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Adenosine deaminase deficiency: Treatment and prognosis

Adenosine deaminase deficiency: Treatment and prognosis
Literature review current through: Jan 2024.
This topic last updated: Jul 02, 2023.

INTRODUCTION — Adenosine deaminase (ADA) deficiency (MIM #102700) is an autosomal recessive genetic disorder [1]. In approximately 90 percent of cases, it leads to a severe combined immunodeficiency (ADA-SCID) with dysfunction of T, B, and natural killer cells (T-B-NK- SCID) that presents in the first few months of life. ADA-SCID is often fatal in the first year or two of life without treatment. There are also a few patients with a later onset and relatively milder disease, as well as a few with spontaneous somatic reversion of the ADA mutation and partial reversal of the deficiency. The wide spectrum of the ADA deficiency phenotype is partially related to the variability in genetic mutations.

All patients should begin treatment as soon as the diagnosis is established [2,3]. Early intervention is critical since life-threatening severe or opportunistic infections are common in the first weeks or months of life. Furthermore, the accumulation of toxic metabolites may interfere irreversibly with the ontogenic development of the immune system, as well as pulmonic, gastrointestinal, neurologic, and other organ systems.

The treatment and prognosis of ADA deficiency are presented in this topic review. Our approach to treatment is consistent with the 2019 consensus guidelines for the management of ADA-SCID [4]. The pathogenesis, clinical manifestations, and diagnosis of ADA deficiency are discussed separately, as is the related combined immunodeficiency disorder, purine nucleoside phosphorylase deficiency. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "Purine nucleoside phosphorylase deficiency".)

Gene therapy and hematopoietic cell transplantation (HCT) for inborn errors of immunity are also discussed in detail separately. (See "Overview of gene therapy for inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

IMMEDIATE MANAGEMENT OF ADA-SCID — Starting treatment as soon as possible is critical in patients with all forms of severe combined immunodeficiency (SCID). Early diagnosis and treatment minimize complications and improve outcomes in a disease that is otherwise fatal in infancy. Newborn screening for SCID that has led to earlier diagnosis and advances in transplantation, gene therapy, and enzyme replacement therapy (ERT) has influenced the approach to treatment in ADA-SCID. Newborn screening for SCID is reviewed in detail separately. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

General measures — General protective measures for patients with known or suspected SCID are briefly reviewed here and discussed in detail separately (see "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Severe combined immunodeficiency (SCID): An overview", section on 'Initial management'):

Exposure to contagious illnesses should be minimized as best as possible. The decision of whether to keep the patient in the hospital under strict protective isolation while workup for treatment is being done or to allow them to remain at home in confinement depends on multiple factors such as the assessed reliability of the family at maintaining isolation vigilance at home, the presence of other siblings attending day care or school, and the proximity of the home to a clinical site.

Patients should receive prophylactic antibiotics, including prophylaxis for Pneumocystis jirovecii pneumonia. However, patients with ADA-SCID may be at increased risk of antibiotic-induced myelotoxicity [5], especially from trimethoprim-sulfamethoxazole. Thus, neutrophil counts should be monitored every one to two weeks until the patient undergoes definitive therapy or until the patient is switched to an alternative antibiotic (eg, pentamidine or atovaquone) [6,7]. Many centers also initiate antiviral and antifungal prophylaxis, while others rely on close monitoring for infections and initiate treatment accordingly.

Certain products should not be administered, including live vaccines (eg, rotavirus vaccine) [8], Bacillus Calmette-Guérin (BCG) [9], and nonirradiated, cytomegalovirus (CMV) positive blood products, because patients can develop infection. Similarly, the benefits and risks of breast milk from CMV-positive donors should be weighed [10].

Immune globulin replacement therapy, including additional respiratory syncytial virus (RSV) prophylaxis, should be given. (See "Immune globulin therapy in inborn errors of immunity" and "Respiratory syncytial virus infection: Prevention in infants and children".)

