Treatment and prognosis of common variable immunodeficiency

INTRODUCTION — Common variable immunodeficiency (CVID) is an immune disorder characterized by impaired B cell differentiation with hypogammaglobulinemia. The disorder is associated with a broad spectrum of clinical manifestations, including recurrent infections, chronic lung disease, gastrointestinal disease, and autoimmune disorders.

The cornerstone of therapy is immune globulin replacement, which has dramatically altered the clinical course of CVID by reducing the burden of recurrent infections and subsequent complications. Management also involves vigilant monitoring and appropriate treatment for associated problems, such as pulmonary damage, gastrointestinal, autoimmune, and granulomatous diseases, and malignancy [1].

The treatment and health maintenance of patients with CVID will be discussed here, with an emphasis on adults. The clinical manifestations, diagnosis, and pathogenesis of this disorder and issues particularly relevant to pediatric patients are presented separately. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Common variable immunodeficiency in children" and "Pathogenesis of common variable immunodeficiency".)

IMMUNE GLOBULIN REPLACEMENT THERAPY — The definition of CVID includes individuals with varying degrees of loss of antibody. For those with substantial impairments in immune globulin production (eg, generally two standard deviations below the normal range for immunoglobulin G [IgG]) and nonresponse to both protein and polysaccharide vaccines, immune globulin replacement is necessary. For subjects with higher levels of serum IgG and only minor impairments in response to some vaccines, immune globulin replacement therapy may be postponed, but these patients should be followed closely. (See 'Immune globulin in patients without infections or with isolated autoimmune disease' below.)

Overview of administration — Immune globulin replacement therapy may be administered either intravenously or subcutaneously. A typical approach is to begin therapy with intravenous immune globulin (IVIG), although one can also start with subcutaneous immune globulin (SCIG), with or without an initial loading regimen. If the intravenous route is used to initiate therapy, the subcutaneous route may be substituted after two or more months on IVIG, if this is preferred. We occasionally start patients with very poor venous access on SCIG from the outset. A more detailed discussion of the characteristics and safety of various preparations of IVIG, how to initiate therapy with IVIG or SCIG, and how to convert from IVIG to SCIG, is found separately. (See "Immune globulin therapy in inborn errors of immunity" and "Subcutaneous and intramuscular immune globulin therapy".)

Intravenous route — IVIG therapy can be administered in the office, infusion center, or home. Selected patients may also be candidates for self-infusion of IVIG. The placement of indwelling catheters solely for the administration of IVIG is not recommended due to the propensity of CVID patients to develop infectious complications [1,2].

Dosing — The usual initial dosing for IVIG in patients with CVID is 400 to 600 mg/kg every three to four weeks with or without premedication. Patients who are actively infected at the time of the initial infusion are more likely to experience adverse symptoms during infusion, so, when possible, we try to treat the infection first for a few days, then initiate immune globulin. Higher doses may be required in patients with bronchiectasis and in those with protein-losing enteropathy. Premedication with diphenhydramine or nonsedating antihistamine and acetaminophen is commonly used for those who are prone to medication reactions, but, in rare cases, a glucocorticoid (such as intravenous hydrocortisone) is also given. One may also repeat the initial dose (ie, the entire 400 to 600 mg/kg) in a few days or one week later if the patient was clearing an infection when the initial dose was given. Generally, after the first two or three infusions, premedication is no longer needed. Premedications are discussed in more detail elsewhere. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedications'.)

Monitoring — The half-life of immune globulin is approximately 30 days, although variability among individuals exists. Steady-state levels are usually achieved after three to six months of therapy, and we measure trough levels of IgG beginning six months after the first dose and every six months thereafter. The level of IgG in the blood on therapy should be at least near the middle of the normal range, and the patient should experience a significant decrease in major infections [3,4]. Dosing may need to be adjusted periodically, as patient weight and endogenous production or clearance may change over time. Additional monitoring issues are discussed separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Monitoring'.)

Indications for higher dosing — Indications for higher doses of immune globulin in a patient with CVID include the following [4-6]:

●Continued major infections, such as refractory sinusitis at the starting dose of 400 mg/kg. Doses of 500 to 600 mg/kg per month are required in some patients to attain satisfactory trough levels of IgG and to keep them free of major infections [4].

●Chronic lung disease. (See 'On progression of chronic lung disease' below.)

●Enteropathy, as immunoglobulin levels may be difficult to maintain otherwise.

●The third trimester of pregnancy, as discussed separately. (See "Immune globulin therapy in inborn errors of immunity", section on 'Use in pregnancy'.)

Very high doses of IVIG (ie, ≥1 gram/kg), either given as a single dose or repeated every three to four weeks until resolution, may be helpful in patients already on standard therapy who develop autoimmune hematologic disorders [7]. (See 'Autoimmune cytopenias' below.)

