Further Outpatient Care

See the list below:

Intravenous immunoglobulin (IVIG) therapy is typically continued for 6-12 months after bone marrow transplantation. Reimmunization of the patient begins approximately 1 year after transplantation. Live viral vaccines should be avoided.
Bone marrow transplantation does not correct the neurologic problems associated with purine nucleoside phosphorylase deficiency. Ongoing therapy for these problems should continue.

Further Inpatient Care

See the list below:

Patients with adenosine deaminase (ADA) deficiency or purine nucleoside phosphorylase (PNP) deficiency who have acute infections may require hospitalization for diagnostic studies to identify opportunistic pathogens.
For stem cell reconstitution, patients are typically hospitalized in single-occupancy protective reverse-isolation rooms with high-efficiency particulate air-filtration systems. Patients should remain in isolation until engraftment is evident.

Prognosis

See the list below:

The patient's prognosis depends on the success of immune reconstitution of the T-cell and B-cell systems.
If immune reconstitution is successful, the patient's prognosis is good. However, bone marrow transplantation does not correct the neurologic disease.

Patient Education

See the list below:

Genetic counseling: Purine nucleoside phosphorylase deficiency is an autosomal recessive inherited immunodeficiency. If purine nucleoside phosphorylase deficiency is diagnosed in a child, the parents have a 25% risk of having affected children in subsequent pregnancies.
Prenatal diagnosis: Prenatal diagnosis can be performed (see Special Concerns below).