Stabilization/bridge therapy with enzyme replacement therapy — We suggest treating all infants with newly diagnosed ADA-SCID with ERT as a measure to help stabilize patients' clinical status and restore their immune function prior to receiving definitive therapy. Indeed, a review of patients with ADA deficiency registered with the United States Immunodeficiency Network (USIDNET) revealed that 88 percent of those diagnosed since 2010 received ERT at some point in their lives [11]. ERT may also help prevent damage to other tissues and organs prior to definitive therapy [4]. The immune and noninfectious defects seen in patients with ADA deficiency are most likely caused by a direct toxic effect of accumulated purine metabolites on immature lymphocytes and developing organs. Early ERT can reverse and possibly prevent, at least temporarily, further metabolic toxicity to the thymus and nonlymphoid organs.

ERT was initially performed with frequent infusions of irradiated allogenic red blood cells (RBCs) [12]. However, iron overload and risk of bloodborne infections led to the development of polyethylene glycol-modified bovine ADA (PEG-ADA), which has been in clinical use for more than 30 years [13]. The advantage of PEGylation is the prolongation of the protein's biologic half-life by slowing its elimination and blocking access to sites on the ADA protein surface, thereby minimizing enzymatic degradation and formation of neutralizing anti-ADA antibodies [14,15].

Formulations — A recombinant bovine ADA formulation (elapegademase) has replaced the biochemically purified bovine ADA (pegademase), which is no longer being manufactured. The recombinant form was modified to include additional PEGylation sites, which may further extend the biologic half-life and reduce immunogenicity of the bovine-based enzyme. Until gaining further experience with elapegademase, treatment recommendations for this product rely on extrapolation from the knowledge gained with pegademase. Early studies in an animal model of ADA deficiency and in a small number of patients with ADA deficiency suggest that elapegademase activity is equivalent to or better than pegademase [16]. Future studies will also help determine whether the elapegademase form of PEG-ADA provides a more reliable production source and potentially better efficacy for ADA ERT than the original animal-sourced preparation.

Dosing — The starting dose of elapegademase for patient not previously on ERT is 0.4 mg/kg weekly, based upon ideal body weight or actual weight, whichever is greater, divided into two weekly doses that are given by deep intramuscular injection. This dose is thought to be equivalent to the 30 units/kg twice a week starting dose of pegademase bovine.

The maintenance dose of elapegademase is 0.2 mg/kg once a week if they were receiving less than 30 units/kg of pegademase bovine. For patients receiving more than 30 units/kg of pegademase bovine, a conversion formula was suggested by the manufacturer: elapegademase (dose in mg) = pegademase bovine (dose in units) divided by 150.

The maintenance dose is adjusted depending upon metabolic normalization (plasma ADA levels and RBC deoxyadenosine nucleotide [dAXP] levels) and immune reconstitution. If anti-ADA antibodies are detected, increasing the dose or dosing twice weekly instead of weekly may help overcome the neutralizing effect of the antibodies, as suggested previously for patients receiving pegademase bovine [14,17].

Efficacy — Based upon comparisons with historical controls, the initial clinical effects of PEG-ADA ERT are often good, especially when started in the first few months of life and in the absence of infections [18,19]. General well-being and nutritional status of the patient usually improve over a period of four to eight weeks [4,13,19,20]. RBC total dAXP and S-adenosylhomocysteine hydrolase (SAHase) levels are also noted to improve during this time period. B and natural killer (NK) cell numbers and antibody production may normalize in the first month of therapy. In contrast, T cell numbers only increase after two to four months of therapy [19,21]. In addition, ERT can improve hepatocellular abnormalities [22], pulmonary alveolar proteinosis [23], and bone dysplasia [24] and may prevent injury to the developing brain and auditory system, particularly if started shortly after birth.

The ultimate levels of lymphocytes that are reached following PEG-ADA therapy can vary from normal to relatively low (eg, CD3+ T cell counts of 300 to 600 cells/mm3). Failure of PEG-ADA to induce substantial immune reconstitution has been reported in up to 20 percent of patients [2]. Some patients receiving PEG-ADA achieve sufficiently reconstituted immunity such that they do not require immune globulin replacement or prophylactic antibiotics, but others may need both in addition to PEG-ADA to decrease recurrent infections. Normal immunoglobulin A (IgA) and immunoglobulin M (IgM) levels support a trial of immune globulin withdrawal in patients treated with PEG-ADA ERT [25]. Symptoms of immune dysregulation such as hemolytic anemia and immune thrombocytopenia [26] have been reported after initiation of PEG-ADA and may be related to dysregulated cellular and humoral recovery [27].