We usually increase the dose in 5 to 10 gram increments, starting after the first six months of therapy, if higher doses are needed. Another way to increase the effective dose is to shorten the dosing interval from every four to every three weeks, which increases the monthly dose by 33 percent. To monitor the need for higher doses, reduced infections and/or need for antibiotics should be observed.

Subcutaneous route — An alternative to IVIG for maintenance therapy is SCIG. A number of products are available and are usually administered weekly or every other week, depending on body weight and immune globulin requirements. There is also an additional subcutaneous preparation that is facilitated by hyaluronidase, which allows for infusion of larger doses and thus can be administered every three to four weeks. This is discussed elsewhere. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Available products'.)

Compared with IVIG, SCIG may help maintain more stable levels of serum IgG and is particularly helpful for patients with reactions to IVIG or difficult intravenous access. SCIG can be self-infused at home, which is more convenient for many patients and can improve quality of life. Initial dosing of SCIG and conversion of patients from IVIG to SCIG are reviewed elsewhere. (See "Subcutaneous and intramuscular immune globulin therapy".)

Efficacy of immune globulin therapy — Immune globulin replacement therapy reduces the number of infections and decreases antibiotic use and hospitalizations [8-10]. The effectiveness of immune globulin replacement in hypogammaglobulinemic patients was immediately apparent after this therapy became available, and so randomized, controlled trials were never undertaken. In one retrospective series of 50 patients treated with IVIG, the annual incidence of pneumonia decreased from 81 percent before treatment to 35 percent on therapy, and the rate of hospitalization decreased from 89 to 46 percent [10]. In a large series of 2212 patients with CVID enrolled in a European primary immunodeficiency registry, patients receiving IVIG at doses yielding higher serum levels had fewer serious infections and days of hospitalization for primary immunodeficiency, compared with those with lower serum levels [11]. However, treatment with immune globulin does not entirely eliminate infections in most patients, and the upper sinopulmonary and gastrointestinal systems, in particular, remain susceptible. (See 'Sinusitis' below and 'Gastrointestinal infections' below.)

On progression of chronic lung disease — Immune globulin replacement may slow the progression of chronic lung disease in patients with CVID, although this has not been conclusively established. A prospective study of 24 patients receiving standard-dose IVIG found a significant improvement in forced expiratory volume in one second (FEV₁) and high-resolution computed tomography (HRCT) scores in patients with chronic pulmonary disease [12]. However, another study documented progressive lung changes by HRCT of 21 in 22 patients followed over three years, despite maintenance of trough IgG levels of 500 mg/dL, although some experts argue that this trough value was not sufficient [3].

Chronic lung disease is one of the indications for higher immune globulin doses, which may provide additional benefit for some patients [4,13,14]. One study showed radiographic improvement of chronic lung disease in 4 of 12 CVID patients receiving a dose of 600 mg/kg compared with no radiographic improvement in any patient receiving a dose of 200 mg/kg. In addition, all six patients switched to higher dose IVIG in this study showed improvement in forced vital capacity (FVC) and FEV₁ [14]. There are no studies directly comparing 600 mg/kg (or other doses) with 400 mg/kg in order to determine the optimal dose in such patients. Until more data are available, it is our practice to initiate immune globulin replacement therapy at a higher dose of 600 mg/kg in patients who have evidence of chronic lung disease at diagnosis. The goal trough level is the same as that for standard dosing. (See 'Dosing' above.)

On other disorders in CVID — Gastrointestinal infections and/or complications are relatively unaffected by immune globulin replacement, for reasons that are not well understood. Immune globulin replacement therapy may exert a protective effect in those with autoimmune disease, although it is not known to alter the development of malignancy or to impact granulomatous disease [3,12].

Immune globulin in patients without infections or with isolated autoimmune disease — About 8 to 10 percent of patients with laboratory-confirmed CVID have little or no significant medical history of infections [15,16]. These patients may have low serum IgG discovered incidentally or, more commonly, in association with autoimmunity or other complications of CVID. Studies to confirm the absence of infection may include normal sinus imaging, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level.

●For patients with minor decrements in serum IgG and only mild impairment in vaccine response to polysaccharide or protein antigens, immune globulin replacement therapy may be postponed, but the patient should be followed at reasonable intervals (eg, 6 to 12 months). For these patients, antibiotic prophylaxis may be useful [17].

●Patients with very low levels of serum IgG who have little or no vaccine responses have clear CVID and are at risk for severe infections [18]. We believe that withholding immune globulin replacement therapy on the basis of lack of past infections would be unwise.

One study prospectively followed 59 patients with CVID who were asymptomatic with regard to infections and found that most remained well over a mean observation period of approximately 11 years without receiving immune globulin [19]. The majority had moderate hypogammaglobulinemia (300 mg/dL to 690 mg/dL), but five had levels of IgG <300 mg/dL. One patient had progressive decline in IgG levels over the follow-up period and initiated immune globulin replacement, but 18 percent had spontaneous improvement, reinforcing the importance of measuring IgG levels on several occasions, especially if there is no immediate need to initiate immune globulin. None suffered catastrophic infections or autoimmune or inflammatory disorders. However, some of the subjects studied had retained IgA and functional antibody, and the patients' use of antibiotics during follow-up was not reported.

