Pediatric Common Variable Immunodeficiency Treatment & Management

A major component of medical care is anti-infective and prevention of further infectious episodes by regular infusion of human immunoglobulin and antimicrobial therapy. Patients with autoimmune manifestations may require immunosuppressive therapy.

Immunoglobulin (Ig) replacement therapy, by intravenous infusion or subcutaneous injection, remains the mainstay of therapy. The primary goal is the prevention of infection. Ig replacement therapy has decreased the frequency of life-threatening infections in these patients significantly. Most patients with common variable immunodeficiency (CVID) and sinopulmonary disease without severe bronchiectasis do well once they are placed on regular intravenous immunoglobulin therapy. If replacement therapy is started early, and if appropriate amounts are given with sufficient frequency, the cycle of recurrent infections and progressive lung damage can be arrested. However, silent progression of bronchiectasis was reported in a small number of patients while receiving adequate Ig replacement therapy.

Currently available immunoglobulin products in the United States are derived from pooled human plasma (see Medication). The manufacturing processes include cold ethanol fractionation of Ig and viral inactivation and removal steps. Biological activity of the IgG molecule, not simply the antibody titer, but opsonic and complement activity and circulating half-life, may be affected by discrete steps in the manufacturing and isolation of IgG. Only one report has compared two different IVIG products. In this randomized double-blind multicenter study, the Gamunex (purified using caprylate treatment and chromatography) treated group had a significantly lower number of infections compared with the group treated with Gamimune N (solvent-detergent treated) from the same company (annual infection rates were 0.18 compared with 0.43; p=0.023).

Reportedly, IVIG significantly decreased the frequency of lower respiratory tract and severe infection; however, IVIG did not change the frequency of nonrespiratory or upper respiratory infections. Also IVIG did not change the clinical course of autoimmune manifestations in patients with common variable immunodeficiency.

Intravenous infusion of immunoglobulin

Ig replacement is intravenously administered on a regular basis. The half-life of IgG widely varies among patients with common variable immunodeficiency but is usually longer than 18-23 days in healthy individuals. Tailor dose and frequency to the Ig trough levels and to clinical symptoms. Measure serum IgG level before each infusion, and accordingly adjust the dose of IVIG. Maintain trough serum IgG concentrations at 400-500 mg/dL in adults, a value close to the lower limit of normal. For most patients, a dose of 400-600 mg/kg every 3-4 weeks suffices to reduce the frequency of infection. Some patients with chronic lung disease require up to 600-800 mg/kg per month. Once established on a regular regimen, IVIG can be administered at home.

Adverse reactions to IVIG include nonanaphylactic reactions, anaphylactic reactions, transmission of infectious agents, and acute renal failure.

Nonanaphylactic reactions

These are the most common reactions to IVIG and manifest by backache, nausea, chills, low-grade temperature, or vomiting within the first 30 minutes of infusion.

Headache, chills, flushing, chest tightness, dyspnea, fever, myalgia, nausea, and fatigue may begin at the end of the infusion and continue for several hours. Slowing the infusion rate or interrupting the infusion for a few minutes can prevent most of these reactions.

Febrile or phlogistic reactions are thought to be secondary to immune aggregates that fix complement, either IgG aggregates or IgG-antigen, complexes.

These reactions tend to occur more frequently in patients with severe hypogammaglobulinemia, particularly at the initiation of treatment, and in those with intercurrent infections or bronchiectasis. These symptoms may be treated with acetaminophen, diphenhydramine, and/or hydrocortisone.

To minimize the risk of these reactions, treat or eradicate preexisting infection before administering IVIG for the first time or after a hiatus in therapy. Initiate therapy with one-half the calculated dose of IVIG and then repeat the dose 2 weeks later before going to a 3-week to 4-week schedule. Alternatively, premedication with antipyretics, diphenhydramine, and/or corticosteroids may be given.

Reactions caused by fluid volume, salt, or protein overload may be problematic for patients with cardiovascular limitations, particularly at higher doses. Closely monitor these patients during and after infusions; administer diuretics if necessary.

Anaphylactic reactions

True anaphylactic reactions to IVIG are rare. Patients who have selective IgA deficiency (SIgAD) or common variable immunodeficiency with undetectable IgA may develop IgE antibodies against IgA, following exposure to serum IgA. These patients may develop anaphylactic reactions during subsequent IVIG administrations.

Exercise caution during IVIG administration to patients with common variable immunodeficiency, particularly those with no detectable IgA.

The prekallikrein activator has been associated with hypotension and circulatory collapse, and IgG aggregates may result in anaphylaxis via complement activation.

The World Health Organization (WHO) recommendations for IVIG include no prekallikrein activator activity, low IgA content, and IgG aggregate content.

Transmission of infectious agents

The potential for transmission of pathogens cannot be completely ruled out. In 1993 and 1994, transmission of hepatitis C virus (HCV) was reported in recipients of one of two IVIG products that did not undergo viral inactivation steps during manufacturing. All IVIG products currently marketed in the United States now undergo viral inactivation and removal.

In order to reduce potential contamination of pathogens, all plasma for manufacture is tested at various levels and retested by viral marker and nucleic acid technology (NAT).

Viral inactivation is achieved by dry heat, pasteurization, or irradiation solvent-detergent treatment, low pH exposure, or caprolate treatment. Viral removal is necessary to reduce the risk of transmission of nonenveloped viruses and include precipitation, chromatography, and filtration including nanofiltration.

Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and HCV, are readily inactivated and can be effectively removed.

No case of HIV infection has resulted from treatment with IVIG because retroviruses are readily inactivated by the cold ethanol precipitation. The main concern is prions that transmit spongiform encephalopathy or referred to as variant Creutzfeldt-Jacob disease (vCJD).

