Keywords

Introduction: Historical Perspective and Epidemiology

Common Variable Immunodeficiency (CVID) refers to a heterogeneous group of primary immune deficiency disorders (PIDD) presenting with recurrent sinopulmonary infections, hypogammagloblunemia, inadequate vaccination responses, and in a subset, co-existent autoimmune and inflammatory disease. The definition and diagnosis of CVID has evolved since its recognition in 1971 from one of exclusion to include the laboratory and clinical manifestations of hypogammaglobulinemia [1]. In 1991, the European Society for Immunodeficiency and the Pan American Group for Immunodeficiency (ESID/PAGID) established formal diagnostic criteria as probable indicators of CVID: a decrease in serum immunoglobulin G (IgG) of at least two standard deviations below the mean for age, a decrease in one or both of the isotypes IgM and IgA, age of onset greater than 2 years, absent hemagglutinins or poor response to vaccines, and a lack of other causes for hypogammaglobulinemia [2]. These diagnostic criteria remained in effect until 2014 when the ESID registry released slightly refined criteria that contains the following additions and alterations: minimum age of diagnosis of 4 years, at least one symptom related to the PIDD or evidence of family history of the disorder, and no evidence of profound T cell deficiency (Table 3.1) [3]. As there is no universally accepted definition or diagnostic criteria, efforts are continuously being made to more clearly define exactly what constitutes CVID both clinically and biologically with the recognition that it likely represents several different genetic defects with phenotypic variation.

Table 3.1 Clinical differentiation of CVID from select monogenetic mimics
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Epidemiology

Although PIDD are rare, CVID is the most frequently diagnosed after IgA deficicency and presents with symptoms that are usually first recognized in adolescence and adulthood; this is in stark contrast to the majority of PIDD presenting in infancy or early childhood. The United States Immunodeficiency Network registry contains 4665 subjects, of which 1609 have CVID (34%) [4]. The exact prevalence of CVID is unknown, but it has been estimated to be in the range of 1:100,000 to 1:10,000 [5].

The disease affects both genders equally; however, the most recent analysis of a large European cohort (2212 subjects) showed a trend toward males being diagnosed at a younger age than females [6]. Patients are most often diagnosed between the ages of 20 and 40, but a significant number of children and older adults also fit the criteria for CVID [7].

There is typically a significant delay between symptom onset and the formal diagnosis of CVID, which may be due to lack of consideration among medical providers as well as the insidious nature of select symptoms. American and Italian cohort studies conducted in the 1990s showed mean diagnostic delays of 5–6 years and 8.9 years, respectively, from time of symptom onset [8, 9]. A more recently conducted and larger European cohort also demonstrated a diagnostic delay of 4 to 5 years from symptom onset, suggesting that advances in research and efforts to spread awareness of CVID have not yet reached a wide enough audience of physicians [6].

Interestingly, prevalence of CVID is more commonly reported among Caucasian populations; the major cohort studies have all been performed in countries with a Caucasian majority [8, 10]. However, individuals of Asian, African, and Hispanic descent can develop CVID [8]. Indeed, the reported prevalence in Japan is only slightly below that reported in European and North American countries but is much lower elsewhere in Asia [11]. It is postulated that in India and other Southeast Asian countries, this apparent rarity may be the result of under-diagnosis as opposed to differences in disease prevalence [12]. Analysis of the first Mexican CVID cohort was published in 2014, and the Latin American Group for Immunodeficiency has CVID patients in its registry [13, 14]. As alluded to previously, the variance in prevalence among ethnicities may be partially attributable to health care access and physician education [15]. It should be noted that the normal range of IgG serum levels, a crucial diagnostic marker for CVID, also may vary among different racial and ethnic groups [16].

Pathogenesis

Given the signature finding of hypogammaglobulinemia in CVID patients, B cells are invariably defective in the context of this disease. However, several additional genetic and cellular defects have been identified with regard to the pathogenesis of CVID. Of note, there is no defined cause for the immune defect in the vast majority of clinical cases.

B Cell Defects Are a Hallmark of CVID

CVID is a heterogeneous disorder marked by several immune abnormalities and clinical phenotypes; however, B cell dysfunction is thought to be fundamental to its pathogenesis [17]. Loss of B cell function may result from a B cell production defect, an early peripheral B cell maturation or survival defect, a B cell activation and proliferation defect, a germinal center defect, or a postgerminal center defect, and individual patients may exhibit one or several of these mechanisms [18]. Although B cell dysfunction underlies disease pathogenesis, many patients deceptively have normal numbers of total B cells. However, such patients often lack appropriate numbers of isotype-switched B cells and plasma cells capable of producing functional IgG, IgM, and IgA antibodies. This may be secondary to defective B cell activation as a consequence of impaired CD86 cell surface expression [19]. Another possible aberrant mechanism includes alterations in genetic recombination of the VDJ immunoglobulin regions, which are responsible for creating the diverse repertoire of human antibodies produced by B lymphocytes during B cell development and maturation. A recent article utilizing high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients demonstrated impaired VDJ rearrangement relative to control subjects that resulted in abnormal formation of complementarity determining region 3 (CDR3) , a critically diverse component of the immunoglobulin variable region that contributes to binding and recognition of antigens [20]. When B cells were sorted into naïve versus memory populations, the authors noted decreased diversity and abnormal clonal expansion of the naïve B cell pool as well as fewer mutations in variable genes that correlate with memory development. Despite the longstanding idea that aberrant germinal center activation is the causative factor in CVID pathogenesis, this analysis demonstrates that genetic abnormalities during early B cell development may significantly contribute to the abnormal generation of the full, human B cell repertoire and can subsequently result in many of the immune deficiencies associated with CVID.