ANTIMICROBIAL THERAPY — Antibiotics may be administered prophylactically, as well as for the treatment of acute infections or exacerbations of chronic infections.

Prophylactic antimicrobials — The efficacy of prophylactic antibiotics for preventing infections in patients with CVID has been studied in a double-blinded placebo-controlled trial and found helpful [17]. While we do not routinely administer prophylactic antibiotics to all patients with CVID, we do find this approach helpful in CVID patients with frequent infections and/or ongoing lung disease. The use of antibiotics in this manner and specific regimens are reviewed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

Prevention of lung infections — Many patients with CVID do not require prophylactic antibiotics to prevent pneumonia once immune globulin therapy has been started. However, in those with chronic lung disease, infectious causes may lead to worsened inflammatory/lymphocytic infiltrates, and patients may continue to get lung infections due to underlying structural damage or other noninfectious processes. In such patients, prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or macrolides may diminish exacerbations. A general discussion of prophylactic antibiotics in patients with immunodeficiency is found separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

Prophylactic antibiotic therapy may be particularly helpful for patients with bronchiectasis, frequent exacerbations, and declining lung function and should target Haemophilus influenzae and mycoplasma [17,20]. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Antibiotics for prevention of exacerbations'.)

Prevention of recurrent sinusitis — We do not routinely recommend daily antibiotics to prevent recurrent sinusitis in patients with CVID who are receiving immune globulin replacement therapy, although there are no published studies examining this issue. Instead, we encourage patients to maintain good nasal hygiene with saline and antibiotic irrigations, and we treat infections as they arise. We also try to avoid surgical treatment of chronic rhinosinusitis, as disease almost invariably returns. The medical management of chronic rhinosinusitis is reviewed separately. (See "Microbiology and antibiotic management of chronic rhinosinusitis" and "Chronic rhinosinusitis without nasal polyposis: Management and prognosis".)

Gastrointestinal infections — There is no antibiotic prophylaxis that prevents gastrointestinal infections in patients with CVID, and the impact of immune globulin replacement therapy on the gastrointestinal tract appears to be minimal. (See 'Efficacy of immune globulin therapy' above.)

Patients with low CD4 counts — Prophylactic antibiotics to prevent infection with Pneumocystis jirovecii may be given to patients with CVID and CD4 counts <200 cells/microL. However, it is not as standard as it is in patients with human immunodeficiency virus (HIV) infection. Patients with CVID are generally not susceptible to P. jirovecii pneumonia unless given glucocorticoids or other immune suppressants (eg, methotrexate or azathioprine) for prolonged periods. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Treatment'.)

Treatment of specific infections — Antibiotics are essential for treating acute infections in patients with immunodeficiency. It is our experience that CVID patients typically do not clear common infections without the use of antibiotics. As examples, acute sinusitis or bronchitis is unlikely to clear spontaneously in patients with CVID, unlike in the general population, even in patients receiving immune globulin replacement therapy. Thus, prompt identification and treatment with antibiotics can help prevent chronic infections and infectious complications. It is also important to ensure that the infection has cleared completely at the end of a course of antibiotics, as patients with immunodeficiency often require longer durations of therapy.

Antibiotic resistance does not seem to be a prominent problem in patients with CVID, for reasons that are not clear. One study found that the lungs of patients with primary antibody deficiency were persistently colonized with H. influenzae (identified in approximately two-thirds of patients) and that the isolates remained sensitive to commonly used antibiotics; resistant strains were not found despite repeated treatment [21]. This is consistent with our clinical experience that the same antibiotics continue to be useful, despite prolonged or repeated exposure.

Sinusitis — Acute bacterial sinus infections in patients with CVID are commonly caused by Streptococcus pneumoniae, H. influenzae, and Moraxella catarrhalis, similar to in the general population [7]. Management of sinusitis in patients with CVID is similar to that in patients without immunodeficiency, although the treatment duration may need to be longer. If a patient's past sinusitis episodes did not clear with the standard 10 days or two weeks of antibiotics, it is reasonable to prescribe three weeks as initial treatment for future episodes. Recommendations for antibiotics for acute bacterial sinusitis are found separately. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Antibiotics'.)

