X-linked Immunodeficiency With Hyper IgM Treatment & Management

Medical care should be focused on treatment and prevention of infection. Infectious episodes can be prevented with regular infusion of human immunoglobulin (Ig) and early initiation of P jiroveci prophylaxis. Antimicrobial therapy should be based on culture and sensitivity results and should be pathogen-specific. Every effort should be made to obtain a specimen for culture and sensitivity. Prevention of Cryptosporidium infection using boiled or filtered water is recommended. Patients with neutropenia may benefit from treatment with granulocyte colony-stimulating factor (G-CSF). Bone marrow transplantation (BMT) or cord blood stem cell transplantation has been tried in a few patients, with variable outcome.

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 significantly decreased the frequency of life-threatening infections in patients with X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM). If replacement therapy is started early and appropriate amounts are administered with sufficient frequency, the cycle of recurrent infections and progressive lung damage can be arrested.

Intravenous immunoglobulin therapy

See the list below:

• Intravenous immunoglobulin (IVIG) therapy has reportedly significantly decreased the frequency of lower respiratory tract and severe infection; however, IVIG therapy has not changed the frequency of nonrespiratory or upper respiratory infections.

• Regular IVIG infusions replace the IgG and often result in a reduction or normalization of the serum IgM level. IVIG therapy does not change the clinical course of neutropenia, chronic diarrhea, or chronic cholangitis, hepatitis, or other autoimmune manifestations.

• Ig products currently available in the United States are derived from pooled human plasma (see Table 2). 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 also 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 2 IVIG products. In this randomized, double-blind, multicenter study, patients treated with Gamunex (purified using caprylate treatment and chromatography) 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, respectively (P =.023).

• Ig replacement is intravenously administered on a regular basis. The half-life of IgG is usually longer than 18-23 days in healthy individuals. Tailor the dose and frequency to the Ig trough levels and to clinical symptoms. Measure the serum IgG level before each infusion and adjust the dose of IVIG accordingly. Maintain trough serum IgG concentrations of 400-500 mg/dL in adults, a value close to the lower limit of the reference range. 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/mo. Once a regular regimen is established, IVIG can be administered at home.

• Adverse reactions to IVIG therapy include the following:

  • Nonanaphylactic reactions

    • These are the most common reactions to IVIG therapy and frequently manifest as 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 IgG-aggregate or IgG-antigen complement complexes. These reactions tend to occur more frequently in patients with severe hypogammaglobulinemia, particularly at the initiation of treatment, and in patients 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 of the calculated IVIG dose and then repeat the dose 2 weeks later before changing to a 3-week to 4-week schedule. Alternatively, antipyretics, diphenhydramine, and/or corticosteroids may be administered prior to IVIG administration to attenuate adverse reactions.

    • 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 and administer diuretics if necessary.

  • Anaphylactic reactions

    • True anaphylactic reactions to IVIG therapy are rare. Patients who have selective IgA deficiency (sIgAD) or common variable immunodeficiency (CVID) 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 in patients with no detectable IgA levels.

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

    • In patients with XHIGM, production of IgE antibodies against IgA is very rare due to a defect in class-switch recombination (CSR).

  • Transmission of infectious agents

    • The potential for transmission of pathogens cannot be completely ruled out. In 1993 and 1994, transmission of hepatitis C virus was reported in recipients of one of 2 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 using dry heat or pasteurization or irradiation solvent-detergent treatment, low pH exposure, or caproate treatment. Viral removal is necessary to reduce the risk of nonenveloped virus transmission and includes 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) and hepatitis B and C, 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, referred to as variant Creutzfeldt-Jacob disease (vCJD). No blood tests or inactivation methods are currently applicable to prions. Fortunately, prions have not been directly detected in human blood, and the potential for efficient removal of prions by the current manufacturing processes has been documented.

  • Acute and chronic renal failure

    • This is most often reported in patients with preexisting renal disease who receive 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, or paraproteinemia or patients receiving known nephrotoxic drugs. Products that contain sucrose as a stabilizer account for a disproportionate share of the total number of renal failure cases.

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

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

Subcutaneous immunoglobulin therapy

See the list below:

• Subcutaneous immunoglobulin (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG.

• Vivaglobin (ZLB Behring; King of Prussia, Penn) is the first SCIG product to be approved in the United States for the prevention of serious infection in patients with primary immune deficiency diseases (See Medication).

• Vivaglobin is administered weekly using an infusion pump, allowing patients to self-administer the injection at home.

• The 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, and then dividing this dose into weekly doses based on the patient's previous IVIG treatment interval; for example, if IVIG was administered every 3 weeks, divide by 3. This dose of Vivaglobin provides a systemic IgG exposure comparable with 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 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 such as fever, chills, nausea, and vomiting.

• As with all Ig products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to Ig preparations and in persons with selective IgA deficiency 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 CJD agent, cannot be completely eliminated.

P jiroveci prophylaxis

Patients with XHIGM also have a marked susceptibility to P jiroveci pneumonia. Initiating prophylactic treatment with trimethoprim-sulfamethoxazole as soon as the diagnosis of XHIGM is established is important.

Granulocyte-colony stimulating factor therapy for neutropenia

Patients with persistent severe neutropenia who do not respond favorably to IVIG infusions are candidates for treatment with G-CSF.

Antimicrobial treatment

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

Immunosuppressants

Treatment of associated autoimmune disorders may require immunosuppressants such as prednisone. Therapy should be directed to the specific conditions.

Bone marrow transplantation

BMT may be considered in young patients without bronchiectasis or severe chronic infections who have a human leukocyte antigen (HLA)–matched sibling who can serve as a BMT donor. Cord blood stem cells (fully or partially matched) or bone marrow from an unrelated matched donor may be considered if a matched sibling donor is not available.

Experimental therapy: Recombinant CD40L

Three patients were treated with subcutaneous injection of human recombinant CD40L 3 times a week. ^[13] After 22 weeks of treatment, the patient mounted delayed-type hypersensitivity reactions and produced T helper (T_H 1) effector cytokines after activation but failed to induce differentiation of naïve B cells in the periphery.

Patients may need to undergo endoscopic sinus surgery to treat chronic sinusitis. Biopsy samples should be taken from rapidly enlarging lymph nodes to rule out infection or malignancy.

Patients with XHIGM and multiple organ system involvement may benefit from a multidisciplinary team of consultants, including a pulmonologist, gastroenterologist, hematologist, oncologist, and nephrologist.

Patients with chronic lung disease may require high-calorie diet supplementation because of high energy expenditure. Patients with chronic enteropathy may require an elemental diet and, at times, supplemental parenteral nutrition.

Normal activity including regular exercise is recommended.