The clinical phenotypes of CVID patients and their risk for complications has been closely associated with abnormalities of the memory B cell compartment. Memory B cells can be further subdivided into IgM memory B cells and switched memory B cells. Studies have identified deficiencies in both of these cellular compartments that correlate with risk for CVID . IgM memory B cells play a pivotal role in the immune response against bacterial polysaccharide (T cell independent) antigens, the most classic examples of which are associated with the streptococcus capsule. Defective IgM responses can thus predispose individuals to streptococcus lower respiratory tract infections. One study examined 54 patients with CVID that were further subcategorized into those with and without history of recurrent lower respiratory tract infections [21]. Memory B cell frequency in CVID patients with recurrent lower respiratory tract infections was significantly decreased compared to healthy subjects and to CVID subjects without a history of recurrent lower respiratory tract infections. While both CVID cohorts demonstrated a reduction in switched memory B cells, only CVID patients with recurrent lower respiratory tract infections were shown to have a reduction in IgM memory B cells with 22 out of 26 patients in this subgroup demonstrating a complete lack of or severely reduced frequency of these cells. Although a decrease in switched memory B cells among patients with CVID is reproducible across several cohorts [21,22,23], the Carsetti et al. study suggests that the presence of IgM memory B cells is more critical for protection against encapsulated pathogens than the presence of switched memory B cells. However, the finding of altered memory B cell development strongly supports the idea that dysregulated germinal center reactions are important to the pathogenesis of CVID.

The nuclear factor kappa B (NK-kB) plays an important role in B cell development, B cell maturation, and isotype switching [24]. Patients with monoallelic mutations in NF-kB2 have been shown to demonstrate a CVID-like disease with autoimmunity and impairment of early B cell maturation [25]. Recently, two patients with monoallelic mutations in NF-kB1 were described, both of which showed almost exclusive expansion of the CD21low population of B cells on flow cytometry, a finding that was not shown in patients with NK-kB2 mutations [24]. This suggests that NF-kB1 may play a role in the maturation of this specific B cell subset, and expansion of this population of B cells has been associated with the development of systemic lupus erythematosis and other autoimmune phenomena [26]. In addition, both of these patients showed an absence of CD27+ switched memory B cells, suggesting that NF-kB1 likely plays a role in late stages of B cell maturation and immunoglobulin isotype class switching. Thus, understanding defects in critical signaling pathways may offer greater insight into the biology of various CVID phenotypes (e.g., those with and without autoimmunity).

Several other genetic defects have been identified in CVID that impair B cell activation and B cell function. Four patients from two unrelated families who presented with hypogammaglobulinemia, increased susceptibility to infections, impaired vaccination responses, and otherwise normal peripheral B cell frequency were noted to share a homozygous mutation in the CD19 gene that led to complete absence or severe reduction in the presence of this B cell surface protein [27]. CD19, in conjunction with other B cell surface proteins, forms a complex with the B cell antigen receptor and plays a critical role in lowering the threshold for B cell activation. Thus, it is plausible that defects in other proteins involved in formation of this complex (e.g., CD21, CD81, CD225) may lead to a similar clinical presentation.

Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand (TACI) have been identified in patients with and without CVID and impair the removal of autoreactive B cells at the level of the bone marrow [28]. TACI plays an important role in the generation and maintenance of class-switched B cells and assists in the process of somatic hypermutation [29]. However, studies in TACI expression between CVID and unaffected carriers remain intriguing and highlight the complexity of this signaling protein. While healthy patients that carry TACI mutations and lack clinical manifestations of antibody deficiency have been shown to have intact peripheral B cell tolerance (as this is not dependent on TACI function), the 8–10% of CVID patients that carry TACI mutations have defective peripheral tolerance. Such polymorphisms should therefore be regarded as disease-susceptibility mutations rather than disease-determining mutations [29]. Furthermore, these data suggest that additional immunologic insults must likely be present in CVID subjects with TACI mutations (e.g., deficiencies in other cellular compartments or other signal impairments) in order for disease symptoms to manifest. B cell activating factor (BAFF) concentrations have, for example, been shown to be elevated in several patients with CVID and may contribute to the development of autoimmune manifestations by favoring the expansion of autoreactive B cell clones [30, 31]. However, the frequency with which such mutations co-exist in individuals who also have mutations in TACI-associated genes remains largely unclear.

Primary Immunodeficiency Syndromes Associated with T Cell Defects May Be Mistaken for CVID

Although T cell intrinsic defects and susceptibility to T cell pathogens are not typically linked with CVID, T cells do play an influential role in immunoglobulin synthesis by providing critical co-stimulatory and cytokine signals. Cytokine production abnormalities in T cells are not infrequently observed in this patient population. Intriguingly, an increase in the production of Th1-associated cytokines has been observed [32], which may contribute to the global immune dysregulation associated with this disorder. When peripheral blood mononuclear cells (PBMCs) were isolated from CVID versus control subjects and stimulated for 72 h in vitro to induce T cell activation, a significant and similar increase in transitional activated (defined as CD19+CD24hiCD38hi) B cells was noted in both groups [33]. However, a significantly lower percentage of regulatory (IL-10 producing) B cells was noted in CVID patients relative to healthy controls. This correlated with an increase in both tumor necrosis factor-alpha and interferon-gamma producing T cells in CVID patients, production of which was reduced following IL-10 blockade using an in vitro assay. These data suggest that reduced B regulatory cell production may be responsible for aberrant T cell activation and cytokine production in CVID.

Reduced frequencies of peripheral Foxp3+ regulatory T cells may also contribute to disease pathogenesis [34], which may be linked to decreases in IL-2 production in patients with CVID [35], although some groups dispute this [36]. Moreover, it was noted by Genre et al. that high and stable expression of Foxp3 in regulatory T cells was protective against development of autoimmune disease in CVID subjects. Thus, analysis of regulatory lymphocyte status, particularly of IL-10 production in B cells and Foxp3 expression in T cells may offer a potential strategy for further disease risk stratification.