Monitoring — Monitoring includes assessment of adherence to therapy by history and measurement of serum or RBC ADA, deoxyadenosine, and dAXP levels monthly until immune function improves. Testing is then performed every two to three months for the first year after initiating therapy, every three to four months for the second year, and at least one to two times per year thereafter. General immune function (lymphocyte subsets and functional studies) should be monitored with the same frequency. The frequency of monitoring is increased to once a month if there is a change in formulation, dose adjustment, or change in clinical status. Patients should be tested for neutralizing ADA antibodies if there is an unexplained decrease in plasma ADA activity, especially when accompanied by an increase in RBC dAXP levels.

PREFERRED DEFINITIVE THERAPY FOR ADA-SCID — Definitive therapy includes gene therapy and hematopoietic cell transplantation (HCT). We recommend ADA gene therapy or unconditioned HCT from a human leukocyte antigen (HLA) identical matched sibling donor (MSD) or matched family donor (MFD), consistent with the 2019 consensus guidelines for the management of ADA-severe combined immunodeficiency (SCID) [4]. Both therapies have high cure rates and good survival. Survival has been better in the patients selected for gene therapy studies, but there are less long-term data than for HCT. Retreatment after gene therapy may also be easier than after HCT. (See 'Treatment in patients who fail first definitive therapy' below.)

The primary rate-limiting factor for both of these treatments is availability and cost [4]. Only approximately 15 percent of patients will have an available MSD or MFD for HCT at the time of diagnosis. Gamma retrovirus-based gene therapy was approved for therapy only in the European Union in 2016 at an estimated cost of approximately 600,000 Euros, which does not include the procedure or associated travel and accommodation expenses (patients and caregivers need to stay for an extended period near the treatment center). However, gamma retrovirus-based gene therapy was put on hold because one patient developed a T cell lymphoid leukemia. Lentivirus-based ADA gene therapy is only offered through clinical trials performed at a handful of centers worldwide and is not yet approved for clinical use. Therefore, insurance companies are more likely to cover HCT, although some patients and caregivers may incur additional transportation and accommodation costs if they need to travel to a distant HCT center and remain there for an extended period. Gene therapy will most likely see increased use after it reaches wider regulatory approval for commercial application.

Gene therapy — Permanent restoration of normal ADA gene expression can be achieved either by gene addition using a viral vector or potentially by gene editing in a patient's hematopoietic stem cells with transplantation of these altered, ADA-proficient cells back into the patient. Graft rejection and graft-versus-host disease should not occur with this autologous procedure, unlike with allogeneic procedures such as HCT. Patients may also need less chemotherapy conditioning prior to transplant and do not require immune suppression afterward. The rationale for and techniques of gene therapy are discussed separately. (See "Overview of gene therapy, gene editing, and gene silencing" and "Overview of gene therapy for inborn errors of immunity".)

Efficacy and safety

Retroviral vector gene therapy — Gene therapy for ADA-SCID was initiated using a retroviral vector targeting peripheral blood T cells in two patients receiving enzyme replacement therapy (ERT) [28]. Subsequent studies targeted hematopoietic stem and progenitor cells from bone marrow or peripheral blood. A 2019 review ascertained 108 patients who had undergone gene therapy in clinical trials since 2000 at one of four centers worldwide (Milan, Italy; London, England; and, in the United States, in Los Angeles and at the National Institutes of Health [NIH]). All were alive at the time of the report, and the majority of patients achieved immune reconstitution, restoration of thymic activity, systemic detoxification of adenosine metabolites, and long-term engraftment [4]. Growth and neuropsychomotor development also improved after gene therapy. Overall, 18 percent of patients had to restart ERT or receive a second definitive therapy (HCT or repeat gene therapy). Relatively higher rates of treatment failure were seen in early patients (23 to 70 percent across the centers) and decreased over time to 8 percent in the lentiviral vector studies performed to that time. Reported adverse events include prolonged neutropenia, catheter-related infections, Epstein-Barr virus (EBV) reactivation, hypertension, and autoimmune hepatitis [29,30].

