AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Two immunodeficiency disorders are associated with 2 enzyme deficiencies of the purine salvage pathway that result in severe combined immunodeficiency (SCID). One of the disorders is known as adenosine deaminase (ADA) deficiency, and the other is purine nucleoside phosphorylase (PNP) deficiency.

ADA deficiency results in a T-, B-, and natural killer (NK)–cell form of SCID with marked lymphopenia. PNP deficiency causes decreased numbers of T cells and lymphopenia. Serum immunoglobulin (Ig) levels are normal to near-normal, but antibodies are deficient.

ADA and PNP deficiency are autosomal recessive disorders. In both disorders, the enzyme deficiencies result in accumulation of toxic metabolites. In ADA deficiency, the toxic metabolites block T-, B-, and NK-cell development; whereas in PNP deficiency, the metabolites are toxic to T-cell development. PNP deficiency is also associated with neurologic symptoms, including mental retardation and muscle spasticity, in 67% of patients. In addition, PNP deficiency is associated with increased risk of autoimmune disorders, such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, and lupus.

Pathophysiology

PNP is an enzyme in the purine salvage pathway that metabolizes inosine and guanosine to hypoxanthine. In the preceding step of the pathway, ADA metabolizes adenosine to inosine. ADA deficiency causes an SCID that accounts for approximately 20% of all SCID cases. In both metabolic disorders, the enzyme deficiencies cause the accumulation of metabolites that are toxic to T and B cells.

In ADA deficiency, adenosine and adenine accumulate in the plasma. ATP accumulates in erythrocytes, and ADP, guanosine triphosphate (GTP), and ATP accumulate in lymphocytes. Deoxy-ATP (dATP) can reach toxic levels that inhibit ribonucleotide reductase, an enzyme essential for synthesis of DNA precursors.

In PNP deficiency, similar changes occur in elevated deoxy-GTP (dGTP) levels. dATP and dGTP predominantly accumulates in lymphoid tissue. dGTP inhibits ribonucleotide reductase, which is needed for synthesis of deoxynucleotides. In both ADA and PNP deficiencies, thymocytes are thought to be selectively destroyed because of elevated levels of dATP and dGTP.

In a further description of the mechanism of T-cell depletion in PNP deficiency in a murine model, Arpaia et al reported increased in vivo apoptosis of T cells and increased in vitro sensitivity to gamma irradiation.¹ The immune deficiency in PNP deficiency may be the result of inhibited mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells and thymocytes to spontaneous mitochondrial damage, leading to T-cell depletion due to apoptosis.

With ADA deficiency, destruction of resting T and B cells is increased. In comparison, PNP deficiency results in selective destruction of T cells, with little effect on B cells. Numerous mutations of the ADA gene (on chromosome 20) and PNP genes (on band 14q13) have been identified. PNP is a trimer with molecular weight of 84-94 kDa. Most identified mutations are missense mutations, but deletion is also described. All reported patients with homozygous mutations of PNP have been symptomatic. Because only small amounts of ADA are necessary for competent immunity, some patients with ADA mutations may still have 8-42% ADA activity and no profound immunodeficiency.

Frequency

United States

PNP deficiency is rare. PNP deficiency accounts for approximately 4% of all cases of combined immunodeficiency (CID), and ADA deficiency accounts for approximately 20% of all cases of CID.

International

The prevalence of primary immunodeficiency ranges from approximately 1 case per 54,000 population in Switzerland to 1 case per 200,000 population in Japan. CID accounts for 11-13% of all primary immunodeficiency disorders.

Mortality/Morbidity

Patients with PNP deficiency are at risk for life-threatening recurrent viral, bacterial, fungal, mycobacterial, and protozoal infections. In addition, failure to thrive eventually ensues.

• The risk of lymphoma is also increased in patients with PNP deficiency.
• Neurologic symptoms, including mental retardation and muscle spasticity, are major comorbid conditions that affect 67% of patients with PNP deficiency.
• Bone marrow transplantation may cure the immunodeficiency but does not correct the neurologic disorder. Patients are at risk for autoimmune diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, thyroiditis, neutropenia, and lupus.