There are many conditions that resemble CVID but are mistakenly diagnosed as such. A recent case report of a 27-year-old female who was classified as having CVID for years highlights this point. This patient presented in childhood with allergic eczema, elevated IgE, and was hospitalized repeatedly for recurrent mucosal infections and a lack of response to polysaccharide vaccines. Her diagnosis of dedicator-of-cytokinesis 8 (DOCK8) deficiency became clearer over time given that she developed recurrent skin infections with papillomavirus and molluscum contagiosum, which are viral pathogens not characteristic of CVID and more suggestive of a combined immune deficiency involving T cell defects [37].

Loss of function of the immune checkpoint protein CTLA-4, which is expressed constitutively by regulatory T cells (Tregs) and induced on activated T cells, has been associated with antibody deficiency and immune dysregulation. Schubert et al. described a cohort of five family members who presented with a complex autosomal dominant syndrome marked by hypogammaglobulinemia, recurrent respiratory tract infections, autoimmune cytopenia, autoimmune enteropathy, and infiltrative lung disease [38]. Further analysis of this cohort revealed a heterozygous mutation in exon 1 of the CTLA-4 gene, and screening of 71 unrelated patients with comparable clinical phenotypes revealed nine additional individuals with similar mutations. Notably, CTLA-4 expression and Treg function was shown to be markedly decreased in these patients despite elevated Treg numbers. Intriguingly, CTLA4 mutation was associated with decreased circulating B cells, and in turn, was associated with a complex immune dysregulation syndrome that could easily be mistaken for CVID at first glance (Table 3.1).

Monogenetic Illnesses Have Shed Further Light on the Pathogenesis of CVID

CVID is by far and away the most common symptomatic PIDD; however, other (more rare) monogenetic illnesses that were previously characterized as CVID are now defined as their own entities and have shed further light on the pathogenesis of CVID (Table 3.1). X-linked proliferative disorder (XLP) is a PIDD in males characterized by hypogammaglobulinemia and a reduction in invariant natural killer (iNKT) cells that is attributed to deficiency in the SH2D1A gene [39]. XLP patients typically present with life-threatening mononucleosis following EBV infection with later-stage hypogammaglobulinemia and non-Hodgkin’s B cell lymphoma. This observation has led to investigation of iNKT cell presence and function in CVID. Intriguingly, many CVID patients have reduced number and function of invariant natural killer (iNKT) cells with 40% of patients showing a complete absence of these cells and 75% of patients having at least partial iNKT cell deficiency in one study cohort [40]. This is of clinical relevance to the evaluation of hypogammaglobulinemic patients because iNKT deficiency can no longer be used to rule in XLP since CVID patients may present with a comparable deficiency in this population of cells. However, the presence of iNKT cells is certainly useful in reducing the likelihood of XLP as the underlying cause of immunoglobulin deficiency. Defects in iNKT cells are otherwise quite distinctive to CVID among antibody-deficient patients who share similar clinical presentations to this population. For example, X-linked agammaglobulinemia, a monogenetic disorder marked by a defect in the Bruton tyrosine kinase (Bkt) enzyme, shows no genetic defect in iNKT cell function or numbers but is associated with an absence of B cells. The pathologic basis for the contribution of iNKT cells to the overall clinical presentation of patients with CVID may be owed to the role of iNKT cells in supporting B cell responses, as they, like T helper cells, can offer important co-stimulatory and cytokine support. Thus, deficiency in this cellular compartment may presumably contribute to overall B cell dysfunction and impaired antibody responses.

Inducible co-stimulator (ICOS) deficiency was the first monogenetic defect that was reported to cause a CVID-like presentation [41]. ICOS, which is upregulated on the surface of activated T cells, is important for cellular proliferation, differentiation, and survival as well as for the maintenance of Tregs [42]. Moreover, ICOS deficiency leads to impaired germinal center formation, which results in memory B cell deficits and impaired immunoglobulin class-switching responses [43]. ICOS deficiency is marked by progressive B cell loss and impaired T cell memory responses throughout a patient’s lifetime [44] and should be considered in the differential diagnosis for any patient with CVID-like features. Distinguishing characteristics of various PIDDs that commonly mimic CVID are provided in Table 3.1. Though there are certainly many subtleties regarding the various antibody-deficiency disorders that can make the precise diagnosis of CVID a challenge, continued exploration of these monogenetic defects with targeted genetic testing has the potential to improve the accuracy of diagnosis , which will better inform clinical prognosis and therapy.

Clinical Presentation and Associated Conditions

The most common initial symptoms of CVID are recurrent, severe sinopulmonary infections. A cohort study conducted at Mt. Sinai Hospital which followed 473 subjects with CVID over four decades reported a history of serious infections in 94% of its patients [45]. Although CVID is predominantly diagnosed as the result of a pattern of repeated infection, non-infectious inflammatory or autoimmune disease may also be the presenting or a concomitant symptom. In the French DEFI cohort, 10% of patients presented with autoimmune cytopenias, 7% had chronic non-infectious diarrhea, and 6% presented with splenomegaly as their initial symptom of CVID [10].

It is widely acknowledged that CVID patients can be divided into two distinct clinical phenotypes—those who present with infections only, and those who also experience one or more of the non-infectious complications described below [15]. In the Mt. Sinai cohort, 32% of patients were of the infection-only phenotype while 68% had non-infectious complications [45]. The actual prevalence of each phenotype is unknown as the numbers vary widely among CVID cohorts and are likely subject to referral bias to tertiary medical centers.