One patient who received a retroviral vector gene therapy for ADA-SCID developed T cell leukemia [31], similar to cases occurring in trials of gene therapy for X-linked SCID [32-34] and other inborn errors of immunity [35,36]. Retroviral vectors contain strong enhancer elements that may trans-activate cellular proto-oncogenes present at the sites of vector integration into the chromosomes to lead to cellular transformation. It is not known why leukoproliferative complications have been markedly infrequent in patients with ADA-SCID who have undergone retroviral vector gene therapy.

Long-term follow-up was reported about a cohort of 10 patients with ADA-SCID who received gene therapy with a retroviral vector between 2009 and 2012 [37]. There was a 100-fold range in the level of engrafted gene-corrected stem cells across the group, which correlated with multiple biochemical, molecular, and immunologic outcome parameters. All patients were alive, and most had sufficient immunity to discontinue ERT, but only four were able to discontinue immune globulin replacement. There were no leukoproliferative complications, although there were prominent cell clones observed in several of the patients with the vector integrated near MDS1 and EVI1 complex locus (MECOM) and other genes associated with insertional leukemogenesis in trials for other immunodeficiencies.

Lentiviral vector gene therapy — A lentiviral vector carrying the ADA gene and lacking strong enhancer elements was developed because of the potential risk of leukemia-like complications from retroviral vectors [38]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Types of vectors'.)

A subsequent report combined results from three phase-I/II ADA gene therapy trials of 50 infants and young children who were transplanted with autologous CD34+ hematopoietic stem and progenitor cells transduced ex vivo with a self-inactivating lentiviral vector (30 in the US and 20 in the UK) [39]. They noted 100 percent survival at 24 and 36 months with only two treatment failures (4 percent). The remaining patients had robust and sustained immune reconstitution, with 90 percent of US patients at 24 months and all UK patients at 36 months able to discontinue immune globulin replacement therapy. Another indication for the robust immune reconstitution achieved by this strategy was normalization of the immunoglobulin repertoire [40]. The most significant adverse event reported was immune reconstitution inflammatory syndrome in four patients. No leukoproliferative or other vector-related complications were noted, and all had polyclonal vector integration patterns over the time of follow-up.

Two primary strategies are believed to have improved gene therapy outcome. The first was improved gene transfer efficiency with better vector preparations, notably self-inactivating lentiviral vectors, and refined stem cell processing methods. The second was enhanced engraftment of the autologous gene-corrected stem cells following a reduced-intensity conditioning regimen, most commonly with low-dose busulfan [29,30,41-45]. Busulfan area under the concentration time curve (AUC) correlated with the eventual percentage of engrafted gene-corrected stem cells and greater production of ADA [46].

Timing of PEG-ADA discontinuation — It is not yet clear whether discontinuing polyethylene glycol-modified bovine ADA (PEG-ADA) prior to gene therapy improves outcomes. The hypothesis behind this approach is that PEG-ADA may blunt the potential selective advantage of genetically engineered T cells over the defective cell population. In the first trials that achieved immune reconstitution for ADA-SCID, PEG-ADA ERT was stopped approximately one week before bone marrow harvest and subsequent gene therapy transplant [29,41-43,45]. The protocol for ADA gene therapy with the retroviral vector specifies stopping ERT two to three weeks before gene therapy. However, only partial immune recovery was seen in one human study that discontinued PEG-ADA but did not use cytoreductive conditioning [47]. In addition, results from a murine model suggested that continued used of PEG-ADA for a month after gene transfer does not diminish, and may actually promote, engraftment of gene-corrected cells [48]. Thus, the approach of continuing ERT for one month after gene therapy was incorporated into the lentiviral vector trials. Further research is needed to determine the optimal timing for discontinuation of PEG-ADA in patients undergoing gene therapy.

HCT with MSD or MFD — Hematopoietic cell transplantation (HCT) from an HLA-identical sibling donor (matched sibling donor [MSD]) or matched family donor (MFD) is an equal alternative to gene therapy, but these donor types are only available for approximately 15 percent of all patients [2,3,49-52]. No immunosuppressive or marrow cytoreductive conditioning is needed since the ADA-proficient lymphoid cells of the donor have a survival advantage over the ADA-deficient lymphoid cells of the host.

However, donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which is associated with poor metabolic correction and more frequent failure to discontinue immune globulin replacement therapy [53]. A single-center study also found that approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced-intensity conditioning prior to HCT improved the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction [53].

The best outcomes are seen when HCT is performed early, before any opportunistic infection or advanced immune attrition occurs [54-57]. HCT, when successful, is almost uniformly curative of the immunodeficiency. In addition, pulmonary alveolar proteinosis and bone abnormalities also reverse after transplantation [23,24]. By contrast, transplantation does not seem to impact the neurologic complications of the disease, possibly because these complications occurred prior to transplant and are static [58]. Future studies will help determine whether newborn screening for SCID leading to earlier diagnosis and treatment will help prevent the neurologic complications. HCT for SCID is reviewed in greater detail separately. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Overall survival rates in a series of patients with ADA-SCID who received HCT from 1981 to 2009, prior to the widespread implementation of newborn screening for SCID, were 86 percent for MSD and 83 percent for MFD with a median posttransplant follow-up of 6.5 years (range 1.6 to 27.6 years) [20]. The majority of deaths occurred in the first 100 days after HCT. Graft-versus-host disease and graft rejection as well as infections are common complications and causes of mortality. Improved transplantation practices, graft manipulation, and supportive measures are also expected lead to better outcomes of HCT.

As with gene therapy, the optimal time to discontinue ERT relative to HCT is not clear. There is concern that the positive effects of ERT on immunity could interfere with engraftment and the "survival advantage" of the donor cells, particularly in patients who do not receive conditioning, as is the case in MSD and MFD HCT. Some centers have elected to stop ERT two to four weeks prior to MSD and MFD transplants while continuing ERT for other types of HCT requiring conditioning [53].

ALTERNATIVES TO PREFERRED DEFINITIVE THERAPY — If neither gene therapy nor a matched sibling or family donor (MSD or MFD) hematopoietic cell transplantation (HCT) is available, treatment options include continued enzyme replacement therapy (ERT) or HCT with an alternative donor. Alternative donors include a haploidentical (matched at half of the human leukocyte antigen [HLA] loci) related donor or a matched (or mismatched) unrelated donor (URD). However, availability of preferred therapy (gene therapy or HCT with an MSD or MFD) should be periodically reassessed since outcomes are much better with these therapies. The decision to continue ERT while waiting for one of the preferred definitive therapies or proceeding with haploidentical or URD HCT is done following extensive discussion with the patient and caregiver(s) with the medical team. It takes into account unique circumstances as well as current and projected treatment availabilities and effectiveness.

Longer-term ERT — As noted above, enzyme replacement therapy (ERT) can restore, at least partly and temporarily, protective lymphocyte immune function [13,14,59]. Overall survival was reported as good (78 percent in one series of 180 patients who received ERT) [2]. However, lymphocyte counts and function have been shown to wane over time in many patients, leading to increased susceptibility to infections, malignancy, and other noninfectious complications [2,60-62]. In addition, ERT is costly ($100,000 to 350,000 USD annually for the drug component alone for the purified bovine product; a higher cost is expected for the recombinant product).

Thus, ERT is primarily a useful bridge to definitive therapy but is not a preferred choice for long-term therapy in most patients.

A retrospective study of nine patients treated with polyethylene glycol-modified bovine ADA (PEG-ADA) therapy (16 to 60 units/kg per week) for 5 to 12 years found lower than normal levels of T, B, and natural killer (NK) lymphocytes, as well as decreased in vitro T cell immune function, at most time points [59]. Specifically, the initial improvement in T cell numbers observed one to three years after treatment initiation was followed by a progressive decline to levels similar to those observed at the time of presentation. Despite this, immune globulin replacement therapy could be stopped in most patients, with only two requiring ongoing therapy, and no major infections were reported. Similarly, a retrospective longitudinal study comparing allogeneic HCT with PEG-ADA treatment revealed that ERT was associated with decline in circulating CD19+ lymphocytes [63]. Additionally, patients receiving ERT demonstrated abnormally low numbers of total lymphocytes and CD4+ T cells; decreasing or low proportions of T cells containing T cell receptor excision circles, which is a measurement of thymic function; and progressive narrowing of T cell repertoires.