Sex

PNP deficiency is an autosomal recessive disorder with equal incidence in boys and girls.

Age

Although symptoms typically appear in the first year of life in patients with PNP deficiency, gradual deterioration of the T-cell immune system may delay the onset of symptoms until the second year of life.

CLINICAL

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History

Most patients have a history of recurrent viral, bacterial, fungal, mycobacterial, and protozoal infections, similar to patients with severe T- and B-cell immunodeficiency. Oral candidiasis that is recalcitrant to therapy occurs in approximately 85% of patients with severe T-cell immunodeficiency. In addition, the presenting infections are often those caused by opportunistic microorganisms, such as Pneumocystis carinii pneumonia.

Neurologic problems are commonly associated with purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) deficiencies and have therapeutic implications. More than 50% of patients with PNP deficiency have neurologic impairments that may predate the onset of infections. Neurologic problems include developmental delay, hypertonia, spasticity, and tremors. Patients with ADA deficiency may also have neurologic problems, principally neurodevelopmental delays. Of importance, polyethylene glycol (PEG) ADA therapy does not correct the neurodevelopmental problems in ADA deficiency, whereas immune reconstitution does. Likewise, bone marrow transplantation does not correct neurological deficits in both PNP and ADA deficiencies.

• PNP deficiency
• • Patients with PNP deficiency may have recurrent sinopulmonary infections that may result in a delay in diagnosis until late childhood.
  • Patients with PNP deficiency, similar to patients with serious T-cell immune deficiency, are susceptible to herpes infections (eg, varicella).
  • Patients with PNP deficiency are also susceptible to recurrent urinary tract infections.
• ADA deficiency
• • Infections typically appear in infancy. However, T-cell function can fluctuate and might not be completely absent. Therefore, a spectrum of T-cell immune deficiency is reported in patients with ADA deficiency.
  • Four major clinical phenotypes of ADA deficiency have been described, as follows:
  • • Neonatal or infantile onset - Indistinguishable from other forms of SCID; bony abnormalities in 50%
    • Delayed onset - Onset at 0-2 y of life; retention of Ig with later attrition, susceptibility to infection similar to that of ADA SCID
    • Late onset -  May present with recurrent bacterial sinopulmonary infections typical for antibody immunodeficiency, lymphopenia (measure ADA and PNP activity), hyper-immunoglobulin E (IgE), eosinophilia, autoimmunity; may be misdiagnosed as common variable immunodeficiency (CVID) or immunoglobulin G (IgG)2-subclass deficiency/specific antibody deficiency
    • Adult onset - Same as late onset, but in adolescents or young adults, plus persistent warts, recurrent herpes zoster, idiopathic thrombocytopenic purpura, lymphopenia; may be misdiagnosed as CVID or IgG2-subclass deficiency/specific antibody deficiency
  • Both partial ADA deficiency and somatic mosaicism have no confirmed immunodeficiency.

Physical

Physical examination reveals a paucity of peripheral lymphoid tissue, such as lymph nodes, tonsillar tissue, and adenoids. The liver and spleen are usually normal in size but can be enlarged in patients with accompanying hemolytic anemia or lymphoma. In neonates, the thymic shadow is typically small on chest radiography. Neurologic symptoms, consisting of developmental delay, hypertonia, spasticity, and tremors, may be present. Patients may fail to thrive.

Causes

PNP deficiency is a genetic disorder caused by a deficiency of the enzyme PNP. The PNP gene has been localized to band 14q13. Missense mutations have been identified in some patients. The PNP protein is a trimer with a molecular weight of 84-94 kDa, with the highest levels in lymphoid tissue. The mechanism by which PNP deficiency causes neurologic disease is unknown.

DIFFERENTIALS

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Other Problems to be Considered

Because multiple genetic and metabolic disorders can cause CID, purine nucleoside phosphorylase (PNP) deficiency should be included in the evaluation when the patient's clinical history and physical findings suggest severe combined T- and B-cell immunodeficiency.

