Pediatric Severe Combined Immunodeficiency Medication
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD more...
Medication Summary
Drug therapy is not a major part of therapy for the primary disease. Trimethoprim-sulfamethoxazole is prescribed routinely after the second month of life in children with severe combined immunodeficiency (SCID) until after bone marrow transplant (BMT) engraftment. This is Pneumocystis jiroveci prophylaxis. Intravenous immunoglobulin (IVIg) is used to prevent infection before BMT and, in selected patients, after BMT, if B-cell function remains poor.
Aggressive therapy for suspected or proven infection is essential. Antibiotic coverage typically must be broad-spectrum. Antiviral agents include acyclovir, foscarnet, or ganciclovir for varicella-zoster virus (VZV), herpes simplex virus (HSV), and cytomegalovirus (CMV). Antifungal therapy includes fluconazole for mucocutaneous candidiasis; amphotericin B is first-line therapy for invasive fungal infections such as Aspergillus.
Intravenous immunoglobulin
Class Summary
IVIg is the usual choice. It is derived from human plasma and is composed of all 4 immunoglobulin G (IgG) subclasses. The antibody distribution of IVIg is approximately the same as that of human serum. IVIg can be used to restore antibody levels until the B-cell system is restored with BMT. However, long-term use fails to change the terminal course of SCID.
Immune globulin intravenous (Carimune NF, Gammagard, Octagam, Gammaplex)
IVIg is a human serum fraction that contains IgG. It provides IgG antibodies that the patient cannot make. The therapeutic function is passive immunization to prevent infection.
Enzymes, Metabolic
Class Summary
Replacement enzymes are used in patients with adenosine deaminase (ADA) deficiency and SCID who benefit from BMT. Improved immune function and clinical response are observed with polyethylene glycol–conjugated ADA (PEG-ADA) replacement therapy for ADA deficiency.
Pegademase bovine (Adagen)
Modification of ADA by PEG conjugation of bovine ADA increases the half-life of the enzyme and reduces the immunogenicity of the protein. Pegademase provides enough ADA activity in the bloodstream to eliminate the toxic effect of both deoxyadenosine and adenosine that may result in the immune deficiency. ADA deficiency can be treated with a weekly intramuscular injection of PEG-ADA; this is effective in 90% of cases.
Sulfonamides
Class Summary
Antibiotics are used in the primary treatment and prophylaxis of Pneumocystis jiroveci (carinii) pneumonia (PCP).
Trimethoprim-sulfamethoxazole (Septra DS, Bactrim DS, Cotrim DS)
Trimethoprim-sulfamethoxazole is used because of low levels of T cells or poor T-cell function in children with SCID. It inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Its antibacterial activity affects common urinary tract pathogens, except Pseudomonas aeruginosa. Each 5 mL vial for intravenous (IV) administration contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole. Each 5 mL vial must be added to 125 mL of 5% dextrose in water. Please consult the hospital pharmacist when preparing this medication.
Antivirals, Other
Class Summary
HSV, CMV, and VZV are treated with acyclovir. Oral absorption is poor; thus, most patients require IV administration. Ganciclovir is an alternative drug, also administered IV, for the same viral infections. Both drugs are used for prophylaxis after exposure to VZV beyond the 72- to 96-hour period within which varicella zoster immune globulin (VZIG) is effective at 50% of the therapeutic dose.
Acyclovir (Zovirax)
Acyclovir is given in a high dose of 45-60 mg/kg/day or 1500 mg/m2/day divided every 8 hours for central nervous system (CNS) infection. Good hydration is essential, and lower doses must be calculated in the presence of renal compromise.
Ganciclovir (Cytovene)
Ganciclovir is the drug of choice for CMV infection and is used for HSV and VZV infections that are resistant to acyclovir.
Antifungal Agents
Class Summary
Mucocutaneous candidiasis usually can be treated with fluconazole. Invasive Candida, Aspergillus, and other fungal infections require IV amphotericin B. Prevention of Aspergillus infection and treatment of certain Candida infections that are resistant to fluconazole may be accomplished effectively with itraconazole.
Fluconazole (Diflucan)
Fluconazole has fungistatic activity. It is a synthetic oral antifungal (a broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.
A loading dose is given on day 1, followed by maintenance at 50% of the loading dose. Fluconazole may be administered either IV orally with similar efficacy. Length of treatment is a minimum of 10 days; longer courses are determined individually, with other risk factors (eg, ongoing broad-spectrum antibiotic therapy) taken into account.
Itraconazole (Sporanox)
Itraconazole is used most commonly to prevent Aspergillus infection. An oral solution, 10 mg/mL, is administered on an empty stomach; capsules, 100 mg, are taken with food.