Questions

la Marca G, Giocaliere E, Malvagia S, Villanelli F, Funghini S, Ombrone D, et al. Development and validation of a 2nd tier test for identification of purine nucleoside phosphorylase deficiency patients during expanded newborn screening by liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med. 2016 Apr. 54 (4):627-32. [QxMD MEDLINE Link].
Hirshhorn R, Canotti F. Immunodeficiency due to defects of purine metabolism. Ochs HD, Smith CIE, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. 2nd ed. New York, NY: Oxford University Press, Inc; 2007. 169-96.
Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill; 2001. 2585-2625.
Arpaia E, Benveniste P, Di Cristofano A, et al. Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice. J Exp Med. 2000 Jun 19. 191(12):2197-208. [QxMD MEDLINE Link].
Bzowska A, Kulikowska E, Shugar D. Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther. 2000 Dec. 88(3):349-425. [QxMD MEDLINE Link].
Markert ML, Hershfield MS, Schiff RI, Buckley RH. Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients. J Clin Immunol. 1987 Sep. 7(5):389-99. [QxMD MEDLINE Link].
Markert ML. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991. 3(1):45-81. [QxMD MEDLINE Link].
Hirschhorn R. Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res. 1993. 33:S35-41.
Hershfield MS. Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol. 1998. 35:291-298.
Purine nucleoside phosphorylase deficiency. Genetics Home Reference. Available at https://ghr.nlm.nih.gov/condition/purine-nucleoside-phosphorylase-deficiency. 2019 Jul 16; Accessed: April, 2019.
Purine nucleoside phosphorylase deficiency. Orphanet. Available at https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=760. Accessed: April, 2015.
Aytekin C, Dogu F, Tanir G, et al. Purine nucleoside phosphorylase deficiency with fatal course in two sisters. Eur J Pediatr. 2010 Mar. 169(3):311-4. [QxMD MEDLINE Link].
Parvaneh N, Ashrafi MR, Yeganeh M, Pouladi N, Sayarifar F, Parvaneh L. Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency. Brain Dev. 2007 Mar. 29(2):124-6. [QxMD MEDLINE Link].
Bradford KL, Moretti FA, Carbonaro-Sarracino DA, Gaspar HB, Kohn DB. Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. J Clin Immunol. 2017 Oct. 37 (7):626-637. [QxMD MEDLINE Link].
Manson D, Diamond L, Oudjhane K, Hussain FB, Roifman C, Grunebaum E. Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life. Pediatr Radiol. 2013 Mar. 43(5):589-92. [QxMD MEDLINE Link].
Grunebaum E, Cutz E, Roifman CM. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency. J Allergy Clin Immunol. 2012 Jun. 129(6):1588-93. [QxMD MEDLINE Link].
Hirschhorn R. In vivo reversion to normal of inherited mutations in humans. J Med Genet. 2003. 40:721-728.
Routes JM, Grossman WJ, Verbsky J, et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA. 2009 Dec 9. 302(22):2465-70. [QxMD MEDLINE Link].
Grunebaum E, Zhang J, Roifman CM. Novel mutations and hot-spots in patients with purine nucleoside phosphorylase deficiency. Nucleosides Nucleotides Nucleic Acids. 2004 Oct. 23(8-9):1411-5. [QxMD MEDLINE Link].
[Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May. 94(5 Suppl 1):S1-63. [QxMD MEDLINE Link].
Kohn DB, Gaspar HB. How We Manage Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA SCID). J Clin Immunol. 2017 May. 37 (4):351-356. [QxMD MEDLINE Link].
Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012 Oct 25. 120(17):3615-24; quiz 3626. [QxMD MEDLINE Link].
Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis. 2018 Apr 24. 13 (1):65. [QxMD MEDLINE Link]. [Full Text].
Broome CB, Graham ML, Saulsbury FT, et al. Correction of purine nucleoside phosphorylase deficiency by transplantation of allogeneic bone marrow from a sibling. J Pediatr. 1996 Mar. 128(3):373-6. [QxMD MEDLINE Link].
Myers LA, Hershfield MS, Neale WT, et al. Purine nucleoside phosphorylase deficiency (PNP-def) presenting with lymphopenia and developmental delay: successful correction with umbilical cord blood transplantation. J Pediatr. 2004 Nov. 145(5):710-2. [QxMD MEDLINE Link].
Classen CF, Schulz AS, Sigl-Kraetzig M, et al. Successful HLA-identical bone marrow transplantation in a patient with PNP deficiency using busulfan and fludarabine for conditioning. Bone Marrow Transplant. 2001 Jul. 28(1):93-6. [QxMD MEDLINE Link].
O'Reilly RJ, Keever C, Kernan NA, et al. HLA nonidentical T cell depleted marrow transplants: a comparison of results in patients treated for leukemia and severe combined immunodeficiency disease. Transplant Proc. 1987 Dec. 19(6 Suppl 7):55-60. [QxMD MEDLINE Link].
Fischer A, Griscelli C. [Bone marrow graft: graft versus host reaction and rejection]. Nephrologie. 1986. 7(3 Suppl):1-4. [QxMD MEDLINE Link].
Hershfield MS. Enzyme replacement therapy of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase (PEG-ADA). Immunodeficiency. 1993. 4(1-4):93-7. [QxMD MEDLINE Link].
Toro A, Paiva M, Ackerley C, Grunebaum E. Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro. Cell Immunol. 2006 Apr. 240(2):107-15. [QxMD MEDLINE Link].
Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA- deficient SCID neonates. Nat Med. 1998 Jul. 4(7):775-80. [QxMD MEDLINE Link].
Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002 Jun 28. 296(5577):2410-3. [QxMD MEDLINE Link].
Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29. 360(5):447-58. [QxMD MEDLINE Link].
Cicalese MP, Ferrua F, Castagnaro L, Rolfe K, De Boever E, Reinhardt RR, et al. Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. Mol Ther. 2018 Mar 7. 26 (3):917-931. [QxMD MEDLINE Link]. [Full Text].
Cooper AR, Lill GR, Shaw K, Carbonaro-Sarracino DA, Davila A, Sokolic R, et al. Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients. Blood. 2017 May 11. 129 (19):2624-2635. [QxMD MEDLINE Link]. [Full Text].
Liao P, Toro A, Min W, Lee S, Roifman CM, Grunebaum E. Lentivirus gene therapy for purine nucleoside phosphorylase deficiency. J Gene Med. 2008 Dec. 10(12):1282-93. [QxMD MEDLINE Link].
Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008 Jul. 122(1):210-2. [QxMD MEDLINE Link].
Durandy A, Wahn V, Petteway S, Gelfand EW. Immunoglobulin replacement therapy in primary antibody deficiency diseases - maximizing success. Int Arch Allergy Immunol. 2005. 136:217-229.
Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. 2008 Nov. 28(4):833-49, ix. [QxMD MEDLINE Link]. [Full Text].
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. 2008 Nov. 28(4):765-78, viii. [QxMD MEDLINE Link].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005 Aug 15. 62(16 Suppl 3):S5-11. [QxMD MEDLINE Link].
Markert ML, Finkel BD, McLaughlin TM, et al. Mutations in purine nucleoside phosphorylase deficiency. Hum Mutat. 1997. 9:118-121.
Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med. 2000 Nov 2. 343(18):1313-24. [QxMD MEDLINE Link].
Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997 Mar. 130(3):378-87. [QxMD MEDLINE Link].
Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc. 2009. 84(1):16-22. [QxMD MEDLINE Link]. [Full Text].
Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. Cleveland, OH: Lexi-Comp, Inc; 2009.
Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005 Nov. 25(11 Pt 2):78S-84S. [QxMD MEDLINE Link].

Media Gallery

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.

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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 ^{[39, 40, 41]}

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).