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Treatment and prognosis of common variable immunodeficiency Author: Charlotte Cunningham-Rundles, MD, PhD Section Editor: E Richard Stiehm, MD Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2018. | This topic last updated: Nov 14, 2017. 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 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 '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 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 primary immunodeficiency" 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 [2]. Dosing — The usual initial dosing for IVIG in patients with CVID is 300 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, then initiate immune globulin. Premedication with diphenhydramine and acetaminophen is commonly used for those who are prone to medication reactions, and in some cases, a glucocorticoid (such as IV hydrocortisone) is also given. One may also repeat the initial dose (ie, the entire 300 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 [4-7]: ● 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 'Progression of chronic lung disease' below.) ● Enteropathy, as immunoglobulin levels may be difficult to maintain otherwise. 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 [8]. (See 'Autoimmune disorders' 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. This is usually administered weekly or every other week, depending on body weight and immune globulin requirements. There is also a 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'.) SCIG is particularly helpful for patients with reactions to IVIG or difficult intravenous access. SCIG can be selfinfused 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".)

Impact of therapy — Immune globulin replacement therapy reduces the number of infections and decreases antibiotic use and hospitalizations [9-11]. 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 [11]. 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 [12]. However, treatment with immune globulin does not entirely eliminate infections in most patients, and the sinopulmonary and gastrointestinal systems, in particular, remain susceptible. (See 'Sinusitis' below and 'Gastrointestinal infections' below.) 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 [13]. 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 [4,14,15]. 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.) 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 [3,13]. 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 [16,17]. 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 subjects 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). ● 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 feel that withholding immune globulin replacement therapy on the basis of lack of past infections would be unwise. 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 not been adequately studied. We do not routinely administer prophylactic antibiotics to all patients with CVID, although we do find this approach helpful in CVID patients with ongoing lung disease. The use of antibiotics in this manner is reviewed separately. (See "Primary immunodeficiency: Overview of management", section on 'Prophylactic antimicrobial therapy'.) 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 irrigations, and we treat infections as they arise. We also try to avoid surgical treatment of chronic rhinosinusitis, as disease invariably returns. The medical management of chronic rhinosinusitis is reviewed separately. (See "Chronic rhinosinusitis: Management" and "Microbiology and antibiotic management of chronic rhinosinusitis".) Chronic bronchiectasis — Prophylactic antibiotic therapy may be helpful for patients with bronchiectasis, frequent exacerbations, and declining lung function and should target Haemophilus influenzae and mycoplasma [6,19]. (See "Treatment of bronchiectasis in adults", section on 'Prevention of exacerbations'.) 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 'Impact of therapy' above.) Patients with low CD4 counts — Prophylactic antibiotics to prevent infection with Pneumocystis carinii (P. jirovecii) may be given to patients with CVID and CD4 counts