PNP deficiency may be misdiagnosed as thymic dysplasia (Nezelof syndrome). In both disorders, lymphopenia is observed, with decreased T-cell numbers but normal numbers of B cells, and specific antibody deficiency with normal serum Ig levels is present. However, autoimmune complications and neurologic symptoms are more likely to occur in patients with PNP deficiency than in those with Nezelof syndrome.

Because of the recurrent bacterial sinopulmonary infections, PNP deficiency may also be misdiagnosed as B-cell immunodeficiencies, such as CVID, hyper–immunoglobulin M (IgM) syndrome, or Bruton agammaglobulinemia. However, in contrast to PNP deficiency, these primary B-cell immunodeficiencies are typically characterized by profound decrease in serum Ig levels. In variants of adenosine deaminase (ADA) and PNP deficiency, in which the clinical picture resembles predominant B-cell immunodeficiency (eg, CVID, Bruton agammaglobulinemia), the presence of lymphopenia may provide a clinical clue.

Lymphopenia should prompt an evaluation for both ADA and PNP deficiency. DiGeorge anomaly (DGA) also causes variably decreased numbers of T cells, normal B cell numbers, and normal serum Ig levels with variably deficient antibody responses. Physical examination usually reveals facial dysmorphism, including low-set ears, hypognathia, and hypertelorism. Conotruncal cardiac defects may or may not be present in DGA. Monosomic deletion of 22q11.2 is present in more than 95% patients with DGA and can be identified by fluorescence in situ hybridization (FISH) analysis.

WORKUP

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Lab Studies

• Patients often have autoimmune cytopenias, such as autoimmune hemolytic anemia, idiopathic thrombocytopenia, or autoimmune neutropenia. Patients with purine nucleoside phosphorylase (PNP) deficiency may develop other autoimmune diseases, such as systemic lupus erythematosus (SLE) and thyroiditis.
• • IgG autoantibodies should be measured when warranted.
  • Autoantibodies (eg, antinuclear antibodies [ANA], antibodies to double-stranded DNA [dsDNA], thyroid antibodies) should be measured when clinically indicated.
• PNP deficiency
• • In PNP deficiency, immunologic evaluation reveals lymphopenia and markedly decreased CD3⁺ T cells (<15%), but the percentages and number of B cells are normal. T-cell function may be normal at birth but progressively decreases with age. T-cell function may also fluctuate.
  • Serum Ig levels may be decreased but are often normal. Antibody responses to immunizations and infectious pathogens are depressed.
  • Diagnosis is confirmed by low PNP activity in erythrocytes, lymphocytes, and fibroblasts. Low levels of serum uric acid suggest PNP deficiency but not adenosine deaminase (ADA) deficiency.
• ADA deficiency
• • In infantile-onset ADA deficiency, lymphopenia and attrition of T-, B-, and NK-cell function occurs (Table 1). Profound lymphopenia of more than 500 cells/mcL, is typical of ADA SCID and distinguishes it from other genetic causes of SCID. Percentages of T cells and numbers of CD3⁺, CD4⁺, and CD8⁺ T cells are markedly decreased. Percentages of CD19⁺ B cells and CD16⁺/CD56⁺ NK cells vary, but numbers of B and NK cells are markedly decreased, resulting in a T^-, B^-, NK^- phenotype of SCID. T-cell function as measured by lymphoproliferative responses to mitogens, antigens, and alloantigens are absent. Hypogammaglobulinemia and antibody deficiency complete the immune profile of SCID.
  • In late-onset ADA deficiency, serum Ig levels are low or absent, with decreased antibody deficiency. Lymphopenia and reduced CD3⁺ and CD4⁺ T cells are present. Although T-cell responses may be decreased, they are not so suppressed as to predispose patients to intracellular and opportunistic infections. This form may be misdiagnosed as CVID. Lymphopenia in a patient with CVID warrants consideration of possible ADA deficiency. Eosinophilia and elevated serum IgE levels are present.
  • In adult-onset ADA, IgG2-subclass deficiency with decreased antibody responses to polysaccharide antigens may be present, predisposing patients to sinopulmonary infection by encapsulated bacteria. Lymphopenia, decreased numbers of CD3⁺ and CD4⁺ T cells, elevated serum IgE levels, and eosinophilia are present, as is seen in late-onset ADA deficiency. Recurrent varicella-zoster, herpes simplex, and Candida infections may be present.
  • Several immunologic studies may be helpful in assessing ADA deficiency, including those seen in the following table: 

