eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
X-linked Immunodeficiency With Hyper IgM: Treatment & Medication
Updated: Feb 20, 2009
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Treatment
Medical Care
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 carinii (PCP) 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
- 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.
- Nonanaphylactic reactions
Subcutaneous immunoglobulin therapy
- 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 carinii prophylaxis
Patients with XHIGM also have a marked susceptibility to PCP. 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.
Surgical Care
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.
Consultations
Patients with XHIGM and multiple organ system involvement may benefit from a multidisciplinary team of consultants, including a pulmonologist, gastroenterologist, hematologist, oncologist, and nephrologist.
Diet
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.
Activity
Normal activity including regular exercise is recommended.
Medication
The mainstay of therapy for X-linked immunodeficiency with hyperimmunoglobulin M (XHIGM) is intravenous immunoglobulin (IVIG).
The overall consensus among clinical immunologists is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels of more than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months, until a steady state is achieved, and then every 6 months, if the patient is stable, may be helpful in adjusting the IVIG dose to achieve adequate serum levels.
All brands of IVIG are probably equivalent, although viral inactivation processes differ (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times a year, is also recommended. The US Food and Drug Administration (FDA) recommends that, in patients at risk for renal failure, doses should not be exceeded and infusion rates and concentrations should be the minimum practicable levels.
The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatment is high, especially in patients with infections and in those who form immune complexes. With the new generation of IVIG products, adverse effects are greatly reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.
Activation of complements by IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause.
Most adverse reactions are related to infusion rate. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.
Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products that use sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. 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. IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency.
A few reports describe true anaphylaxis in patients with IgA-deficiency (<7 mg/dL) who have autoantibodies to IgA. IVIG preparations with very low concentrations of contaminating IgA are advised.
Other rare, serious adverse events include aseptic meningitis, thromboembolic events, immune hemolysis, and transfusion-related acute lung injury. These events are related to hyperosmolality, activated coagulation factor, high sodium content, or presence of anti-D antibody.
Potential for transmission of pathogens cannot be completely ruled out. In order to reduce potential contamination of pathogens, all manufactured plasma is tested at various levels and retested with 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 capreolate treatment. Viral removal is necessary to reduce the risk of nonenveloped virus transmission and includes precipitation, chromatography, and nanofiltration.
Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as HIV, and hepatitis B and C, are readily inactivated and can be effectively removed. 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 with the current manufacturing processes have been documented.
Table 2. Immune Globulin, Intravenous9,10,11,12
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Table
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | Parenteral Form and Final Concentrations | IgA Content (mcg/mL) |
| Carimune NF (CSL Behring) | Kistler-Nitschmann fractionation; pH 4 nanofiltration | 6.4-6.8 | 6% solution: 10% sucrose, <20 mg NaCl/g protein | Lyophilized powder 3%, 6%, 9%, 12% | Trace |
| Flebogamma (Grifols USA) | Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization | 5.1-6 | Sucrose free, contains 5% D-sorbitol | Liquid 5% | <50 |
| Gammagard Liquid 10% (Baxter Bioscience) | Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation | 4.6-5.1 | 0.25 M glycine | Ready-for-use liquid 10% | 37 |
| Gamunex (Talecris Biotherapeutics) | Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation | 4-4.5 | Contains no sugar, contains glycine | Liquid 10% | 46 |
| Iveegam EN (Baxter Bioscience) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% glucose, 0.3% NaCl | Lyophilized powder 5% | <10 |
| Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) | Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated | 6.4-7.2 | 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose | Lyophilized powder 5%, 10% | <1.6 (5% solution) |
| Octagam (Octapharma USA) | Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization | 5.1-6 | 10% maltose | Liquid 5% | 200 |
| Panglobulin (Swiss Red Cross for the American Red Cross) | Kistler-Nitschmann fractionation; pH 4.0 incubation, trace pepsin, nanofiltration | 6.6 | Per gram of IgG: 1.67 g sucrose, <20 mg NaCl | Lyophilized powder 3%, 6%, 9%, 12% | 720 |
| Privigen Liquid 10% (CSL Behring) | Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration | 4.6-5 | L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) | Ready-for use liquid 10% | <25 |
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | Parenteral Form and Final Concentrations | IgA Content (mcg/mL) |
| Carimune NF (CSL Behring) | Kistler-Nitschmann fractionation; pH 4 nanofiltration | 6.4-6.8 | 6% solution: 10% sucrose, <20 mg NaCl/g protein | Lyophilized powder 3%, 6%, 9%, 12% | Trace |
| Flebogamma (Grifols USA) | Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization | 5.1-6 | Sucrose free, contains 5% D-sorbitol | Liquid 5% | <50 |
| Gammagard Liquid 10% (Baxter Bioscience) | Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation | 4.6-5.1 | 0.25 M glycine | Ready-for-use liquid 10% | 37 |
| Gamunex (Talecris Biotherapeutics) | Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation | 4-4.5 | Contains no sugar, contains glycine | Liquid 10% | 46 |
| Iveegam EN (Baxter Bioscience) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% glucose, 0.3% NaCl | Lyophilized powder 5% | <10 |
| Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) | Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated | 6.4-7.2 | 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose | Lyophilized powder 5%, 10% | <1.6 (5% solution) |
| Octagam (Octapharma USA) | Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization | 5.1-6 | 10% maltose | Liquid 5% | 200 |
| Panglobulin (Swiss Red Cross for the American Red Cross) | Kistler-Nitschmann fractionation; pH 4.0 incubation, trace pepsin, nanofiltration | 6.6 | Per gram of IgG: 1.67 g sucrose, <20 mg NaCl | Lyophilized powder 3%, 6%, 9%, 12% | 720 |
| Privigen Liquid 10% (CSL Behring) | Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration | 4.6-5 | L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) | Ready-for use liquid 10% | <25 |
*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).