There are a few reports of patients who have received PEG-ADA for prolonged periods since the first year of life. One patient who had received PEG-ADA for more than 24 years was described as being in good clinical health with adequate numbers of lymphocytes, normal quantitative immunoglobulin levels (immunoglobulin G [IgG], IgA, and IgM), and protective antibody titers to tetanus, although the patient did have several invasive infections in the first decade of life and membranous glomerulonephritis at 18 years of age [64]. The patient's lymphocytes demonstrated decreased viability, and the number of CD4+ T cells was reduced, yet the response of T cells to phytohemagglutinin (PHA) stimulation was normal. Another patient, treated with PEG-ADA for more than 25 years, suffered from recurrent oral candidiasis, persistent molluscum contagiosum, and invasive biopsy-proven gastrointestinal Mycobacterium genavense infection, Guillain-Barré syndrome, and extranodal lymphoma [62].

HCT with other donor types — Full immune reconstitution with alternative donors, such as HLA-matched URDs or HLA-haploidentical donors, is less likely, and survival is relatively poor. In a large, multicenter study, overall survival was 66 percent for URDs and 43 percent for haploidentical donors [20]. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Hematopoietic cell transplantation (HCT) with unmodified grafts from HLA-incompatible donors invariably result in fatal graft-versus-host disease. However, recipient cytoablation prior to transplantation and graft manipulation to remove mature T cells to limit the risk of graft-versus-host reaction increase the morbidity in the pre-engraftment period. Despite advances that have allowed for successful transplantation with haploidentical stem cells from which postthymic T cells were removed, the three-year survival rate for patients with ADA deficiency after HLA-mismatched and haploidentical transplants is still lower than with MSDs or MFDs [20,57]. An alternative strategy aiming to target alloreactive activated T cells using post-HCT cyclophosphamide was used in one patient [65]. For haploidentical transplantation, parental donors are preferable over other family members [66,67]. (See "Donor selection for hematopoietic cell transplantation".)

Engraftment of donor cells and onset of T cell production usually take considerably longer with haploidentical transplants than with HLA-identical transplants. Functional T cells may take four to seven months to appear, and engraftment may be incomplete. B cell production may take years to begin, and, in many cases, the B cells remain of host origin, leading to lifelong requirement of immune globulin replacement.

TREATMENT IN PATIENTS WHO FAIL FIRST DEFINITIVE THERAPY — If the initial definitive gene therapy or hematopoietic cell transplantation (HCT) fails, the options are to repeat the same therapy or choose the alternative [4]. Enzyme replacement therapy (ERT) is usually restarted until definitive therapy is attempted again. A second matched sibling donor/matched family donor (MSD/MFD) HCT may require a different donor or adding conditioning to the preparative regimen. The possibility of repeat lentiviral gene therapy has not been investigated. Repeat gene therapy is also potentially challenging because the chemotherapy that is now considered an essential component of the conditioning can have a negative effect on the hematopoietic stem cells in the bone marrow, making them unusable as a donor source for second attempt at gene therapy. Such concerns also apply for gene therapy after haploidentical or unrelated donor (URD) HCT, but not after nonconditioned MSD or MFD HCT.

ADDITIONAL MANAGEMENT FOR ADA-SCID — General measures specific to patients with ADA-severe combined immunodeficiency (SCID) may include the following:

Patients who develop Omenn syndrome [68] or significant autoimmunity [69] may benefit from glucocorticoids or other immunosuppressive medications until definitive therapy is commenced. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Patients with respiratory abnormalities should undergo extensive assessments for the possibility of infectious or noninfectious etiologies as the findings will help target therapies. Management of alveolar proteinosis, which is often seen in patients with ADA deficiency [23], may include ADA enzyme replacement therapy (ERT) for metabolic detoxification, oxygen supplementation, whole lung lavage, or recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) (see "Pulmonary alveolar proteinosis in children"). Pulmonary macrophage transplantation was beneficial in an animal model of ADA deficiency [70].