Bacterial Infections

The vast majority of CVID patients (>90%) have a heightened susceptibility to bacterial pathogens and suffer from recurrent infections, which often include but are not limited to infections of the sinopulmonary tract [10, 45]. The most common infection types are thought to be recurrent respiratory infections (91–98%), pneumonia (40–76.6%), and Giardia enteritis (2.3–13.9%) [46]. In the Mount Sinai cohort study, 187 of 473 subjects (40%) had suffered from 1 or more episodes of pneumonia prior to initiating treatment [45]. The most common causal agents were noted to be encapsulated organisms such as Streptococcus and Hemophilus influenza. Recurrent sinopulmonary infections have been shown, in turn, to contribute to development of chronic lung disease in patients with CVID.

Acute or chronic infectious diarrhea is also common in CVID patients, with Giardia, Campylobacter, and Salmonella being the most frequently noted [10, 47]. Clostridium difficile infection has also been shown to affect patients with CVID, which may be owed to frequent antibiotic use among this population [10]. Fortunately, replacement immunoglobulin products which contain antibodies to C. difficile do confer some degree of protection against this bacterium as well as others [47, 48].

Meningitis may present in patients with CVID though this is far less common than sinopulmonary and gastrointestinal infections. Infections of the skin and urinary tract are not commonly seen in this disorder and may suggest a misdiagnosis of CVID [15].

Viral Infections

Although bacterial infections are the hallmark of CVID, there are a number of viral infections associated with this condition. In one report, a young boy who presented with arthritis and Parvovirus B19 infection was ultimately found to have CVID [49]. Intriguingly, both his presenting symptoms and his viral infection cleared readily after initiation of treatment for CVID.

Two common herpes viruses, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), may contribute to T cell abnormalities in CVID patients [50]. In a study of 76 CVID patients, Raeiszadeh et al. found that over half CVID patients had circulating CD8+ T cells specific for CMV epitopes and that those patients had a 13-fold increase in T cell responses to CMV peptides compared to healthy controls [50]. CMV infection is also associated with a CD4/CD8 ratio inversion due to an expansion of the late effector CD8+ T cell subset [51]. The exaggerated T cell response described above in a subset of CVID patients infected with CMV correlates with inflammatory complications [51].

Noroviral infections are increasingly observed in CVID, particularly in those with underlying inflammatory bowel disease. Although the development of CVID-associated enteropathy is not fully understood, a recent study implicated chronic Norovirus infection as a contributing factor. In the CVID cohort at the Immunodeficiency Clinic at Addenbrooke’s Hospital in Cambridge, Woodward et al. found that all eight patients diagnosed with enteropathy exhibited sustained fecal excretion of Norovirus, while CVID patients without enteropathy showed no evidence of Norovirus infection [52].

Malignancy

In two CVID cohorts, approximately 15–20% of CVID subjects developed a malignancy with lymphomas being the most common type [45, 53]. Lymphomas in CVID patients tend to be B cell in subtype, are slightly more common in females, are more often extranodal and Epstein–Barr Virus negative, and most commonly occur between the fourth and seventh decade of life [54]. In the Mount Sinai Hospital CVID cohort, 8.2% of subjects developed a lymphoid malignancy [45]. While other studies have not shown quite as high a percentage of CVID subjects that have developed lymphoma, analyzed collectively, the literature indicates that it nevertheless remains the most common malignancy type in CVID patients [15, 54]. It remains unclear why CVID patients are at an increased risk for lymphoid malignancies, but it is likely that a combination of genetics, chronic infection, radiosensitivity, and immune dysregulation contribute to the heightened susceptibility [54].

Other malignancies that appear to disproportionately affect CVID patients include gastric cancer and solid tumors. One study found CVID patients to be at a tenfold greater risk for gastric cancer than the general population [55]. There appears to be variability in the risk among different cohorts, potentially due to the prevalence of H. Pylori infections, a known risk factor for gastric cancer and infection to which CVID patients likely have heightened susceptibility [54]. A recent European CVID cohort showed that patients with solid tumors outnumbered those with lymphomas [6].

Hematologic malignancies other than lymphoma in CVID patients are less common, but a number of cases have been reported and include disorders such as myelodysplastic syndrome (MDS) and acute lymphocytic leukemia (ALL) [56].

Lymphoproliferative, Granulomatous, and Inflammatory Diseases

Lymphoproliferation and granulomatous disease (GD) are non-infectious, non-malignant complications of CVID. Recent cohort studies suggest that granulomatous disease occurs in approximately 9–14% of CVID patients and can have strong radiographic similarities to systemic sarcoidosis [6, 10, 45, 57]. CVID-associated GD (CVID-GD) is characterized by non-necrotizing granulomatous inflammation and is often systemic [57]. The lungs are the most common location of granulomas, but GD can also affect with decreasing frequency the spleen and lymph nodes, liver, GI tract, bone marrow, skin, CNS, and other locations [57]. In the French DEFI cohort, 51% of patients with CVID-GD had granulomas in the lungs, and 47% had granulomas in two or more organs [57]. CVID-GD is similar to sarcoidosis both clinically and histologically, but a recent study confirmed that the two inflammatory conditions have distinct genetic backgrounds, indicating a unique pathophysiology for CVID-GD [58].

Benign lymphoproliferation, including splenomegaly, lymphoid hyperplasia, and polyclonal lymphocytic infiltration, is found in up to two thirds of CVID cohort subjects [59]. These patients typically exhibit higher IgM levels relative to their counterparts without evidence of lymphoproliferation [60]. A recent study of 55 patients found that proinflammatory innate lymphoid cells (ILCs) with an IFNγ signature are increased in the blood, GI, and lung tissue of CVID patients, especially those with associated inflammatory disease [60]. Treatment of inflammatory conditions in CVID patients may thus necessitate a means of reducing circulating ILCs. Although lymphoproliferation is not necessarily felt to be a precursor to malignancy, CVID patients presenting with benign lymphoproliferative conditions are at a greater risk of developing future lymphoid malignancy than other CVID patients [60].