Table 3. Subcutaneous Immune Globulin
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Table
| Brand(Manufacturer) | Manufacturing Process | pH | Additives | Parenteral Form and Final Concentrations | IgA Content mcg/mL |
| Vivaglobin (ZLB Behring) | Cold ethanol fractionation; pasteurization | 6.4-7.2 | 2.25% glycine, 0.3% NaCl | Liquid 16% (160 mg/mL) | <50 mcg/mL |
| Brand(Manufacturer) | Manufacturing Process | pH | Additives | Parenteral Form and Final Concentrations | IgA Content mcg/mL |
| Vivaglobin (ZLB Behring) | Cold ethanol fractionation; pasteurization | 6.4-7.2 | 2.25% glycine, 0.3% NaCl | Liquid 16% (160 mg/mL) | <50 mcg/mL |
Immune globulin
These agents are used for replacement of functional antibodies in IgG isotype.
Immunoglobulin, intravenous
Neutralize circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG levels (10%).
Adult
400-600 mg/kg/mo IV or a dose that maintains trough serum IgG levels >500 mg/dL
Pediatric
Administer as in adults
Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Documented hypersensitivity; IgA deficiency
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Check serum IgA before IVIG administration, use an IgA-depleted product if deficient (eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory finding changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia
Immune globulin, subcutaneous (Vivaglobin)
IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower and trough IgG levels are higher than those achieved with IVIG. SC administration results in stable steady-state IgG levels when administered weekly. Available as a 160-mg/mL SC injectable.
Adult
Do not exceed 15 mL (3200 mg) SC per injection site; administration rate not to exceed 20 mL/h per injection site
Previously on IVIG: Weekly SC dose (g/wk) = (previous IVIG dose X 1.37) divided by previous administration interval in wk; initiate 1 wk after last IVIG dose
Recommended weekly dose: 100-200 mg/kg/wk SC
Pediatric
<2 years: Not established
>2 years: Administer as in adults
Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination); patients with XHIGM should not receive live virus vaccine because of T-cell deficiency
Documented hypersensitivity; IV administration; selective IgA deficiency (serum IgA level <0.05 g/L) with known antibody against IgA
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include swelling, redness, and itching at injection site; for SC administration only; preferred SC administration sites include abdomen, thighs, upper arms, or lateral hip; initiate 1 wk after regularly scheduled IVIG infusion; does not contain preservative (discard unused portion); may cause fever, chills, nausea, or vomiting when switching from one immune globulin product to another or if > 8 wk since last administered; do not shake product
Antiprotozoal agents
These agents are used for treatment of cryptosporidiosis.
Nitazoxanide (Alinia)
Inhibits growth of Cryptosporidium parvum sporozoites and oocysts and G lamblia trophozoites. Elicits antiprotozoal activity by interfering with pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction, which is essential to anaerobic energy metabolism. Available as a 20-mg/mL oral susp or 500-mg tab.
Adult
500 mg PO q12h with food
Pediatric
1-3 years: 100 mg (5 mL oral susp) q12h with food
4-11 years: 200 mg (10 mL oral susp) q12h with food
>12 years: Administer as in adults
Tizoxanide (nitazoxanide metabolite) is >99.9% bound to plasma protein and may increase toxicity of other highly plasma protein–bound drugs; use caution when administering concurrently with other highly plasma protein–bound drugs (eg, warfarin) with narrow therapeutic indices, because competition for binding sites may occur; in vitro metabolism studies have demonstrated no significant inhibitory effect on cytochrome P450 enzymes
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic function have not been studied; may cause abdominal pain, diarrhea, vomiting, or headache; administer with food
Antibiotics
These agents are used for prophylaxis of PCP.