    Table 1. Immunologic Studies and Findings in ADA 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

Imaging Studies

• The thymic shadow is absent on chest radiography. Adenoid tissue is absent on lateral airway radiographs.
• In ADA deficiency, the characteristic radiographic finding of bony structures are sometimes observed and correlate with bony histologic abnormalities.
• • These findings include cupping or flaring of the ribs, similar to the appearance seen in rickets.
  • In addition, abnormalities of the vertebral transverse processes and scapula may be observed.

Other Tests

Genetic studies to examine mutations of genes that encode for ADA and PNP are readily available and should be performed. In PNP deficiency, Grunebaum et al (2004) identified “hot spots” at chromosomes 58 and 234 with increased frequency of mutations in the gene that encodes PNP.² 

Histologic Findings

If thymic biopsy is performed (which is usually not necessary), the results demonstrate marked loss of corticomedullary differentiation; absence of Hassall corpuscles; and depletion of thymocytes, especially in the thymic cortex and medulla.

Histopathology of lymphoid tissue reveals abnormalities, predominantly in T-cell dependent areas. The thymus is markedly reduced in size, with depleted thymocytes. Hassall corpuscles are present but poorly formed. By comparison, Hassall corpuscles are usually absent in patients with SCID. In the lymph nodes and spleen, paracortical regions are reduced or absent. Germinal centers are reduced; however, plasma cells can be identified.