Amphotericin B
A test dose of 0.1 mg/kg is recommended by the manufacturer but is often omitted. Infusion of the total dose over 2-4 hours has been recommended, but infusion over 1 hour seems to be adequate. Because of the high incidence of toxicity, renal, hepatic, electrolyte, and hematologic status must be monitored closely. In particular, potassium and magnesium levels usually are monitored daily. Salt loading with 10-15 mL/kg of normal saline before each dose is used to decrease the risk of nephrotoxicity.
Premedication with acetaminophen and diphenhydramine 30 min before and 4 hours after infusion decreases the typical adverse effects of fever, chills, hypotension, nausea, and vomiting. Hydrocortisone may be admixed to the IV solution (1 mg to 1 mg of amphotericin, not to exceed 25 mg).
The 3 lipid amphotericin products are amphotericin B lipid complex (Abelcet), amphotericin B cholesteryl sulfate (Amphotec), and amphotericin B liposomal (AmBisome). Lipid amphotericin B is used when toxicity from nonlipid amphotericin B is unacceptable. In some patients, lipid products seem to cause less fever, gastrointestinal irritation, chills, and headache. It is unclear whether their renal toxicity is lower.
Amphotericin B lipid complex (ABLC, Abelcet)
This agent is amphotericin B in phospholipid complexed form; it is a polyene antibiotic with poor oral availability. Amphotericin B is produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Amphotericin B, liposomal (AmBisome)
This is a lipid preparation consisting of amphotericin B within unilamellar liposomes. It delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity.
Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Amphotericin B colloidal dispersion (Amphotec)
Amphotericin B colloidal dispersion is a lipid preparation consisting of amphotericin B attached to lipid discoid structures. Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. Oct 2007;120(4):776-94. [Medline]. [Full Text].
Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S182-94. [Medline].
Rosen FS. Severe combined immunodeficiency: a pediatric emergency. J Pediatr. Mar 1997;130(3):345-6. [Medline].
Al-Herz W, Nanda A. Skin Manifestations in Primary Immunodeficient Children. Pediatr Dermatol. Mar 31 2011;[Medline].
Fischer A. Severe combined immunodeficiencies. Immunodefic Rev. 1992;3(2):83-100. [Medline].
Uribe L, Weinberg KI. X-linked SCID and other defects of cytokine pathways. Semin Hematol. Oct 1998;35(4):299-309. [Medline].
Hong R. Disorders of the T cell system. In: Stiehm ER, ed. Immunologic Disorders in Infants and Children. 4th ed. Philadelphia, Pa: WB Saunders; 1996:339-408.
Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. Sep 7 1995;377(6544):65-8. [Medline].
Candotti F, O'Shea JJ, Villa A. Severe combined immune deficiencies due to defects of the common gamma chain-JAK3 signaling pathway. Springer Semin Immunopathol. 1998;19(4):401-15. [Medline].
Hirschhorn R, Vawter GF, Kirkpatrick JA Jr, Rosen FS. Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency. Clin Immunol Immunopathol. Sep 1979;14(1):107-20. [Medline].
Reith W, Mach B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol. 2001;19:331-73. [Medline].
DeSandro A, Nagarajan UM, Boss JM. The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes. Am J Hum Genet. Aug 1999;65(2):279-86. [Medline]. [Full Text].
Mach B, Steimle V, Reith W. MHC class II-deficient combined immunodeficiency: a disease of gene regulation. Immunol Rev. Apr 1994;138:207-21. [Medline].
Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. Jun 10 1994;264(5165):1596-9. [Medline].
Villa A, Santagata S, Bozzi F, Imberti L, Notarangelo LD. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J Clin Immunol. Mar 1999;19(2):87-97. [Medline].
O'Driscoll M, Cerosaletti KM, Girard PM, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. Dec 2001;8(6):1175-85. [Medline].
Kung C, Pingel JT, Heikinheimo M, et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med. Mar 2000;6(3):343-5. [Medline].
Pannicke U, Hönig M, Hess I, Friesen C, Holzmann K, Rump EM. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet. Jan 2009;41(1):101-5. [Medline].
Rieux-Laucat F, Hivroz C, Lim A, Mateo V, Pellier I, Selz F, et al. Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. N Engl J Med. May 4 2006;354(18):1913-21. [Medline].
Dadi HK, Simon AJ, Roifman CM. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. N Engl J Med. Nov 6 2003;349(19):1821-8. [Medline].
Ijspeert H, Lankester AC, van den Berg JM, et al. Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes Immun. Mar 10 2011;[Medline].
Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR, et al. Omenn syndrome due to ARTEMIS mutations. Blood. Jun 1 2005;105(11):4179-86. [Medline].
Hitzig WH, Landolt R, Müller G, Bodmer P. Heterogeneity of phenotypic expression in a family with Swiss-type agammaglobulinemia: observations on the acquisition of agammaglobulinemia. J Pediatr. Jun 1971;78(6):968-80. [Medline].
Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev. Dec 2004;202:67-83. [Medline].
Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. Oct 15 2000;96(8):2803-7. [Medline].