Trimethoprim and sulfamethoxazole (Septra, Bactrim)
Trimethoprim-sulfamethoxazole (TMP-SMX) is a fixed combination (1:5) of the 2 drugs and is usually bacteriostatic. The dosage ratios are set to produce a 20:1 ratio of SMX to TMP in blood and tissues, which gives maximal antibacterial activity. Both drugs block the folic acid metabolism cycle of bacteria and are much more active together than either agent alone. Sulfonamides are competitive inhibitors of the incorporation of p-aminobenzoic acid. TMP prevents reduction of dihydrofolate to tetrahydrofolate.
Adult
Prophylaxis of Pneumocystis pneumonia : 160 mg TMP and 800 mg SMX (ie, 1 double-strength tab) PO 3 consecutive days/wk
Pediatric
Prophylaxis of Pneumocystis pneumonia:
<2 months: Contraindicated
>2 months: 150 mg/m2/d (based on TMP component) PO divided q12h on 3 consecutive d/wk; not to exceed 320 mg/d TMP; alternatively, 5 mg/kg/d PO divided q12h on 3 consecutive d/wk
May increase the risk of toxicity of the following drugs when coadministered: digoxin, ACE inhibitors (increased hyperkalemia risk), chloral hydrate, class III antiarrhythmic agents (eg, amiodarone, flecainide, dofetilide, bretylium), or other agents that prolong QT interval (eg, amitriptyline, clarithromycin, erythromycin, fluconazole, octreotide); increase metformin plasma concentration; benzocaine or other ester-based anesthetic agents may antagonize the sulfa component
May increase PT when coadministered with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine; coadministration may decrease cyclosporine effect and increase nephrotoxicity; leucovorin antagonizes effect
Documented hypersensitivity; megaloblastic anemia due to folate deficiency; G6PD-deficiency;
age <2 mo; near-term pregnancy; breastfeeding
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Do not use during last trimester of pregnancy because of potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus)
Dosage adjustments (adult adjustments)
CrCl (mL/min) 80-50: Recommended IV dose q18h
CrCl 50-10: Recommended IV dose q24h
CrCl <10: Not recommended
HD: 4-5 mg/kg after HD
During peritoneal dialysis: 0.16-0.8 g q48h
Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if symptoms occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in individuals who are G-6-PD deficient; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation
Granulocyte-Colony Stimulating Factors (G-CSF)
These agents are used for treatment of neutropenia.
Filgrastim (Neupogen)
Recombinant human granulocyte colony-stimulating factor G-CSF. Regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability), priming of the cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some functions associated with cell-surface antigens. G-CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. Daily administration has been shown to be safe and effective in causing a sustained increase in the neutrophil count and a decrease in infectious morbidity in children and adults with severe chronic neutropenia. Long-term daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC.
Adult
Initial dose: 5 mcg/kg/d SC/IV; dose can be increased by 5 mcg/kg/d if no apparent response after 1-2 wk; obtain baseline CBC count and recheck twice weekly to guide therapy duration
Postmarketing surveillance study reported the following median daily doses:
Congenital neutropenia: 6 mcg/kg/d SC/IV; rare instances of doses >100 mcg/kg/d
Cyclic neutropenia: 2.1 mcg/kg/d SC/IV
Idiopathic neutropenia: 1.2 mcg/kg/d SC/IV
Pediatric
Not established
Drugs which may potentiate the release of neutrophils (eg, lithium) should be used with caution
Known hypersensitivity to Escherichia coli– derived proteins, filgrastim, or any component of the product
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause immunogenicity; incidence of antibody development has not been adequately determined, data suggest that a small number of patients developed binding antibodies, although the nature and specificity of these antibodies has not been adequately studied; cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors; patients who develop hypersensitivity reactions may have allergic or hypersensitivity reactions to other Escherichia coli– derived proteins
May cause thrombocytopenia and anemia (regular monitoring of the hematocrit and platelet count is recommended)
Rare reports ( 1/7000 patients) of moderate-to-severe cutaneous vasculitis with long-term therapy, vasculitis symptoms generally developed simultaneously with an increase in the ANC and abated when the ANC decreased; patients may be able to continue treatment at a reduced dose
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References
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Further Reading
Keywords
X-linked immunodeficiency with hyperimmunoglobulin M, XHIGM, HIGM1, primary immunodeficiency disease, immunoglobulin deficiency with increased IgM, hyper-IgM syndrome, HIGM, hypohidrotic ectodermal dysplasia, humoral immunity, somatic hypermutation, SHM, CD40 ligand, CD40L, CD154, gp39, neutropenia, autoimmune disorders, pneumonia, encephalitis, Pneumocystis carinii, diarrhea, Pneumocystis jiroveci pneumonia, sinusitis, otitis, sepsis, hepatitis, sclerosing cholangitis, cellulites, subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection
molluscum contagiosum, warts, Candida esophagitis, cytomegalovirus, CMV, adenovirus, species, herpesvirus type 1, respiratory syncytial virus, histoplasmosis, species, species, type b, Cryptosporidium species, rotavirus, , Yersinia enterocolitica, arthritis, hypothyroidism, osteopenia, rib fractures
