Medication Summary
In October 2018, the FDA approved elapegademase (Revcovi) for treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in adults and children. The drug had been available as an orphan drug prior to approval. Enzyme replacement helps prevent potentially serious, life-threatening infections in this patient population.
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 for 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 IV (IGIV) (Asceniv, Bivigam, Carimune)
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.
Elapegademase (Revcovi)
Elapegademase a recombinant adenosine deaminase based on bovine amino acid sequence and conjugated to PEG. It is indicated for treatment of ADA severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.
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 deoxycholate (amphotericin B conventional)
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.
-
This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
-
This patient with an autosomal recessive type of severe combined immunodeficiency died of cytomegalovirus pneumonia when aged 22 months after prior infections that included recurrent otitis, pneumonia, and oral thrush. A CMV inclusion body is pictured in the upper left of the photo.
-
Histologically, the thymus in severe combined immunodeficiency usually lacks Hassall corpuscles and is depleted of lymphocytes. In this photo, a Hassall corpuscle is identified to the right of center.
Tables
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. |
||||