Chronic sinusitis can be complicated by infections with Staphylococcus aureus, Pseudomonas aeruginosa, and anaerobes [7]. Chronic sinusitis may persist despite immune globulin replacement therapy, possibly because of the multifactorial nature of this condition (ie, chronic infection is just one factor in pathogenesis). The impact of higher dose immune globulin has not been reported. (See 'Indications for higher dosing' above and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

Pneumonia — Management of pneumonia in patients with CVID is similar to that in patients without immunodeficiency, although the treatment duration may need to be longer. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

Pulmonary infections that do not clear and continue to cause fever should prompt evaluation for Mycoplasma. Mycoplasma infections are usually responsive to macrolide antibiotics. This organism can also infect the bones and joint tissues in patients with CVID. (See "Mycoplasma pneumoniae infection in adults" and "Mycoplasma pneumoniae infection in children", section on 'Management'.)

Bronchiectasis — The pathophysiology of bronchiectasis is thought to be driven by a cycle of chronic infection and scarring, resulting in increasing susceptibility to infection. Antibiotics play an important role in the treatment and prevention of this condition. Inhaled glucocorticoids may reduce cough and dyspnea, although they should be used sparingly. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Anti-inflammatory medications'.)

Acute exacerbations of bronchiectasis may be precipitated by bacterial infection, such as H. influenzae, S. pneumoniae, and Mycoplasma species, a commonly missed but important organism in CVID. Although prompt sputum culture to direct therapy should be performed when possible, empiric treatment should include coverage for these organisms. Amoxicillin-clavulanate, third-generation cephalosporins, and fluoroquinolones (except ciprofloxacin) for at least 14 days are frequently used. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations", section on 'Management of infection'.)

Disease progression may be insidious and can be monitored with pulmonary function testing and a computed tomography (CT) scan of the lungs at baseline and possibly every one to two years thereafter if additional therapeutic interventions (eg, a change in antibiotic treatments or an increase in immune globulin dose) are contemplated [13]. In contrast, high-resolution computed tomography (HRCT) examinations should probably not be performed at regular intervals unless the information these tests provide is essential, since radiation exposure should be limited when possible. (See 'Cautious use of radiation-based tests' below.)

In patients who progress to severe bronchiectasis, surgical intervention has been performed in rare cases to remove the significantly diseased segments of lung tissue. This should be reserved for patients in whom intensive antibiotic and immune globulin replacement therapy, over a period of months to years, has failed.

Finally, lung transplantation has been performed with varying success in patients with antibody deficiency, with somewhat worse outcomes than those seen in patients with cystic fibrosis, although there are little published data for analysis [22,23]. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

Gastrointestinal infections — In patients with chronic or recurrent diarrhea, stool cultures should be examined for ova and parasites, because Giardia, Campylobacter, Salmonella, and cryptosporidia are seen with greater frequency in patients with CVID. Chronic norovirus infection can present as nonspecific enteropathy. While it was responsive to ribavirin in one study [24], this has not been our experience. Acute or chronic giardiasis is generally responsive to metronidazole. (See "Approach to the adult with chronic diarrhea in resource-abundant settings" and "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Giardiasis: Treatment and prevention".)

MEASURES TO AVOID INFECTIONS — Since the introduction of immune globulin replacement therapy, the quality of life for most patients with CVID has dramatically improved.

Advice for travel — Once on immune globulin replacement therapy, many patients are able to travel and participate in other activities that might not have been possible in the past for people with immunodeficiencies. In general, we do not advocate restricting foreign travel, unless the travel is to a remote area with no access to health care. Patients should bring antibiotics that they might need and consume bottled water from a clean source. Patients should receive the killed vaccines applicable to that geographic area.

Vaccinations — Certain live vaccines should not be given to patients with CVID (ie, oral polio, live shingles, smallpox, live-attenuated influenza vaccine, yellow fever, or live oral typhoid vaccines), particularly those with significantly impaired T cell function [25]. Family members and household contacts of patients with CVID may receive live vaccines. (See "Immunizations in patients with inborn errors of immunity", section on 'Antibody deficiencies'.)

The utility of killed or inactivated vaccines in patients with CVID has not been studied extensively. By definition, patients with CVID have impaired responses to vaccination, although vaccination might reinforce T cell immunity to viral agents, as shown by enhanced T cell cytokine responses, in addition to inducing the formation of specific antibodies. The later mechanism may be preserved in some patients with CVID, as there is a range of immunologic capacity in this disorder [26,27]. For both reasons, we routinely administer inactivated influenza vaccine to patients with CVID. General vaccination guidelines also support this practice [28,29]. Patients receiving immune globulin replacement therapy may be partially protected from influenza due to the presence of anti-influenza antibodies in immune globulin preparations. Vaccinations to SARS-CoV-2 have demonstrated antibody responses in some, as well as T cell responses, which may provide some protection [30].

THERAPY FOR NONINFECTIOUS DISORDERS — Noninfectious disorders in patients with CVID include pulmonary disease, gastrointestinal autoimmune conditions, liver disease including nodular regenerative hyperplasia (NRH), enteropathy resembling inflammatory bowel disease, splenomegaly and lymphoproliferation, and granulomatous or lymphoid infiltrations of the lungs or other organ systems.