Puck JM. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. Oct 2007;120(4):760-8. [Medline].
Jimenez-Puya R, Vazquez-Bayo C, Rodriguez-Bujaldon A, Gomez Garcia F, Moreno-Gimenez JC. Extensive tinea in a patient with severe combined immunodeficiency. Pediatr Dermatol. Mar-Apr 2009;26(2):213-4. [Medline].
Somech R, Roifman CM. Mutation analysis should be performed to rule out gammac deficiency in children with functional severe combined immune deficiency despite apparently normal immunologic tests. J Pediatr. Oct 2005;147(4):555-7. [Medline].
Baker MW, Grossman WJ, Laessig RH, et al. Development of a routine newborn screening protocol for severe combined immunodeficiency. J Allergy Clin Immunol. Sep 2009;124(3):522-7. [Medline].
Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. Nov 2008;28(4):833-49, ix. [Medline].
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].
Siegel J. The product: all intravenous immunoglobuins are not equivalent. Pharmacotherapy. 2005;25(11 Pt 2):78S-84S.
Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA. Feb 1 2006;295(5):508-18. [Medline].
Tsuji Y, Imai K, Kajiwara M, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. Mar 2006;37(5):469-77. [Medline].
Railey MD, Lokhnygina Y, Buckley RH. Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis. J Pediatr. Dec 2009;155(6):834-840.e1. [Medline]. [Full Text].
Friedrich W, Hönig M, Müller SM. Long-term follow-up in patients with severe combined immunodeficiency treated by bone marrow transplantation. Immunol Res. 2007;38(1-3):165-73. [Medline].
Ariga T. Gene therapy for primary immunodeficiency diseases: recent progress and misgivings. Curr Pharm Des. 2006;12(5):549-56. [Medline].
Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Immunity. Jul 2001;15(1):1-4. [Medline].
Qasim W, Gaspar HB, Thrasher AJ. Progress and prospects: gene therapy for inherited immunodeficiencies. Gene Ther. Nov 2009;16(11):1285-91. [Medline].
Puck JM, Malech HL. Gene therapy for immune disorders: good news tempered by bad news. J Allergy Clin Immunol. Apr 2006;117(4):865-9. [Medline].
Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. Jan 29 2009;360(5):447-58. [Medline].
Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol. May 2007;123(2):139-47. [Medline].
Comeau AM, Hale JE, Pai SY, Bonilla FA, Notarangelo LD, Pasternack MS, et al. Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency. J Inherit Metab Dis. May 20 2010;[Medline].
Brown L, Xu-Bayford J, Allwood Z, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. Mar 17 2011;117(11):3243-6. [Medline].
Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. Feb 2005;115(2):391-8. [Medline].
Lebet T, Chiles R, Hsu AP, Mansfield ES, Warrington JA, Puck JM. Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray. Genet Med. Aug 2008;10(8):575-85. [Medline].
Neven B, Leroy S, Decaluwe H, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood. Apr 23 2009;113(17):4114-24. [Medline].
| Genetic Disease Causing SCID | T-Cell Defect | B-Cell Defect | NK-Cell Defect | Inheritance Pattern |
| Reticular dysgenesis | Yes | Yes | Yes | Autosomal recessive |
| ADA deficiency | Yes | Yes | Yes | Autosomal recessive |
| RAG1 and RAG2 deficiency | Yes | Yes | No | Autosomal recessive |
| TCR and BCR recombination gene deficiency | Yes | Yes | No | Autosomal recessive |
| Common γ chain deficiency | Yes | No | Yes | X-linked |
| JAK3 deficiency | Yes | No | No | Autosomal recessive |
| IL-7Ra deficiency | Yes | No | No | Autosomal recessive |
| Omenn syndrome | Yes | No | No | Autosomal recessive |
| ZAP-70 kinase | CD4+ present | No | No | Autosomal recessive |
| CD4+ lymphopenia | CD8+ present | No | No | Autosomal recessive |
| MHC II deficiency | CD8+ present | No | No | Autosomal recessive |
| p56lck deficiency | CD8+ present | No | No | Autosomal recessive |
| ADA = adenosine deaminase; BCR = B-cell receptor; JAK = Janus-associated kinase; MHC = major histocompatibility complex; RAG = recombination-activating gene; SCID = severe combined immunodeficiency; TCR = T-cell receptor, ZAP = ζ chain-associated protein. | ||||
| Brand (Manufacturer) | Manufacturing Process | pH | Additives | Parenteral Form and Final Concentrations | IgA Content, µg/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 |
| Gammaplex (Bio Products) | Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation | 4.8-5.1 | Contains sorbitol (40 mg/mL); do not administer if fructose intolerant | Ready-for-use solution 5% | < 10 |
| 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, 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; pH4 incubation and depth filtration | 4.6-5 | L-proline (~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). †Withdrawn from US market on September 24, 2010, because of unexplained reports of thromboembolic events. | |||||
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