Neurodevelopmental [67,71,72] and hearing [73] abnormalities are reported at increased frequency in ADA-SCID. Early diagnosis and supportive treatments, educational interventions, and possible avoidance of neuro- and ototoxic medications may benefit these patients.

TREATMENT OF MILDER FORMS OF ADA DEFICIENCY — Limited information is available on the treatment of patients with milder forms of ADA deficiency. Antibiotic prophylaxis and immune globulin replacement therapy should be given to patients with abnormal immune function. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

These patients are typically treated with enzyme replacement therapy (ERT), at least initially [18,74,75], yet patients may eventually suffer from severe infections and lung disease [76,77]. As hematopoietic cell transplantation (HCT) at older age is associated with greater morbidity and mortality [78], and as ADA gene therapy at older age is associated in some studies with increased failure rate [42,45], it is important to consider definitive treatments as early as possible, even in milder forms of ADA deficiency. The decision to pursue definitive treatment with a preferable HCT donor or gene therapy is influenced by the ability of ERT to achieve sustainable immune reconstitution as well as the patient's and caregiver's therapeutic goals.

EXPERIMENTAL THERAPIES

Carrier erythrocyte encapsulated ADA therapy – The efficacy of enzyme replacement therapy (ERT) with polyethylene glycol-modified bovine ADA (PEG-ADA) may be reduced by anti-ADA neutralizing antibody formation. Carrier erythrocyte encapsulated ADA therapy has been suggested as an alternative means of administering ADA. In one study, autologous red blood cells (RBCs) were loaded with ADA using a hypo-osmotic dialysis procedure [74]. The encapsulated ADA was protected from antigenic stimulation and resulted in sustained therapeutic activity when administered in two to three weekly intervals in one patient.

Inhibition of deoxynucleoside kinases – Studies in a chimeric human/mouse fetal thymic organ culture model of ADA deficiency revealed that the effects of ADA inhibition were reversible by treatment with two deoxynucleoside kinase inhibitors [79]. Experimental treatment with a deoxycytidine kinase inhibitor alone in two children with ADA deficiency did not provide clinical benefit [80], and this strategy has not been pursued.

Thymic and fetal liver grafts – Thymic and fetal liver grafts to treat ADA deficiency have been attempted in the past but are not used due to lack of success. A marked increase in T cell percentages and in vitro lymphocyte mitogenic responses was noted in one patient following a fetal liver transplant and two thymic epithelial transplants [81]. An initial biopsy of the transplant showed engraftment with an actual increase in the graft dimensions and a decrease in serum adenosine and deoxyadenosine levels. However, all reconstituted immune parameter disappeared several weeks later, and the graft was rejected. Similar disappointing results were reported using cultured thymic epithelia [82]. The availability of a thymic tissue-based regenerative therapy, such as RVT-802, approved by the US Food and Drug Administration (FDA) in 2021, may provide a better option to combine gene therapy or hematopoietic cell transplantation (HCT) with thymus regenerative capacities.

NATURAL HISTORY AND PROGNOSIS — The prognosis of patients with ADA deficiency is influenced by many factors, including the degree of residual ADA enzyme activity, the patient's age at the time of diagnosis and treatment, the presence of infections and noninfectious complications, irreversible organ damage, the ability to prevent infections, and the availability of treatment.

Patients with mutations that completely disrupt the ADA gene and result in ADA-severe combined immunodeficiency (SCID) have the worst prognosis and usually die in infancy without appropriate therapy. The prognosis for those diagnosed later in life with a milder phenotype due to less deleterious ADA gene mutations is better. However, many will eventually suffer from lethal infections, autoimmunity, and malignancies in the first or second decade of life, and only a small minority of these patients will survive into adulthood.

The prognosis of patients receiving definitive treatment is constantly improving due to earlier diagnosis as well as improved hematopoietic cell transplantation (HCT) and gene therapy techniques. Based upon retrospective reports of more than 40 years of experience, HCT using a matched sibling donor (MSD) or matched family donor (MFD) was associated with 5 percent mortality and 10 to 20 percent failure to achieve normal immunity [4]. For gene therapy, data from compiled studies with up to 17 years of experience indicated no mortality and 5 to 20 percent procedure failure rate [4].