TREATMENT

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Medical Care

• Bone marrow transplantation
• • The European Group for Blood and Marrow Transplantation (EBMT) convened US and European Immunologists in March 2006 and reported their treatment recommendations for adenosine deaminase (ADA) deficiency.³ 
  • • The treatment options discussed included allogeneic hematopoietic stem cell transplantation (HSCT) from a matched family donor (MFD), a mismatched haploidentical donor, and an unrelated bone marrow donor. 
    • The survival following matched sibling donor (MSD) or MFD transplants was extremely good in 27 of 30 patients (90% survival). 
    • Pretransplant conditioning was generally not performed, and rapid engraftment of mature T cells was noted. 
    • Matched unrelated donor (MUD) transplants were performed in 8 patients at 4 centers. These patients received pretransplant preparative regimens. Five survivors were reported (63% survival). 
    • The poorest outcome was in patients who received haploidentical family donor transplants. Overall, 21 of 42 patients (50%) survived; of the survivors, T-cell engraftment was present in 14 patients (66%).
    • MSD/MFD transplants achieved reconstitution of T-cell numbers and function. B-cell recovery varied more, but patients generally developed normal antibody responses to tetanus and diphtheria toxoid immunizations.
    • Chimerism of all lymphoid cells was seen in patients who received pretransplant conditioning but was present only in T cells in unconditional transplants. 
    • Metabolic abnormalities improved with reduction of dATP levels following transplant.
  • In purine nucleoside phosphorylase (PNP) deficiency, human leukocyte antigen (HLA)-matched bone marrow transplantations have been successful in patients with PNP deficiency who have received pretransplantation conditioning.  Haploidentical bone marrow transplantations were difficult to engraft, partly because patients did not receive a conditioning protocol before transplantation. Because residual T-cell function may be present, especially in PNP deficiency, the transplant may have been rejected.⁴
  • Myers et al reported successful immune reconstitution in a patient with PNP deficiency using transplantation of stem cells from umbilical-cord blood.⁵ The conditioning regimen consisted of busulfan, cyclophosphamide, and antithymocyte globulin (ATG). The patients' neurologic impairments resolved.
  • Classen et al reported that a nonmyeloablative conditioning regimen of busulfan and fludarabine resulted in successful immune reconstitution.⁶ The conditioning regimen lowered the risk of vaso-occlusive disease when 2 alkylating agents (eg, busulfan and cyclophosphamide) that potentiate hepatotoxicity were used together.
  • One important issue in the treatment of children with severe T-cell disorders is whether to use a preparative regimen before stem cell infusion for immunosuppression to prevent rejection and myeloablation and, thus, to allow donor T-, B-, and monocytic-cell engraftment. This is an important issue with all options involving hematopoietic stem cells or umbilical cord blood.
  • • In patients who received T cell–depleted transplants of bone marrow grafts without prior cytoreduction, O'Reilly et al and Fischer et al reported graft failures in 30% and 50%, respectively.^{7, 8}
    • In both murine models and in patients with SCID, normal-to-high NK-cell activity is associated with a higher incidence of graft failure or delayed immunologic reconstitution; this is perhaps the foremost cause for graft rejection.
    • The nature of the preparative regimen and the relative importance of immunosuppression versus ablation have not yet been fully defined and may depend on the nature of the hematopoietic stem cell graft. The optimal combination of ablative agents (eg, busulfan) with immunosuppressive agents (eg, ATG, cyclophosphamide), and/or newer agents (eg, fludarabine) has not been systematically studied and should be the focus of future clinical trials.
    • The risks of the preparative regimen are known and include sterility, liver, heart and lung toxicity, and malignancy. These risks must be balanced against morbidity and mortality associated with graft rejection and repeated transplantation, poor T-cell engraftment, and/or poor B-cell function. Children with severe T-cell dysfunction may also have serious infections that cannot be eliminated.
    • Ultimately, the goal of bone marrow transplantation is to provide complete T-, B-, and NK-cell function. The choice of preparative regimen is complicated by the heterogeneity of NK- and B-cell function, which can be expected to develop in various forms of SCID when successful T-cell engraftment occurs. This heterogeneity is not necessarily the case when T cell–depleted haploidentical bone marrow transplantation is performed.
    • The role of myeloablation in the preparative regimen before transplantation remains controversial. Some groups achieved stable immune reconstitution by transplanting umbilical-cord blood in patients with thymic dysplasia and SCID without ablative therapy. However, patients with some severe T-cell immunodeficiency disorders, such as reticular dysgenesis, CID, thymic dysplasia, and Wiskott-Aldrich syndrome, require an immunosuppression regimen for preparation.
    • Patients with PNP deficiency probably also require pretransplantation conditioning. Some groups use a preparative regimen in SCID with high NK-cell function. Further studies are necessary to determine whether this is a true or only theoretical advantage. In addition, patients may need posttransplantation graft-versus-host disease (GVHD) prophylaxis with cyclosporine and corticosteroids, which affect the function of mature T cells in the umbilical cord preparation.
• Preparative regimen and GVHD prophylaxis
• • Transplantation groups disagree on the need for a preparative regimen for transplantations in both ADA and PNP deficiency. Groups who favor a preparative regimen disagree on what regimen should be used. Preparative regimens have included myeloablative treatments (busulfan, cyclophosphamide, ATG), nonmyeloblative treatments (busulfan, fludarabine), or busulfan alone.