Several of these conditions necessitate the administration of chronic immunosuppressive therapy, and a higher incidence of complications (including overwhelming infection) has been reported in patients with CVID [31]. Therefore, patients should be carefully monitored for the specific complications associated with the therapy in question.

Pulmonary disease — Pulmonary complications are common in patients with CVID. Bronchiectasis, bronchospasm, restrictive and obstructive pulmonary disease, interstitial lymphocytic infiltrates, and nonsarcoid granulomatous disease are among the most common. Although the literature is inconclusive, some improvement or stabilization of disease may be achieved with higher doses of intravenous immune globulin (IVIG) [32]. (See 'Indications for higher dosing' above and "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Rarely, hepatopulmonary syndrome (HPS), with ventilation/perfusion mismatch and hypoxemia may develop in the setting of advanced chronic liver disease in CVID (see 'Liver disease' below). Contrast echocardiography with microbubble study is a useful test to diagnose hepatopulmonary syndrome. Reversal of HPS has been reported after orthotopic liver transplantation [33]. (See "Hepatorenal syndrome".)

The use of immunosuppressants and immunomodulators to treat granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with CVID is discussed elsewhere [34]. (See "Pulmonary complications of primary immunodeficiencies", section on 'Common variable immunodeficiency'.)

Gastrointestinal disease — A chronic enteropathy may be present in patients with CVID and chronic diarrhea, in whom infectious causes have been excluded. (See 'Gastrointestinal infections' above.)

CVID enteropathies are similar to other inflammatory bowel diseases (eg, Crohn disease, ulcerative colitis) but have unique features [35]. If an enteropathy is suspected, the patient should be referred to a gastrointestinal specialist so that testing for the mucosal tissue changes characteristic of this condition can be performed.

Therapies with anti-inflammatory (eg, mesalamine) or immunosuppressive therapy, such as oral budesonide or short courses of other glucocorticoids, azathioprine, or 6-mercaptopurine, may be used. Infliximab has been used with clinical improvement in a few patients with severe enteropathy, although this agent may be associated with an increased risk of fungal lung infections [36]. Vedolizumab, a monoclonal that blocks the alpha₄beta₇ integrin, and ustekinumab, a monoclonal directed against the p40 protein subunit shared by interleukin (IL-)12 and IL-23, are agents that have been used in CVID enteropathy as investigational therapies but with variable benefit. (See 'Investigational treatments' below.)

Patients with severe enteropathy and colitis leading to malnutrition may require supplementation with total parenteral nutrition (TPN). (See "Nutrition and dietary management for adults with inflammatory bowel disease", section on 'Parenteral nutrition'.)

Prolonged diarrhea can lead to malabsorption of all fat-soluble vitamins, iron and calcium, and vitamins B12 and E, and patients should be monitored for these deficiencies. Vitamin E deficiency has been described in a CVID patient with severe enteropathy presenting as sensory loss, ataxia, and retinitis pigmentosa [37]. Intake and output should be monitored, and supplements including protein, vitamins, and minerals (iron, zinc) should be supplied as required. (See "Overview of the treatment of malabsorption in adults".)

Nodular lymphoid hyperplasia (NLH) is a generally benign condition that may be found in patients with CVID, as well as in apparently healthy individuals. The hyperplastic nodules are usually located in the small intestine but sometimes in the colon and even the stomach. It is more common in children than adults. When large, nodules can lead to intussusception, gastrointestinal obstruction, and, in some, a reduction of intestinal surface area due to mucosal flattening, which can lead to malabsorption [35,38]. Whether NLH is associated with development of lymphoma is a matter of controversy [39,40]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Predisposing conditions'.)

Liver disease — Liver disease is common in CVID and is often initially noted because of mildly elevated alkaline phosphatase. The most common cause of elevated liver enzymes is nodular regenerative hyperplasia (NRH) [41,42]. Other causes include biliary disease, viral infections, granulomatous involvement, or autoimmunity (primary biliary cirrhosis or primary sclerosing cholangitis). While the synthetic function of the liver is often spared, for unclear reasons, NRH in some patients may lead to cirrhosis and portal hypertension with the development of esophageal varices and ascites, with accompanying high mortality [43]. There is no known treatment for this condition, but lowering portal pressures with beta-blockers is helpful. Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure that may be used to reduce portal pressures and has been used in CVID with benefit, although the safety of this procedure in CVID is not established. Liver transplantation has been performed in CVID, but the data are limited [43]. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)

Autoimmune cytopenias — Hematologic disorders are the most common form of autoimmune disease in CVID patients. A review of 326 patients found that 11 percent had a history of immune thrombocytopenia (ITP), Coombs-positive autoimmune hemolytic anemia (AIHA), or Evans syndrome [7]. Most of these patients had developed hematologic autoimmune disease before or concurrent with the diagnosis of CVID and initiation of IVIG, rather than after [7,44]. Based on chart review in one series, it is possible that IVIG may provide some protection against these disorders or recurrences of them [7].