The morbidity, including engraftment failure, and mortality rates for patients with ADA-SCID receiving haploidentical or unrelated donor (URD) HCT are higher, although precise values have not been determined. The predicted long-term survival for patients treated only with enzyme replacement therapy (ERT) was 78 percent in one series [2]. However, the majority of patients demonstrated waning immunity that might eventually lead to lethal infections, autoimmunity, and malignancies. Some of the noninfectious complications associated with ADA deficiency, including bone dysplasia, alveolar proteinosis, and liver abnormalities, improve with definitive treatments and ERT. In contrast, the effects on neurologic dysfunction may depend upon the timing of treatment and the extent of irreversible tissue damage.

Spontaneous "cure" of ADA deficiency due to revertant somatic mosaicism has been rarely observed [83-85]. In a case report, a healthy young adult had a history of life-threatening infections, lymphopenia, and failure to thrive as an infant [83]. A B cell line established in infancy lacked ADA activity and had a heteroallelic splice-donor-site mutation and a missense mutation leading to Arg110Gln. The B cell messenger ribonucleic acid (mRNA) carried the missense mutations. However, a B cell line established at the age of 16 years expressed 50 percent of normal ADA activity, and 50 percent of the ADA mRNA had the missense mutation while the other 50 percent was normal, suggesting that a somatic mutation or a reversal of the site mutation had occurred. Although rare, the cases of spontaneous reversion of ADA gene mutations associated with some immunologic recovery demonstrate the strong selective advantage of ADA replete lymphocytes that may play a role in immune reconstitution after nonconditioned sibling HCT or gene therapy using only reduced-intensity conditioning. (See 'Preferred definitive therapy for ADA-SCID' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Overview – Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID), as with all forms of SCID, is fatal in the first year or two of life without treatment. Early diagnosis and treatment minimize complications and improve outcomes. Thus, all patients should begin treatment as soon as the diagnosis is established. Initial treatment includes general protective measures as well as disease-specific therapy. (See 'Immediate management of ADA-SCID' above and "Severe combined immunodeficiency (SCID): An overview", section on 'Initial management'.)

Initial treatment with enzyme replacement therapy – We suggest treating all infants with newly diagnosed ADA-SCID with enzyme replacement therapy (ERT) as an immediate stabilizing measure (Grade 2C). ERT improves clinical status, helps restore immune function, and may also help prevent damage to other tissues and organs prior to definitive therapy. It is particularly important if a preferred definitive therapy is not quickly available. (See 'Stabilization/bridge therapy with enzyme replacement therapy' above.)

Preferred definitive therapy – Cure is possible with definitive therapy, which includes gene therapy and hematopoietic cell transplantation (HCT). We recommend gene therapy or HCT with a matched sibling donor (MSD) or matched family donor (MFD), if available, for infants with ADA-SCID (Grade 1B). (See 'Preferred definitive therapy for ADA-SCID' above.)

Alternatives to preferred definitive therapy – If neither gene therapy nor an MSD or MFD for HCT is available, treatment options include continued ERT with ADA enzyme conjugated to polyethylene glycol (PEG-ADA) or HCT with a haploidentical (half-matched) related donor or a matched or mismatched unrelated donor (URD). Availability of preferred therapy should be periodically reassessed as clinical outcomes appear to be inferior with these alternative treatment options. (See 'Alternatives to preferred definitive therapy' above.)

Treatment approach in patient who fail initial definitive therapy – If the initial definitive therapy (gene therapy or HCT) fails, the options are to repeat the same therapy or use an alternative [4]. Patients are usually restarted on ERT while the approach is decided. (See 'Treatment in patients who fail first definitive therapy' above.)

Treatment for delayed- or late-onset or partial ADA deficiency – The choice of therapy for patients with delayed- or late-onset forms or for those with partial ADA deficiency depends upon the extent of ADA deficiency and symptomatology. These patients are typically treated with ERT, at least initially. (See 'Treatment of milder forms of ADA deficiency' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arye Rubinstein, MD, who contributed as an author to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3910 Version 26.0

References

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