Autoimmune Manifestations

Recent studies indicate that approximately 30% of CVID patients exhibit symptoms of autoimmunity [6, 10, 45, 59, 61]. The most common autoimmune manifestations of CVID are autoimmune cytopenias, with immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) being the most frequent, respectively [60, 62]. Other systemic and organ-specific autoimmune diseases, including Sjogren’s Syndrome, seronegative inflammatory arthritis, Evans syndrome, pernicious anemia, autoimmune thyroiditis, psoriasis, autoimmune hepatitis, inflammatory bowel disease, autoimmune enteropathy, and primary biliary cirrhosis have also been noted [60, 63, 64]. Autoimmune cytopenias, lymphoid hyperplasia, splenomegaly, and granulomatous disease are often noted to occur together [6, 60, 65].

The pathogenesis of CVID-associated autoimmunity has not been fully elucidated. Despite impaired responses to many infectious antigens, autoreactive B and T cells are found in a subset of CVID patients [66]. Autoantibody testing is frequently negative given that these patients are hypogammaglobulinemic and when positive, may be more reflective of donor replacement IgG. Multiple studies have observed that CVID patients have elevated CD21low cells, a feature that is also associated with some autoimmune diseases [63]. T cell defects and other cellular abnormalities have also been implicated in CVID-associated autoimmunity. Specifically, CVID patients with autoimmunity exhibit reduced numbers of regulatory T cells [67], impaired dendritic cell function, and abnormal cytokine levels [66]. Interestingly, CVID patients with a single mutation in the tumor necrosis factor superfamily member TACI have heightened susceptibility to autoimmune manifestations while those with two allelic mutations are protected against autoimmunity [28, 66], suggesting that altered B cell tolerance is also likely to play a substantial role in the clinical manifestations of this disorder.

Pulmonary Disease

Approximately 30–60% of CVID patients develop some form of pulmonary disease, which can be infectious or non-infectious in origin [9, 10, 45]. In the Mt. Sinai cohort study, 28.5% of subjects were noted to have chronic lung disease while 11.2% exhibited bronchiectasis [45]. Bronchiectasis is typically the result of recurrent infections that in turn lead to irreversible tissue damage; thus, CVID patients who experience recurrent airway infections are at high risk for pulmonary disease [68].

Chronic lung disease may manifest as interstitial lung disease (ILD), which has a higher morbidity than bronchiectasis. The cause of ILD is unknown, but numerous studies have illustrated an association with immune dysregulation and/or autoimmunity [65]. ILD appears to be progressive in the majority of cases although some patients have exhibited a more stable clinical course [69]. Granulomatous-lymphocytic interstitial lung disease (GLILD) (Fig. 3.1) is a severe form of ILD characterized by the combination of granulomas and lymphoid infiltrations in the lung [70]. Mannina et al. recently identified hypersplenism and polyarthritis as strong risk factors for GLILD although specific pathophysiologic overlaps are yet to be identified [71]. GLILD is itself a risk factor for B cell lymphomas in CVID patients, and a study of CVID-GLILD patients found that the prevalence of B cell lymphotropic human herpes virus type 8 (HHV8) infection is significantly higher in those patients than CVID-controls [72]. HHV8 infection is known to cause lymphoproliferation in immune deficient settings and may contribute to the development of GLILD and lymphomas in CVID patients [54, 72].

Fig. 3.1
figure 1

Representative images of pulmonary GLILD on high resolution spiral CT scan with 5 mm cuts. Images a and b show bilateral basilar predominate tree and bud ground glass opacities with multiple basilar perilymphatic nodules. Images c and d show same areas of the lung after therapy with rituximab and azathioprine; there is almost complete resolution of the pulmonary opacities

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GI Complications

Although infectious diarrhea is the most common GI symptom in CVID patients, non-infectious and non-malignant GI complications are reported in 9–20% of patients and often lead to symptoms of recurrent diarrhea and malnutrition [6, 10, 45]. Common manifestations include immune-mediated enteropathy, nodular lymphoid hyperplasia of the gastrointestinal tract, small intestine bacterial overgrowth, small bowel villous atrophy, and gastritis [47].

CVID enteropathy and small bowel villous atrophy often resemble celiac disease (CD) (Fig. 3.2a, b). This poses a diagnostic challenge to physicians because CVID patients will not test positive for CD-specific antibodies. There is ongoing debate regarding how best to differentiate between the two conditions and ensure appropriate treatment. Some suggest that a lack of plasma cells, a hallmark histological feature of CVID, and evidence of lymphoid hyperplasia on biopsy is sufficient to exclude CD (Fig. 3.2c) [15]. However, results from a 2012 retrospective clinical study indicate that the only means of excluding CD in CVID patients is a lack of response to a gluten free diet or HLA typing [73]. CVID enteropathy may also resemble inflammatory bowel disease (IBD) with regard to both symptomatology and disease mechanisms. CVID patients with inflammatory complications have increased ILCs, which have also been implicated in the pathogenesis of IBD [47, 60].