For both ITP and AIHA, glucocorticoids have traditionally been the first-line treatment. If ITP occurs while on immune globulin replacement therapy, higher doses (eg, 1 to 2 grams/kilogram) can be administered [7] with or without intravenous solumedrol. The treatment of these conditions is reviewed elsewhere. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Immune thrombocytopenia (ITP) in children: Initial management" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)

Rituximab has been used successfully and should be considered for patients with CVID and ITP or AIHA refractory to glucocorticoids [45-47]. In most cases, glucocorticoids are continued until the effects of rituximab can be assessed. In a retrospective analysis of 33 adults and children with ITP, AIHA, or both, overall response rate to rituximab was 85 percent [45]. Ten patients relapsed, of whom seven of nine responded to repeat treatment. The incidence of serious infections was not increased in patients who were receiving adequate immune globulin replacement. Thus, rituximab would be preferred over splenectomy. Immune globulin should be continued during rituximab therapy. Rituximab dosing for ITP and AIHA is reviewed separately.

When autoimmune cytopenias reappear after treatment, azathioprine, 6-mercaptopurine, or mycophenolate mofetil have been used with benefit. These agents can also be used in combination with rituximab. Sirolimus, which may permit stabilization of platelet and/or red blood cell counts, has also been administered as an additive therapy [48]. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Rituximab' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Rituximab (alone or added to glucocorticoids)' and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome".)

Splenectomy can be used as a last resort treatment of severe refractory ITP and AIHA in patients with CVID. Earlier series reported significant rates of serious infections [44], although later studies are somewhat more encouraging. The largest series available analyzed outcomes in 45 patients with CVID from multiple centers who underwent splenectomy, 24 of whom had autoimmune cytopenias [49]. Of these, 19 had failed glucocorticoids, immune globulin therapy, or both, and 2 had failed rituximab. Seventy-five percent experienced a clinical response to splenectomy (defined as needing no further therapy beyond low-dose maintenance glucocorticoids), while the remaining 25 percent either responded initially but suffered multiple relapses or did not respond and required subsequent alternative therapy. There were nine episodes of bacterial meningitis or septicemia in 40 patients (infections believed to be directly related to splenectomy), although six of these were in patients not receiving immune globulin therapy. No deaths resulted from these infections. However, there were 16 other episodes of viral reactivations, fungal infections, and other serious bacterial infections, at least 4 of which were fatal. Overall, the mortality rate in the splenectomized patients was 1.6 percent per patient-year, compared with an estimated rate of 2.3 percent in all patients with CVID and autoimmune cytopenias [50]. Thus, splenectomy is a reasonable option for patients with refractory disease and does not appear to increase mortality. However, we recommend that immune globulin therapy should be in place prior to surgery and on an ongoing basis.

Granulomatous disorders — Anti-inflammatory or immunomodulatory therapy may also be needed for the granulomatous disease associated with CVID [23,31,32]. However, a number of protocols have been presented, and responses are variable [31,34,51].

●In a retrospective analysis of 59 patients with granulomatous infiltration of various organs, 32 patients were treated most commonly with glucocorticoids (initial dose, 30 to 60 mg daily for a median of 18 months) [52]. Overall, 58 percent of those receiving glucocorticoids showed a complete or partial response. Granulomas of the lymph nodes seemed more responsive than granulomas in other organs, although none of the four patients with gastrointestinal granuloma responded. In our experience, glucocorticoids are difficult to taper as the conditions reoccur, thus are not useful overall. Steroid-sparing regimens using abatacept, a fusion protein that blocks the activity of T cells, have been proposed [53].

●Other drugs that were helpful in some patients included mycophenolate, rituximab, cyclophosphamide, hydroxychloroquine, azathioprine, and methotrexate.

●An older suggestion that a small subgroup of patients with CVID may have elevated production of tumor necrosis factor (TNF)-alpha has led to use of TNF inhibitors in some patients with granulomatous conditions. Case reports describe successful use of etanercept and infliximab in cutaneous granulomas refractory to other therapies [54,55].

The diagnosis and management of granulomatous pulmonary disease is discussed in more detail separately. (See "Pulmonary complications of primary immunodeficiencies", section on 'Common variable immunodeficiency'.)

DETECTION OF MALIGNANCY — Patients with CVID must be monitored for lymphoma, gastric cancer, and other malignancies [31,56-59].

Early detection — We suggest the following:

●Patients with CVID should receive all age-appropriate cancer screening procedures that are recommended for the general population.