Currently, no blood tests or inactivation methods are applicable to prions. Fortunately, prions have not been detected directly in human blood and the potential for efficient removal of prions by the current manufacturing processes have been documented.

Acute and chronic renal failure has been reported, most often in patients with preexisting renal disease who received sucrose-containing IVIG solutions. IVIG products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients at risk for acute renal failure include patients with any degree of preexisting renal insufficiency, diabetes mellitus, age older than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Those products containing sucrose as a stabilizer accounted for a disproportionate share of the total number.

For patients at increased risk, monitoring BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Other rare reactions to IVIG include aseptic meningitis, lymphocytic pleural effusion, thromboembolism, coagulopathy, and immune hemolysis. Suspected causes of these adverse events are hyperosmolarity, presence of activated factor XI, and high sodium content. However, these are from anecdotal observation, and establishing precise guidelines for reducing the risk of adverse events is difficult.

Subcutaneous infusion of immunoglobulin

Subcutaneous infusion of Ig (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG. Vivaglobin (ZLB Behring) is the first product to be approved in the United States for SCIG therapy for the prevention of serious infection in patients with primary immune deficiency diseases (PIDD) (see Table 2).

Vivaglobin is given on a weekly basis using an infusion pump, allowing patients to self-administer the injection at home. Recommended weekly dose of Vivaglobin is 100-200 mg/kg administered subcutaneously. The dose may be adjusted over time to achieve the desired clinical response and serum IgG levels. Initial dose can be calculated by multiplying the previous IVIG dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IGIV treatment interval; for example, if IVIG was administered every 3 weeks, divide by 3. This dose of Vivaglobin provides a systemic IgG exposure comparable to that of the previous IVIG treatment. Weekly administration of this dose leads to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared with monthly IVIG treatment.

The SCIG is well accepted by patients, mostly administered at home, and the risk of infusion reactions is even less than for intravenous infusions. SCIG was well tolerated in patients who had a history of severe reactions to IVIG infusions with the same product.

In clinical trials, the most frequent adverse event was injection-site reaction, consisting of mild or moderate swelling, redness, and itching. No serious local site reactions were observed, and reactions tended to decrease substantially after repeated use. Other adverse events irrespective of causality included headache, GI disorder, fever, nausea, sore throat, and rash. As with all immune globulin (Ig) products, patients receiving Ig therapy for the first time, receiving a new product, or not having received Ig therapy within the preceding 8 weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting.

As with all immune globulin products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with SIgAD who have known antibody against IgA. Vivaglobin is derived from human plasma. As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

Infections should be treated early with full doses of antimicrobial agents. Whenever possible, narrow-spectrum drugs should be used on the basis of microbial sensitivity testing. Prophylactic antibiotics should be avoided because they increase the hazard of infection with fungi or other resistant organisms. Antiviral agents may be useful in some patients with persistent or severe viral infections.

Most patients with common variable immunodeficiency and arthritis report reduced arthritic symptoms once they are placed on regular IVIG replacement therapy. GI diseases associated with common variable immunodeficiency, with a few cases of ulcerative colitis, did not benefit from regular infusion (even high dose) of IVIG.

Corticosteroid

In some patients with a severe autoimmune process, steroids or other immunosuppressive drugs may be needed. Use these drugs with caution and only in patients who have autoimmune disorders that cause significant clinical disease. In general, a short course of steroid therapy is well tolerated.

Cyclosporin A

Use of cyclosporin A with favorable outcome in a patient with common variable immunodeficiency and lymphoid interstitial pneumonitis has been reported.

Anti-CD20 monoclonal antibody (rituximab) and anti-TNF monoclonal antibody (infliximab)

Successful treatment of autoimmune thrombocytopenia and neutropenia using anti-CD20 monoclonal antibody administration was reported. Anti-TNF monoclonal antibody, infliximab, has been used successfully in the treatment of cutaneous granulomas in a patient with common variable immunodeficiency. A review of patients with granulomas reported no benefit with rituximab, etanercept, or infliximab in the treatment of granulomatous disease.

IL-2

An experimental preparation of IL-2 conjugated with polyethylene glycol (PEG) was administered to a select group of patients with CVID because of the observation that lymphocytes from a subgroup of patients with CVID, when activated in vitro, produce markedly decreased amounts of IL-2. After several months of therapy, a significant increase was noted in in vitro Ig production by patients' B lymphocytes, in vitro IL-2 production, and serum antibodies. Long-term outcomes of this therapy remain to be seen.

Specific therapy directed to involved organs should be based on clinical manifestations and nature of the disease. Patients with common variable immunodeficiency and chronic lung disease frequently manifest airway obstructive disease indistinguishable from asthma. These patients may require inhaled corticosteroids and other long-term asthma medications along with albuterol therapy as needed. Patients with bronchiectasis may benefit from mucolytic inhalation therapy and chest physiotherapy.

Often, patients with common variable immunodeficiency need a surgical procedure for treatment of complications (eg, endoscopic sinus surgery for chronic sinusitis). Some patients require splenectomy secondary to severe autoimmune thrombocytopenia or hemolytic anemia. Postoperative complications include sepsis and fistula. Perform a biopsy in patients with rapidly enlarging lymph nodes to rule out infection or malignancy.

Patients with common variable immunodeficiency and multiple organ system involvement may benefit from a multidisciplinary team of consultants.

Patients with common variable immunodeficiency and chronic lung disease may require a high-calorie diet supplementation because of high-energy expenditure. Patients with chronic enteropathy may require an elemental diet.

Regular physical activity is encouraged.