  • Pretransplantation conditioning for patients typically includes busulfan 1 mg/kg (1.25 mg/kg if patient <2 y) given orally every six hours on days -9 through -6, where transplantation is on day 0. The dose of busulfan is adjusted on the basis of first-dose kinetics (steady-state level or 400-600 ng/mL). This is followed by cyclophosphamide 50 mg/kg intravenously (IV) on days -5 through -2 and ATG 30 mg/kg given IV on days -3 through -1.
  • Prophylaxis for acute GVHD includes a continuous IV infusion of cyclosporin A beginning on day -2 (target whole blood levels of 250-350 ng/mL) and methylprednisolone 10 mg/kg/d IV on days 5-7, 5 mg/kg/d on days 8-10, and 3 mg/kg/d on days 11-13, followed by a 10% weekly reduction taper. Patients are evaluated daily for acute GVHD during hospitalization and at least weekly after their discharge home for the first 100 days after transplantation. Corticosteroids are generally discontinued by day 60 after transplantation, and cyclosporin A is discontinued between days 100 and 365, depending on clinical evidence of GVHD.
• Enzyme replacement therapy
• • Approximately, 150-160 patients with ADA deficiency worldwide have received PEG-ADA, and approximately 90 patients were currently receiving treatment in 2006. In these investigators' experience, of 31 patients who received PEG-ADA, 14 patients went on to HSCT or GT, 14 patients continued well on PEG-ADA therapy, and 3 patients died. PEG-ADA therapy was generally well-tolerated. Immune reconstruction varied. In the first 6 months of therapy, absolute lymphocyte count (ALC), CD3+, and CD4+ T cell numbers did increase, with good lymphoproliferation responses to phytohemagglutinin (PHA), and thymopoiesis increased. However, over a prolonged time, T-cell numbers and naive T cells were reduced compared with normal controls. Metabolic abnormalities improved with PEG-ADA but not as effective as that seen with HSCT.
  • In PNP deficiency, RBC transfusions have offered limited improvement.
  • Initial attempts to develop a PEG-PNP similar to PEG-ADA were disappointing in that both human and bovine PNP enzymes were too unstable at 37°C. Subsequently, Hershfield et al used the more stable hexameric Escherichia Coli PNP and replaced 3 arginine residues in each of the 6 subunits with lysine by means of site-directed mutagenesis.⁹ In murine models, this PEG-PNP was biologically active. This enzyme also had the ability to phosphorylate Ado, which may permit its use in the treatment of ADA deficiency in addition to PNP deficiency. 
  • Recently, Toro et al (2006) reported a novel technique to intracellularly transduce PNP protein.¹⁰ They used an 11 amino acid human immunodeficiency virus (HIV) transactor (TAT) protein transduction domain (PTD) and created a fusion protein with PNP protein. This PNP-PTD fusion protein rapidly transduced lymphocytes in vitro. Using lymphocytes from patients with PNP deficiency and PNP -/- mice, they demonstrated that the PNP-PTD fusion protein rapidly restored metabolic function and T-cell function in vitro. Furthermore, because the PNP-PTD was cellularly transduced, neutralizing antibodies had little effect.
  • These studies hold promise of treating patients with PNP deficiency with enzyme replacement therapy.
  • Live viral immunizations (eg, with oral polio vaccine) should be avoided.
  • Trimethoprim (TMP)-sulfamethoxazole (SMZ) (Bactrim, Septra) is used for P carinii prophylaxis.
  • Fluconazole is used as prophylaxis against Candida species.
• Gene therapy
• • Since the initial trials of ADA gene therapy performed at the National Institute of Health (NIH) and University of Southern California, gene therapy for ADA deficiency has been performed in Milan and London.³ 
  • • In these centers, autologous CD34+ human stem cells, using retroviral vectors encoding the ADA gene, were used to transfect the human stem cells. 
    • In contrast to the US trials, these patients received mild conditioning regimens prior to infusion of the gene-modified human stem cells, consisting of either busulfan (Milan) or melphalan (London). PEG-ADA was discontinued prior to gene therapy. 
    • In the Milan experience, in 6 of 8 children who were monitored more than 6 months after gene therapy, vector-ADA+ cells progressively became most of the T, B, and NK cells. Stable engraftment of gene corrected cells was seen in 0.1-10% of the myeloid cells. Thymopoiesis, T-cell number and function, and B-cell antibody responses improved. Metabolic abnormalities with decreased dAXP levels were seen. No adverse events in toxicity related to gene therapy were observed. 
    • In London, one patient received ADA gene therapy. This patient experienced similar immune reconstitution and improvement of dAXP toxic metabolites as that observed in the Milan experience.
    • Despite immunologic reconstruction and decreased dAXP toxic metabolites, significant cognitive and behavioral abnormalities have persisted following HSCT and PEG-ADA therapy. Specifically, the London group documented significant reduction in both verbal and performance intelligence quotient (IQ) levels. Metabolic detoxification is not complete with both HSCT and PEG-ADA therapies, especially in erythrocytes. However, with gene therapy, erythrocyte ADA enzyme activity does improve, leading to decreased levels of dAXP metabolites in erythrocytes. Clinically, these patients have normal development to date.
  • PNP deficiency, similar to ADA deficiency, may be amenable to correction with gene therapy. In reports of in vitro studies, gene therapy corrected PNP-deficient cells.
  • A proposed alternative to gene therapy is in situ repair of the defective gene. The principle is to synthesize a short oligodeoxyribonucleotide complementary to the section of the defective gene containing the error, except for the site corresponding to the error. Here, an oligomer contains the nucleotide complementary to that of the normal gene. The oligomer is transfected into the cells by using liposome vectors and binds to its complementary sequence in the defective gene. DNA repair enzymes then delete the defective sequence and insert the correct sequence.
• Supportive care
• • All the patients are hospitalized in single rooms with high-efficiency particulate air-filtration systems.
  • All blood product transfusions are irradiated with 25 Gy before their administration to prevent GVHD.
  • Live viral immunizations (eg, with oral polio vaccine) should be avoided.
  • TMP-SMZ (Bactrim, Septra) is used for P carinii prophylaxis.
  • Antifungal prophylaxis (fluconazole) is used as prophylaxis against infection with Candida species.