●Many patients have lymphadenopathy and splenomegaly, although the development of constitutional symptoms, new or solitary nodules, expanding lymph nodes, or other masses should prompt consideration of lymphoma. Peripheral blood studies or lymph node or bone marrow biopsy may be indicated to assess histologic features and clonality, but careful review by pathologists familiar with the lymphoid features in CVID is required [58]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●Bronchoscopy with biopsy may be indicated for focal pulmonary findings that fail to resolve with treatment. Granulomatous changes may warrant treatment with agents, such as rituximab, usually with T cell immune suppression.

●In older studies, gastric cancer was found more commonly in CVID patients, although it has not been seen with the same higher incidence in subsequent studies [11,59]. Although it is not universally agreed that all patients require screening for gastric cancer, surveillance protocols have been suggested [60,61]. This approach calls for screening all patients (at diagnosis) for Helicobacter pylori infection with urea breath testing, eradication therapy if infection is detected, and repeat breath testing to demonstrate clearance. In addition, serum B12 and iron concentration are measured annually for all patients. Patients who develop dyspepsia or unexplained weight loss during their follow-up period, those with positive urea-breath testing, and those with low serum B12 level should undergo upper gastrointestinal endoscopy, including biopsies of the antrum and fundus. A more conservative approach would be to perform endoscopy and biopsy for H. pylori in patients only if they develop symptoms of gastritis or gastroesophageal reflux disease. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

Cautious use of radiation-based tests — Use of radiation-based imaging studies in patients with CVID should be conservative and thoughtful [62], since they are at higher baseline risk for malignancies [56-61]. Cellular radiosensitivity has been demonstrated in some patients with CVID [63,64]. Clinicians should attempt to minimize cumulative radiation exposure by choosing computed tomography (CT) protocols that use reduced radiation dose intensity whenever possible or magnetic resonance imaging (MRI). In a cohort study of 21 patients with CVID, findings of MRI and chest CT scans are analyzed. The concordance between the two techniques was good in detecting bronchiectasis severity and extension in patients with severe and moderate degrees of bronchial pathology. However, MRI was less sensitive in detecting mild defects, mainly due to the low MRI sensitivity in the assessment of prebronchial alterations. Therefore, CT scan is still the gold standard for diagnosing initial bronchial alterations [65].

INVESTIGATIONAL TREATMENTS — Therapies that have been evaluated for specific complications in patients with CVID include interleukin (IL-)2, vedolizumab, ustekinumab, and allogeneic stem cell transplant.

●IL-2 treatment has undergone evaluation in patients with CVID because of data demonstrating a deficiency of IL-2 production in some patients, as well as T cell defects leading to a deficiency in IL-2. Investigational studies of low-dose IL-2 treatment resulted in improved T cell function as well as novel antibody production in response to neoantigen vaccination [66,67]. However, there were only modest improvements of clinical parameters. This therapy might be considered in the treatment of refractory infections in subjects with CVID who have demonstrated defects in T cell function.

●For gastrointestinal enteropathy, vedolizumab, a monoclonal that blocks the alpha₄beta₇ integrin, has shown benefit in some patients with CVID enteropathy, as it blocks T cell interaction with gut-associated addressin, MadCAM [68-70]. However, evidence of benefit remains anecdotal, and treatment failures have also been reported [70].

●Patients with CVID and inflammatory bowel or liver disease have been found to display increased tissue expression of gamma-interferon and IL-12, leading to clinical trials of the monoclonal antibody ustekinumab, a treatment approved for Crohn disease [71].

●Allogeneic stem cell transplant (ASCT) has been performed in a small number of patients with CVID, either for the treatment of hematologic malignancies or for severe manifestations of CVID that were not responding to other interventions [72,73]. In a review of 25 patients, overall survival was 48 percent, with graft-versus-host disease the leading cause of death. Among those who survived, one-half were able to discontinue immune globulin, and the condition prompting ASCT resolved in 92 percent [73]. Thus, ASCT could be considered in individuals with malignancies or severe disease refractory to other options after a careful risk:benefit analysis.

PROGNOSIS — The incidence of death associated with acute bacterial infection in CVID decreased dramatically with the advent of adequate immune globulin treatment. Thereafter, the major causes of death have been complications of chronic lung disease and malignancies [15,16,56,74,75]:

●A large series of 473 patients reported long-term data for 411 individuals, followed over a period of 40 years [15]. During this time, 19.6 percent died, with a median age at death of 44 and 42 for females and males, respectively. The leading causes of death were respiratory failure due to chronic lung disease (36 percent), lymphoid and other malignancies (29 percent), and liver disease (9 percent). Reduced survival was seen in patients with gastrointestinal disease, chronic lung disease, hepatic disease, and lymphoma, although not in those with other complications, such as autoimmune disorders, granuloma, or bronchiectasis without other lung disease. Long-term survival was excellent in patients with only infectious complications, but significantly lower in those with one or more noninfectious complications (95 versus 42 percent at 40 years, respectively). Immunologic parameters associated with higher mortality were lower levels of serum immunoglobulin G (IgG), increased serum immunoglobulin M (IgM), and lower percentages of circulating B cells.

