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Purine Nucleoside Phosphorylase Deficiency Medication

  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Sep 22, 2015
 

Medication Summary

Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

Regarding replacement therapy with intravenous immunoglobulin (IVIG) in patients with primary immune deficiencies, the overall consensus among clinical immunologists is that a dose of IVIG at 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels of more than 500 mg/dL is desirable.[33, 34] Patients with meningoencephalitis (X-linked agammaglobulinemia) require higher doses (eg, 1 g/kg) and perhaps intrathecal therapy.

Preinfusion, or trough, serum IgG levels are measured every 3 months until a steady state is achieved and then every 6 months if the patient is stable. These levels may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons with high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of IgG elimination may be increased during active infection; therefore, measuring serum IgG levels and adjusting to higher doses or shorter intervals may be required.

Precautions and adverse reactions to intravenous immunoglobulin therapy

The US Food and Drug Administration (FDA) advises against exceeding the recommended doses and infusion rates and suggest the use of minimal practical concentrations in patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia; those older than 65 y; and those using nephrotoxic drugs).

Initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions with initial treatments is high, especially in patients with infections and in those who form immune complexes. In patients with active infection, infusion rates may need to be reduced and the dose halved (ie, 200-300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After normal serum IgG levels are achieved, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with profound immunodeficiency or active infections have reactions more severe than those of other patients.

The adverse reactions are thought to be related to the anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and that trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. 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 adverse effects, doses of analgesic and antihistamine may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products that contain sucrose as a stabilizer are associated with an increased 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/kg/min based on sucrose content. Risk factors for this adverse reaction are preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, BUN and creatinine levels should be monitored before the start of treatment and before each infusion. If renal function deteriorates, the product should be discontinued.

IgE antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in patients with IgA deficiency. The literature has a few reports of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with Ig. In actual experience, however, this is rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG-subclass deficiencies. IVIG preparations with low concentrations of contaminating IgA are advised (see Table 2).

Comparison of intravenous immunoglobulin products

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although their viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized) may differ (see Table 2). The choice may depend on the formulary, local availability, and/or cost. The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording all adverse effects that occur during the infusion is crucial. Periodic monitoring of liver and renal function about 3-4 times yearly, is also recommended.

Table 2. Intravenous Immunoglobulin[35, 36, 37] (Open Table in a new window)

Brand (Manufacturer) Manufacturing Process pH Additives* Parenteral Form and Final Concentration 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, polyethyline glycol (PEG) precipitation, ion-exchange chromatography, pasteurization 5.1-6 Sucrose-free, contains 5% D-sorbitol Liquid 5% < 50
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
Gammagard S/D, Polygam S/D (Baxter Bioscience for the American Red Cross) Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 6.4-7.2 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose Lyophylized powder 5%, 10% < 1.6 (5% solution)
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 0.25M glycine Ready-for-use Liquid 10% 37
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; pH 4 incubation and depth filtration 4.6-5 L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers 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).
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Antimicrobials, prophylactic

Class Summary

Prophylactic treatment for P carinii pneumonia is TMP-SMZ. Administer IVIG therapy to provide functional antibodies.

Trimethoprim and sulfamethoxazole (SMZ-TMP, Bactrim, Septra, Cotrim)

 

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid; for prophylaxis of P carinii pneumonia.

Fluconazole (Diflucan)

 

Synthetic PO antifungal (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. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for PO administration, as a powder for PO suspension, and as a sterile solution for IV use. Indicated for fungal prophylaxis during immunosuppression

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Bone marrow ablative and immunosuppressive agents

Class Summary

The optimal combination of an ablative agent (ie, busulfan) with immunosuppressive agents (eg, antithymocyte globulin, cyclophosphamide) has not been systematically studied and should be the focus of future clinical trials. The risks of this preparative regimen are sterility, liver, heart and lung toxicity, and malignancy.

Busulfan (Myleran)

 

Potent cytotoxic drug; causes profound myelosuppression at recommended dose. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Cyclophosphamide (Cytoxan, Neosar)

 

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Lymphocyte immune globulin (Atgam)

 

May modify T-cell function and might eliminate antigen-reactive T-lymphocytes in peripheral blood.

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Immunosuppressive agents

Class Summary

Cyclosporine and corticosteroids are administered to prevent acute GVHD.

Cyclosporine (Sandimmune, Neoral)

 

Cyclic polypeptide; suppresses some humoral immunity and more so cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, GVHD) in many organs. Base dose on ideal body weight.

Methylprednisolone (Solu-Medrol)

 

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

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Contributor Information and Disclosures
Author

Alan P Knutsen, MD Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director Jeffrey Modell Diagnostic & Research Center for Primary Immuodeficiences (CGCMC), Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, Clinical Immunology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD 

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

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Biochemical pathway of purine metabolism. AMP = adenosine monophosphate, APRT = adenine phosphoribosyltransferase, GMP = guanosine monophosphate, HGPRT = hypoxanthine-guanine phosphoribosyltransferase, IMP = inosine monophosphate, NP = nucleoside phosphorylase, PPriboseP = 5-phosphorylribose-1-pyrophosphate.
Table 1. Immunologic Studies and Findings in Adenosine Deaminase Deficiency
Study Infantile Onset Late Onset Adult Onset
Lymphopenia Markedly decreased Decreased Decreased
CD3+ cells Absent or trace Markedly reduced Markedly reduced
CD4/CD8 ratio Too few to test < 1 < 1
Phytohemagglutinin response Absent Reduced Reduced
Antigen response Absent Trace Trace
Mixed lymphocyte culture response Reduced ... ...
Ig response Absent Low to absent Normal (low IgG2)
IgE Low Elevated Elevated
Antibody response Absent Absent to low Low to polysaccharides antigens
Eosinophilia Rare Common Common
Infections Predominantly viral, fungal, opportunistic, bacterial Bacterial sinopulmonary Bacterial sinopulmonary, varicella-zoster, herpes simplex, candidal
Table 2. Intravenous Immunoglobulin [35, 36, 37]
Brand (Manufacturer) Manufacturing Process pH Additives* Parenteral Form and Final Concentration 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, polyethyline glycol (PEG) precipitation, ion-exchange chromatography, pasteurization 5.1-6 Sucrose-free, contains 5% D-sorbitol Liquid 5% < 50
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
Gammagard S/D, Polygam S/D (Baxter Bioscience for the American Red Cross) Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 6.4-7.2 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose Lyophylized powder 5%, 10% < 1.6 (5% solution)
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 0.25M glycine Ready-for-use Liquid 10% 37
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; pH 4 incubation and depth filtration 4.6-5 L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers 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).
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