. Although not commercially available at present, BCMA could be diagnostically useful in the future, would not be affected by prior administration of immune globulin, and could provide information about the patient's potential capacity for antibody production. However, the presence of actual functional antibody would still need to be examined. Prospective studies are needed to confirm the utility of this test in the diagnostic setting.

Other biomarkers – A number of studies have sought useful biomarkers that might help distinguish patients with CVID who develop the numerous noninfectious complications from those with only infections. Examples include potentially useful condition-specific biomarkers, such as [97]:

Normal or elevated IgM for lymphoma or

Normal or elevated IgM, increased BAFF (B cell activating factor of the tumor necrosis factor family) for progressive interstitial lung disease

Additional biomarkers have provided insights into disease pathogenesis, demonstrating systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3 cells), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Elevated circulating bioactive bacterial rDNA levels have also been noted in the subset of patients with autoimmune or inflammatory conditions [97,98]. 

DIAGNOSIS — The diagnosis of CVID can be assigned to a patient over age four who demonstrates all of the following characteristics [1,2,99]:

Significantly reduced total serum concentrations of IgG (see 'Immunoglobulin levels' above) and

Low IgA and/or IgM

Poor or absent response to immunization (see 'Vaccine response' above)

The absence of any other defined immunodeficiency state (ie, CVID is a diagnosis of exclusion) (see 'Differential diagnosis' below)

The diagnosis of IgG deficiency should be differentiated from CVID as the laboratory parameters and clinical outcomes are different [100]. The diagnosis should also not be made definitively in children younger than four years of age, as immune function may not have matured sufficiently. Diagnosis in children is discussed separately. (See "Common variable immunodeficiency in children", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of hypogammaglobulinemia, the primary laboratory feature of CVID, is reviewed in this section. There are several other primary immunodeficiency disorders that must be specifically excluded in children and these are discussed elsewhere. (See "Common variable immunodeficiency in children", section on 'Differential diagnosis'.)

Hypogammaglobulinemia may be classified as primary or secondary. In adults, secondary causes of hypogammaglobulinemia are far more common than primary causes.

Secondary hypogammaglobulinemia — A large number of conditions are associated with secondary hypogammaglobulinemia due to either decreased production or increased loss.

Decreased production — Decreased production of immunoglobulins can be seen with the following disorders:

Drugs (most commonly immunosuppressants, such as glucocorticoids, rituximab therapy, and anti-epileptics) (see "Glucocorticoid effects on the immune system" and "Secondary immunodeficiency induced by biologic therapies")

Malignancy and pre-malignant disorders (such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, or Waldenström macroglobulinemia) [101]

Thymoma with hypogammaglobulinemia (Good syndrome) [102,103]

It is the author's approach to evaluate for secondary causes of hypogammaglobulinemia if a thorough history, physical examination, and laboratory studies reveals suggestive signs or symptoms, rather than as a matter of course. As an example, we would request an abdominal or chest computed tomography (CT) to exclude lymphoma if a patient reported fever or weight loss.

Increased loss — Increased loss of immunoglobulins may result from protein-losing enteropathies, such as intestinal lymphangiectasia, nephrotic syndrome, burns, and other traumas leading to loss of fluids. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption" and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Diagnosis' and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Infection'.)

Primary hypogammaglobulinemia — There are several other primary immunodeficiencies in which significant reductions of IgG are seen, accompanied by and either abnormally high or low IgA or IgM levels. In children, several additional disorders should be excluded, as discussed separately. The discussion here is focused on adults. (See "Common variable immunodeficiency in children", section on 'Differential diagnosis'.)

IgG subclass deficiencies — Deficiency in IgG1 can cause general hypogammaglobulinemia because IgG1 comprises up to 75 percent of the total serum IgG. IgG2 subclass deficiencies can also lead to mild deficiency of total serum IgG or IgG serum levels at the lower norm and to a poor vaccine response. Subclass deficiencies can also occur in conjunction with IgA deficiency and some patients demonstrate poor vaccine response. (See "IgG subclass deficiency", section on 'IgG1 deficiency'.)