●Another center reported on the 353 patients diagnosed as adults also followed over a 40-year period [74]. Mortality in this group was very similar at 19.5 percent, with a median age at death of 54 and 53 from females and males, respectively. The leading cause of death was chronic lung disease (30 percent). A similar percentage of patients succumbed to lymphoma, while a higher percentage died from other types of malignancies.

●In a third series of 334 patients, mortality was highest in patients with bronchiectasis, enteropathy, polyclonal lymphocytic infiltration, and autoimmunity [16]. In this series, there were no associations between survival and sex or initial serum IgG, IgA, or IgM levels.

Subsequent research has demonstrated that the percentage of circulating class-switched memory B cells can be useful in predicting a patient's risk for the development of certain complications of CVID, such as lymphoid hyperplasia, granulomatous disease, or autoimmune disorders. This is discussed elsewhere. (See "Pathogenesis of common variable immunodeficiency".)

Outcomes in COVID-19 — Based on limited initial data, severity of illness in CVID patients varies considerably, and risk factors for severe disease and death appear to be similar to those in the general population.

●An international survey retrospectively collected data on 94 patients with immunodeficiency who became infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developed coronavirus disease 2019 (COVID-19), of whom >30 percent carried a diagnosis of CVID [76]. Four patients died, but these individuals were older than the rest of the cohort and most had preexisting comorbidities. Others had mild disease or asymptomatic infections.

●In a smaller series of 16 patients with primary immunodeficiency that included nine patients with CVID, two individuals who had CVID-related disorders or other comorbidities died of severe disease [77]. Four others did not require hospitalization, and three required hospitalization but were not intubated.

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)".)

SUMMARY AND RECOMMENDATIONS

●Immune globulin therapy

•Standard dosing – We recommend that patients with common variable immunodeficiency (CVID) and recurrent sinopulmonary infections receive immune globulin replacement therapy (Grade 1B). The usual initial dosing for intravenous immune globulin (IVIG) is 400 to 600 mg/kg, given every three to four weeks, with the goal of maintaining a trough immunoglobulin (Ig)G level in the middle of the normal range and reducing the incidence of significant infections. Some patients require more immune globulin than others to attain these goals. (See 'Immune globulin replacement therapy' above.)

•Indications for higher doses – We suggest higher doses of immune globulin replacement therapy for CVID patients with persistent infections (eg, sinusitis), chronic pulmonary disease, gastrointestinal disease, or autoimmune hematologic disorders (Grade 2C). (See 'Indications for higher dosing' above.)

•Subcutaneous administration – Patients may prefer subcutaneous immune globulin (SCIG) therapy, as this can be self-administered at home and is more convenient for many. Subcutaneous administration is medically indicated for patients with reactions to IVIG, those with rapid immune globulin loss, and those with poor intravenous access. (See "Subcutaneous and intramuscular immune globulin therapy".)

•Efficacy – Immune globulin replacement therapy reduces the frequency of most types of infections in patients with CVID. It may also slow the progression of chronic lung disease and offer some protection against autoimmune disorders. However, there is little evidence that immune globulin therapy protects against the development of malignancy or granulomatous disease. (See 'Efficacy of immune globulin therapy' above.)

●Effective use of antibiotics – Patients with CVID do not usually clear common infections without antibiotics, and antibiotic therapy should be instituted early for common infections, such as bronchitis and acute sinusitis. In addition, longer courses of therapy are sometimes required to eradicate infections completely. (See 'Treatment of specific infections' above.)

●Indication for prophylactic antibiotics – We suggest prophylactic antibiotics to prevent infections in CVID patients with ongoing pulmonary infections despite immune globulin replacement therapy and in those requiring immunosuppressive medications (Grade 2C). We do not routinely give prophylactic antibiotics to all CVID patients, and the utility of this intervention for all subjects has not been adequately studied. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

●Vaccinations – We suggest that patients with CVID who plan to travel receive the appropriate inactivated vaccinations (Grade 2C). Live vaccinations should be avoided. Some patients may only mount a partial response. (See 'Vaccinations' above.)

●Autoimmune and inflammatory disorders – Patients with CVID may develop autoimmune, inflammatory, and granulomatous disorders requiring immunosuppressive therapies. Patients should be carefully monitored for the specific complications associated with the agent in question and appear to experience higher rates of infectious adverse effects. (See 'Therapy for noninfectious disorders' above.)

●Monitoring for malignancy – Patients with CVID should undergo all age-appropriate cancer screening and additionally be monitored for signs and symptoms of lymphoma. These include constitutional symptoms, solitary nodules, expanding lymph nodes, other masses, and focal pulmonary findings that fail to resolve with treatment. (See 'Detection of malignancy' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Sam Ahn, MD, who contributed as an author, and E Richard Stiehm, MD, who contributed as a Section Editor, to earlier versions of this topic review.