Surgical Care

No surgical care is needed.

Consultations

Consult a hematologist or an immunologist skilled in bone marrow transplantation.

Diet

No special diet is required.

Activity

Because patients with PNP are susceptible to viral, fungal, and bacterial infections, limit these patients' exposure to other persons.

MEDICATION

Section 7 of 11  

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Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

Regarding replacement therapy with intravenous Ig (IVIG) in patients with primary immune deficiencies, the overall consensus among clinical immunologists is that a dose of IVIG 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 (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 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 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 (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

Drug Category: Antimicrobials, prophylactic

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

Drug Category: Bone marrow ablative and immunosuppressive agents

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.

Drug Category: Immunosuppressive agents

Cyclosporine and corticosteroids are administered to prevent acute GVHD.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients with 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.

Further Outpatient Care

• 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 (PNP) deficiency. Ongoing therapy for these problems should continue.

Prognosis

• The patient's prognosis depends on the success of immune reconstitution of the T- 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

• Genetic counseling: PNP deficiency is an autosomal recessive inherited immunodeficiency. If PNP 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).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Because purine nucleoside phosphorylase (PNP) deficiency is a fatal primary T- and B-cell immunodeficiency and the treatment of choice is immune reconstitution with bone marrow transplantation, failure to accurately diagnose and refer for transplantation may be considered neglect.
• Many primary T-cell immunodeficiency diseases, including PNP deficiency, can be diagnosed prenatally. If increased risk is suspected in a family because of a previously affected child, the option to prenatally diagnose PNP deficiency should be offered.

Special Concerns

• Prenatal diagnosis of PNP deficiency is possible with amniocentesis or sampling of fetal blood.
• • Prenatal diagnosis is performed when the family has another child with PNP deficiency. PNP activity can be analyzed in amniotic fluid. PNP activity in normal amniotic fluid is 4.4-30.2 nmol/h/mg protein.
  • In addition, amniotic cells can be cultured, and PNP activity can be measured. Normal levels have been measured at 1014-2229 nmol/h/mg in 2 unaffected individuals. In one patient with PNP deficiency, activity was undetectable.
  • The purine profile can also be measured. In normal amniotic fluid, the uric acid level is 160-280 mmol/L, and levels of hypoxanthine, xanthine, guanine, inosine, deoxyinosine, guanosine, and deoxyguanosine are undetectable. However, in the amniotic fluid of fetuses with PNP deficiency, levels of these metabolites are elevated, and the uric acid level is low.
• The risk-benefit of prenatal diagnosis must be considered. If the prenatal diagnosis of PNP deficiency does not alter the decision to terminate pregnancy, the risk may outweigh the benefit. The diagnosis is readily made at the time of delivery.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Jan 15, 2008