Fig. 3.2
figure 2

Characteristic clinical and histopathologic findings of CVID enteropathy. (a) Endoscopic photo of the terminal ileum. Mucosal edema characterized by absent vascular markings and swollen villi. (b) Endoscopic photo of the second portion of the duodenum. Note the linear crevasses in the mucosal folds (scalloping) consistent with villous blunting. (c) Duodenum 70× magnification: There is partial villus atrophy with a sparse mononuclear infiltrate in the lamina propria. No lymphoid nodules or granulomas are present

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In the Mt. Sinai cohort, 9.1% of CVID subjects had identified liver disease, with hepatitis and liver granulomas being the most common types. A rare but serious liver complication in CVID patients is nodular regenerative hyperplasia (NRH), a disease defined by characteristic nodules and portal hypertension that likely has an autoimmune basis (Fig. 3.3) [74]. A recent study of 14 CVID patients found that in a majority of the cases, NRH progressed into one of two more serious conditions—severe portal hypertension leading to splenic abnormalities or autoimmune hepatitis-like liver disease [75]. NRH is often concomitant with other autoimmune diseases, most commonly malabsorptive CVID enteropathy. Early detection and treatment are critical, as NRH appears to become unresponsive to image-guided radiation therapy or immunosuppressive therapy as it advances [74, 75].

Fig. 3.3
figure 3

Nodular regenerative hyperplasia of the liver is a rare complication of CVID that portends a poor prognosis. (a) Nodular regenerative hyperplasia is diagnosis made by histopathologic evaluation at low magnification and typically does not represent itself well in pathology images. (b) The reticulin stain shows vague nodularity

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Neurologic Complications

Neurologic complications associated with CVID are rare but have been described. In 62 case reports of neurological complications in CVID subjects, 43 were linked to an infectious etiology (69%), the most common being bacterial meningitis [22], progressive multifocal leukoencephalopathy [6], and HSV encephalitis [3, 76]. Thirteen reported an autoimmune/inflammatory etiology (21%), the most common being myelitis [4] and granulomatous mass [4, 76]. The other 6 case reports listed either endocrine dysfunction or nutrient deficiency as the cause of the neurological disorder [76].

Diagnosis and Differential Diagnosis of CVID

The ESID and International Consensus Document (ICON) diagnostic criteria for CVID are summarized in Table 3.2.

Table 3.2 CVID diagnostic criteria
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Antibody deficiency should be considered in patients with recurrent infections and/or one or more of the clinical manifestations described in Table 3.2. Note documentation of impaired vaccination responses as a major difference between the two sets of criteria. In general, CVID diagnosis should be based on serum immunoglobulin levels, antibody responses, flow cytometry, and clinical presentation [3, 77]. All other defined causes of hypogammaglobulinemia should be excluded, including conditions associated with a primary immunodeficiency or secondary immunodeficiencies (Table 3.3) [46]. Secondary causes of hypogammaglobulinemia include, but are not limited to, malignancy, renal or enteropathic protein loss, genetic syndromes, infections, and medications [59]. Some patients treated for autoimmune conditions with rituximab develop an immunodeficiency, resulting in a CVID-like disease state. Kaplan et al. recently proposed the term persistent immunodeficiency after treatment with immunomodulatory drug (PITID) to distinguish these patients from those with CVID [78]. Patients with hypogammaglobulinemia resulting from profound T cell deficiency and those with combined immune deficiency should also be excluded (Table 3.3) [59].

Table 3.3 Differential diagnosis of persistent humoral immune deficiency
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Laboratory Evaluation

Diagnostic Tests

Laboratory tests required to diagnose CVID include measurement of quantitative serum immunoglobulins and vaccine responses to at least 1 T-dependent antigen (e.g., tetanus, diphtheria, and pertussis toxoids or Haemophilus influenza Type B) and at least 1 T-independent antigen (e.g., Streptococcus pneumonia serotypes and Neisseria meningitides) [15]. Levels of the four major immunoglobulin isotypes (IgG, IgM, IgA, and IgE) should be measured, but quantitation of IgG subclasses for the assessment of immune deficiency is not required for the diagnosis [15]. In three large cohorts, the vast majority of CVID patients had IgG levels less than 4.5 g/L at diagnosis [8, 9, 79]. IgA is typically low or undetectable; IgM levels vary, and some patients may have a complete absence of all immunoglobulin isotypes [15].

Although antibody response to vaccines is widely recommended as a means of diagnosis, specific antibody production is variable in CVID patients, and there is no consensus regarding which vaccines to use [15]. A retrospective chart review of CVID and hypogammaglobulinemia patients at Duke University Medical Center found that immunization with bacteriophage ΦX 174, a T cell-dependent neoantigen, is a useful method of assessing antibody response in patients with suspected primary immunodeficiencies [80]. Other widely available and commonly used vaccines to assess T cell-dependent responses include tetanus and diphtheria toxoids and Haemophilus influenza Type B, both of which are associated with well established, protective levels of specific IgG in order to facilitate an easier diagnosis of immune deficiency [15]. Specific IgG levels following administration of the pneumococcal polysaccharide vaccine can be used to evaluate T-independent responses, albeit the results are frequently imperfect and difficult to interpret with respect to this particular vaccination [15].

Ameratunga et al. recently asserted that assessment of vaccine response may be misleading, as some CVID patients likely developed memory B cells to childhood immunizations prior to the development of hypogammaglobulinemia [15]. However, a 2013 study concluded that polysaccharide responsiveness is not biased by prior pneumococcal-conjugate vaccination, suggesting that pneumococcal polysaccharide vaccination does have some diagnostic value [81].

Flow cytometry can be used to analyze B, T, and natural killer cell populations to exclude combined immunodeficiency [15]. T cell and natural killer cells are typically present at normal levels in the peripheral blood of CVID patients [82]. The number of B cells in peripheral blood, however, varies widely. In a retrospective study of European adults with CVID, 54% of subjects had normal levels, 19% had increased levels, and 24% had reduced or undetectable levels [79]. Flow cytometry has recently been used in conjunction with a memory B cell functionality assay which relies upon enzyme-linked immunosorbent spot (ELIspot) technology to determine the capacity of memory B cells to develop into functional, antibody-secreting cells in response to standard lymphocyte mitogens [83]. Such methods could be incorporated into standard practices as functional assays allow for subgrouping of CVID patients by functional deficit and the potential for individualized treatment.