Hyperimmunoglobulin M syndromes — Hyperimmunoglobulin M syndromes (HIGM) can arise from defects of CD40 ligand, an X-linked disease in which isotype switch from IgM to IgA or IgG does not occur. Other causes of HIGM are rare genetic defects in the nucleic acid modifying enzymes called activation-induced cytidine deaminase (AICDA or AID) or uracil nucleoside glycosylase (UNG), or deficiency of CD40 (more rare than defects in CD40 ligand). Class-switching cannot occur without functional AICDA or UNG, therefore B cells can only produce appreciable quantities of IgM. Patients with AICDA and UNG deficiencies generally present with the recurrent and severe sinopulmonary infections with encapsulated bacteria that are characteristic of antibody deficiencies. Gastrointestinal infections (including Giardiasis), bacterial meningitis, viral encephalitis, and severe hepatitis B infections have also been observed, and patients are susceptible to lymph node hyperplasia and autoimmune disorders.

Among patients with CD40 ligand, AICDA, and UNG deficiencies, IgG levels are generally <200 mg/dL, while IgA is <20 mg/dL, and IgM ranges from 100 to 3700 mg/dL. IgG specific antibody responses are nonexistent. Numbers of T and B cells in the circulation are normal, and T cell function is intact. (See "Hyperimmunoglobulin M syndromes".)

Combined immunodeficiencies — Other combined immunodeficiencies that may mimic clinical or laboratory features of CVID and can present after childhood include milder forms of adenosine deaminase deficiency (ADA), hypomorphic recombination-activating gene (RAG) mutations, and Artemis defects.

It can be difficult to distinguish patients with combined defects, from other CVID subjects since there is overlap between the laboratory features of these two groups. With time, this may become easier as the genetic basis of these disorders is defined, but generally, patients with low CD4 T cells and/or low numbers of CD4 naive T cells are those most likely to have a combined immune defect. These have also been identified as late-onset combined immune defects (LOCID) [14,103]. (See "Combined immunodeficiencies".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

INFORMATION FOR PATIENTS — The Immune Deficiency Foundation and the Jeffrey Modell Foundation have links and information for patients about common variable immunodeficiency (CVID).

SUMMARY AND RECOMMENDATIONS

Definition – Common variable immunodeficiency (CVID) is the most common form of severe antibody deficiency affecting both children and adults. The characteristic immune defect in CVID is impaired B cell differentiation with defective production of immunoglobulin. CVID is defined by low total serum concentrations of immunoglobulin (Ig)G, as well as low IgA and/or IgM, poor or absent response to immunization, and the absence of any other defined immunodeficiency state. (See 'Introduction' above and 'Definition' above.)

Epidemiology – Age of onset is variable. Most patients are diagnosed between the ages of 20 and 40 years. Delayed recognition is common. (See 'Epidemiology' above.)

Typical infections – Bacterial infections of the sinopulmonary tract, particularly sinusitis and pneumonia, are experienced by most patients with CVID (table 1). Opportunistic and unusual infections are uncommon, but do occur. (See 'Infections' above.)

Non-infectious manifestations – In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to autoimmunity, a variety of inflammatory disorders, and malignant disease. Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations, lymphoid hyperplasia, splenomegaly, or malignancy. (See 'Clinical manifestations' above.)

Chronic lung diseases, especially interstitial lung disease and/or bronchiectasis, are seen in 30 to 50 percent of patients, and represent an important cause of morbidity and mortality. (See 'Pulmonary disease' above.)

Gastrointestinal disease is present in about 20 percent of CVID patients, with a variety of different disorders described. The pathophysiology of most of these disorders is not known. Chronic diarrhea is the most common presenting gastrointestinal symptom. Chronic infections with giardia, cytomegalovirus, and cryptosporidium are also reported (table 1). (See 'Gastrointestinal disease' above.)

Twenty five to thirty percent of patients with CVID may develop autoimmune conditions, particularly hemolytic anemia, thrombocytopenia, and rheumatoid arthritis, and an estimated 8 to 20 percent have some form of granulomatous disease. (See 'Granulomatous lung disease' above.)

Patients with CVID are at increased risk for malignancies, and have a particular susceptibility to non-Hodgkin lymphomas (NHL). (See 'Malignancies' above.)

Evaluation and diagnosis – The diagnosis of CVID requires a suggestive clinical history, a reduced total serum concentration of IgG, plus low IgA or IgM, and poor responses to both protein- and polysaccharide-based vaccines. (See 'Evaluation' above and 'Diagnosis' above.)

Differential diagnosis – Various forms of primary and secondary hypogammaglobulinemia must be excluded before the diagnosis of CVID can be assigned. (See 'Differential diagnosis' above.)

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Topic 3928 Version 26.0

References