Imaging

In a patient recently diagnosed with or suspected of having CVID, various imaging techniques can identify non-infectious complications. A baseline chest computed tomography scan should be performed at the time of diagnosis to identify chronic lung disease [59]. Pulmonary radiologic findings in CVID patients may include pulmonary nodules, ground glass opacities, bronchial wall thickening, emphysema, air trapping, bronchiectasis , parenchymal consolidation, scarring, or fibrosis [65]. In a retrospective study of the Mt. Sinai cohort, 84% of patients who underwent a CT scan exhibited pulmonary abnormalities, the most common findings being pulmonary nodules and bronchiectasis [65]. The same study suggested that a combination of pulmonary nodules and ground glass opacities are associated with development of ILD and that ILD is associated with splenomegaly, liver disease, and autoimmune cytopenias [65]. Thus, an initial CT scan to identify ILD may also identify a patient’s susceptibility to other non-infectious complications. In 2010, Annick et al. developed a CT scan scoring system specifically for children with CVID, which may be helpful for monitoring and preventing disease progression, as children tend to present with less severe lung disease than adults [84]. CT scans can also be used to differentiate between granulomatous disease, GLILD, and sarcoidosis. GLILD is associated with parenchymal abnormalities in the lower lung, large, randomly distributed nodules, and bronchiectasis, while sarcoidosis is associated with parenchymal abnormalities in the upper lung, hilar adenopathy, and micronodules in a perilymphatic distribution [85]. Follow-up CT scans should only be used when symptoms or lung function change, as they may further increase the risk of malignancy in CVID patients [59].

In patients with CVID and gastrointestinal complaints, gastroduodenoscopy and ultrasound should be pursued as they are lower risk imaging modalities and can be very informative to the clinician. Ultrasound can be used to evaluate spleen size, liver pathology, and intra-abdominal lymphadenopathy without radiation exposure [59, 86]. A recent case demonstrated successful use of gastroduodenoscopy to identify nodules in the duodenum of a patient who was subsequently found to have hypogammaglobulinemia, leading to a diagnosis of CVID with nodular lymphoid hyperplasia [87]. In patients with known CVID, gastroduodenoscopy with biopsy and histologic assessment can discern infectious from inflammatory or malignant comorbid conditions.

Histopathology

Many of the non-infectious conditions associated with CVID cause characteristic histopathological changes in the affected tissue. In the Mt. Sinai CVID cohort, 11 of 12 (92%) patients with ILD who had a lung biopsy exhibited pulmonary lymphoid hyperplasia, and 3 (25%) had granulomas [65]. On surgical lung biopsy, GLILD appears as cellular interstitial pneumonia accompanied by granulomatous and lymphoproliferative features [71].

Liver biopsies of 14 CVID patients with NRH showed nodular areas of enlarged hepatocytes alternating with compressed liver cell plates [75]. Other histopathological findings in subsets of these NRH patients included peri-sinusoidal fibrosis in compressed zones with spotty lobular inflammatory foci (21%) and focal portal inflammatory infiltrates (43%) [75].

In a retrospective study of 22 adult and pediatric Italian CVID patients with GI complications who underwent gastrointestinal biopsies, histological alterations included an absence of plasma cells in 74% of patients, increased intraepithelial T cell count in 57% of patients, mucosal atrophy in 19% of patients, follicular lymphoid hyperplasia in 9.5% of patients, and polymorphonuclear infiltrate (PMN) in 5% of patients [88]. An absence of plasma cells was notably more common in pediatric patients, while mucosal atrophy was more common in adults [88]. Follicular lymphoid hyperplasia and PMN infiltrates were found exclusively in adults [88]. Graft versus host disease (GVHD)-like lesions have also been found in GI biopsies of CVID patients [89].

Treatment

Immunoglobulin Replacement Therapy (IGRT)

The standard treatment for CVID is immunoglobulin replacement therapy (IGRT ), either intravenous (IVIG) or subcutaneous (SCIG) , and sometimes administered in conjunction with antibiotics [90]. The primary goal of IGRT is to lower the frequency and severity of severe infections. Its efficacy is well established particularly with regard to reduction of pneumonia incidence [90]. IGRT is offered at varying intervals depending on the patient’s condition and mode of therapy (IVIG vs. SCIG) in order to reach the desired IgG trough level [15, 90]. Most national and international guidelines suggest starting IGRT in the range of 0.3–0.5 g/kg/month for IVIG and 0.4–0.6 g/kg/month for SCIG [15, 91]. Higher doses may be necessary for patients with bronchiectasis, enteropathy, or splenomegaly [15]. Systemic adverse reactions occur in 20–50% of patients receiving IVIG, but are usually mild, rate-related, and treatable [92]. Systemic reactions are rare with SCIG, but local reactions such as bruising or swelling can occur in up to 75% of SCIG infusions [92]. These tend to improve over time. IVIG and SCIG have proven to be equally effective for treating complications from hypogammaglobulinemia in PIDD; however, recent case studies suggest that SCIG may be more effective in patients with humoral immunodeficiency and comorbid bowel disease [93]. Further research into the efficacy SCIG versus IVIG in patients with specific complications is warranted.

SCIG can be self-administered in a home setting with minimal training and thus can be more easily tailored to patients’ schedules than IVIG , which requires an in-office visit, a home infusion service, or extensive training in self-infusion [15, 90]. Traditionally, SCIG required weekly or biweekly infusion at multiple sites to achieve an adequate dose on account of its reduced bioavailability [94]. In an attempt to further improve quality of life for patients using SCIG, a formula containing hyaluronidase and subcutaneous immunoglobulin was recently developed [90]. The hyaluronidase facilitates absorption of IgG to such an extent that most patients require just a single subcutaneous infusion every 3–4 weeks [94]. In addition to allowing for improved quality of life, there is evidence for SCIG being a more economical treatment option than IVIG [15, 95].

Clinical Monitoring

CVID patients receiving IGRT in the form of IVIG or SCIG should routinely have serum IgG levels checked to ensure that they are receiving adequate dosages since these can be affected by changes in weight, disease state, or immune suppressive medications [59]. Clinicians should run symptom-directed tests as clinically indicated. Additionally, routine monitoring that might identify the presence or development of non-infectious complications such as liver function tests and complete blood cell counts can be assessed once or twice per year [59]. Pulmonary function testing and lung diffusion capacity can be used to monitor the progression of lung disease without need for repeated radiographic assessments [59]. In patients who develop or have a history of diarrhea and/or other GI symptoms, a colonoscopy and infectious work-up can help identify causal pathogens and/or non-infectious gastrointestinal complications of CVID [96].

Steroids, Rituximab, and Immunosuppressive Therapy

Steroids or corticosteroids are often used to treat autoimmune cytopenias, lymphoproliferation, and granulomatous disease in CVID patients [15]. Rituximab (a monoclonal antibody against CD20) and other immunosuppressive agents may be necessary if steroids are not sufficient to treat these conditions although their use in CVID patients is complicated by the increased risk of infection that they impose. However, a retrospective study of 33 CVID patients treated with rituximab suggests that this is generally safe for use in conjunction with IGRT [97]. Combination chemotherapy consisting of rituximab and azathioprine has been shown to successfully treat GLILD in CVID patients (Fig. 3.1) [98]. Treatment of malignancies in CVID patients typically adheres to protocols used for immunocompetent patients [15]. Other immune suppressants used to treat organ-specific autoimmune disease such as methotrexate, sulfasalazine, hydroxychloroquine, mycophenolate mofetil, and leflunomide have been used successfully, but studies documenting their efficacy are limited [99]. Although anti-TNFα agents can be used in CVID for autoimmune manifestations, they should be used with caution given increased infection risk [51].

Splenectomy

Splenectomy has historically been used to treat autoimmune cytopenia and lymphoma in CVID patients despite the associated life-long heightened risk of severe infections. In the Mt. Sinai cohort, 39 CVID patients (8.2%) underwent a splenectomy as part of their treatment for splenomegaly and autoimmune cytopenias [45]. A retrospective study of splenectomized CVID patients from seven European countries found that splenectomy is equal to rituximab in treatment efficacy for autoimmune cytopenias and that the increased risk of infection can be at least partially mitigated by IGRT [100]. The authors of this study nevertheless concluded that due to the irreversible nature of the procedure and imposed surgical risks, splenectomy should be reserved for patients who do not adequately respond to rituximab [100].

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has traditionally been used to treat patients with T cell immune deficiency [101]. T cell defects have become increasingly implicated in a subset of CVID patients; thus, the potential use of HSCT as a treatment for CVID was the subject of a recent retrospective multicenter study in Europe [102]. Wehr et al. concluded that HSCT has the potential to be an effective curative therapy for some CVID patients with non-infectious complications of the disease but carries a high mortality rate and imposes potential complications from GVHD [102]. In this study, 12 of 25 patients (48%) survived the transplantation. Of this population, 11 (92%) were cured of their non-infectious indication for transplantation and half were able to cease IGRT altogether [102]. Interestingly, HSCT was more effective in CVID patients with hematologic malignancy versus other non-hematologic complications, with 83% and 33% survival, respectively [15, 102]. Further studies are warranted to determine which patients would most benefit from HSCT as a means of reducing mortality from CVID-associated complications.

Special Considerations

CVID is not associated with reduced fertility or negative pregnancy outcomes [103]. The majority of women with PIDD, including CVID, undergo normal pregnancies while receiving IGRT [103]. It may be necessary, however, to increase IgG dosages during pregnancy to account for weight gain and hemodilution, and to test serum IgG levels more frequently in order to mitigate infection risk and improve transplacental immunoglobulin transfer at birth [103, 104].

Outcomes

The prognosis for CVID patients has improved markedly since the development of IgG therapy in the 1990s [15]. According to the International Consensus Document (ICON), there is an overall expected survival of 58% 45 years after initial diagnosis based on analysis of multiple cohorts [15]. Individual prognosis varies significantly depending on clinical phenotype. Analysis of the Mt. Sinai cohort indicated that patients with non-infectious complications have an 11-fold higher risk of death compared to patients with an infections-only phenotype [45]. The conditions associated with reduced survival in that cohort included chronic lung disease (leading cause of death), lymphoma, hepatitis and other liver diseases, and GI inflammatory disease [45]. On the other hand, a large Italian cohort noted malignancy to be the leading cause of death in CVID patients [53].

The prognostic value of various test results at diagnosis is unknown. In the Mt. Sinai cohort, low serum IgG levels, high serum IgM levels and a low peripheral B cell count correlated with reduced survival [45]. Contradictorily, there was no association between survival and serum IgG levels or peripheral B cell count in a large European cohort [79]. Both cohorts did, however, find a correlation between high serum IgM levels at diagnosis and the development of either lymphoma or benign lymphoproliferative disease [45, 79]. Other factors that have been associated with reduced survival include older age at onset, older age at diagnosis, and longer diagnostic delay [6].

Conclusions

  • CVID is a heterogeneous group of primary immune deficiencies characterized by a heightened susceptibility to sinopulmonary and gastrointestinal infection.

  • A subset of CVID patients also exhibit non-infectious complications and such patients tend to have poorer outcomes.

  • Pathogenesis is complex and likely differs among subgroups of patients.

  • IGRT is the standard treatment for hypogammaglobulinemia and may be supplemented with additional therapies to address non-infectious complications.