INTRODUCTION — The predominant clinical consequence of severe combined immunodeficiency (SCID) is an increased frequency and severity of infection, often opportunistic in nature, resulting in death in the first year of two of life. Several medical therapies have provided dramatic improvements in life expectancy and quality of life for patients with a primary immunodeficiency. However, allogeneic hematopoietic cell transplantation (HCT) remains the primary curative treatment of choice for typical SCID (table 1) . Gene therapy is an alternative option for certain forms of SCID.
The molecular pathophysiologies of most of the disorders underlying SCID are now defined (table 1), including some other gene variants associated with combined defects that may be as profound as SCID, such as cartilage-hair hypoplasia (RMRP defects) and immunodeficiency with multiple intestinal atresias (TTC7A defects) (table 2). There is increasing recognition of atypical forms of SCID that are either due to hypomorphic mutations in otherwise typical SCID genes or due to mutations in genes that inherently produce a less profound immunologic defect . Atypical SCID includes both leaky SCID, characterized by diminished, but not absent, T cell number and function, as well as Omenn syndrome, characterized by dysregulated T cells and autoimmune features . Untreated patients with leaky SCID may live longer than patients with typical SCID. However, ultimately, they also require allogeneic HCT to prevent sequelae from opportunistic infections . Infants with Omenn syndrome require immunosuppression and urgent HCT [5,6]. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)
This topic reviews aspects of HCT specific to patients with SCID. HCT for non-SCID primary immunodeficiencies is reviewed separately. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)
Numerous topics discuss other aspects of HCT:
The general aspects of medical therapy for immunodeficiency, including therapy with immune globulin, prophylactic antimicrobials, biologic therapies, vaccination recommendations, and gene therapy, are also discussed separately:
GENOTYPES AND HCT — The vast majority of SCID cases arise from mutations in genes expressed in hematopoietic stem cells (HSCs) or in the downstream progenitors of mature immune cells. As such, replacement of defective HSCs through allogeneic HCT permits the development of a functional immune system and may provide a complete cure for SCID . However, certain subtypes of SCID arise from genetic defects that also have effects in nonhematopoietic cells, which are not corrected by allogeneic HCT. In addition, the genetic etiology of 5 to 10 percent of SCID cases is undetermined, although whole-exome sequencing has begun to identify novel genes responsible for SCID phenotypes [8-10]. Some of these unknown-genotype patients may have defects in thymus-supporting genes , which may be less amenable to correction via allogeneic HCT and may explain poorer survival of these patients in some series . (See 'Genotype-specific considerations' below.)
Gene sequencing can diagnose most cases of SCID [10,13]. In the modern era, over 90 percent of patients who proceed to HCT are genetically characterized . Knowing whether the mutation is new (ie, sporadic) or inherited allows accurate genetic counseling and prenatal testing in the case of future pregnancies. This information permits parents to choose to terminate pregnancies that are affected or have a high risk of being affected with a particular defect. For pregnancies that are continued, in utero testing permits preparation for HCT in the early neonatal period or possibly in utero, although the last option remains highly experimental. Banking cord blood is an option for families with a known history of SCID, either for potential use in future gene therapy if the infant is affected or for future transplant of an existing or future affected sibling if the infant is unaffected. (See 'In utero transplantation' below and "Collection and storage of umbilical cord blood for hematopoietic cell transplantation".)
FACTORS ASSOCIATED WITH IMPROVED SURVIVAL — Survival rates for patients with SCID who undergo HCT have continued to improve due to early identification through newborn screening (NBS) or by genetic testing for a known defect when there is a family history, the availability of an increasing pool of matched unrelated donors (URDs; especially for those belonging to ethnic groups with human leukocyte antigen [HLA] types not well represented in donor banks), advances in the methods of preparing hosts and donor stem cells (especially haploidentical parental and sibling cells), and improved supportive and adjuvant therapies [4,14,15]. In the modern era, survival rates for patients with SCID are as high as 90 percent following HCT, with noninfected patients having survival of 95 percent , though certain SCID genotypes may continue to have worse outcomes. (See "Donor selection for hematopoietic cell transplantation" and "Preparative regimens for hematopoietic cell transplantation" and "Evaluation for infection before hematopoietic cell transplantation" and "Hematopoietic support after hematopoietic cell transplantation" and "Prevention of graft-versus-host disease" and 'Genotype-specific considerations' below.)
Early identification — Historical experience clearly indicates that the best outcome after HCT for SCID greatly depends upon the age at diagnosis and infection status of the patient [14,16-20]. The likelihood of post-HCT survival is improved for patients who have not yet developed any infectious complications of immunodeficiency or in whom infections have been successfully treated, although clearing infections may be challenging to accomplish in the absence of a functional immune system [4,14].
In one study, patients transplanted within the neonatal period (first 28 days of life) had improved survival compared with those who were transplanted later (95 versus 76 percent, respectively) . In another study, children transplanted before 3.5 months of age also had better long-term survival rates than those transplanted after that age (94 percent versus 70 percent) . Infants receiving HCT within the first 3.5 months of age also had significantly improved T cell development. A report summarized 240 infants with SCID who had undergone allogeneic HCT at multiple North American centers participating in the Primary Immune Deficiency Treatment Consortium (PIDTC), a National Institutes of Health (NIH) funded Rare Disease Network . Survival at five years post-HCT was high regardless of donor type among infants transplanted at ≤3.5 months of age (94 percent) and among older infants who had not yet developed infection (90 percent) or whose infections had been successfully treated (82 percent). In addition, patients identified at a very early age due to a previously affected sibling had superior outcomes .
Newborn screening — Early identification through NBS appears to play the greatest role in improving survival outcomes. In a 36-year, multicenter, longitudinal study of HCT in infants with SCID, children identified by NBS from 2010 to 2018 had a higher five-year overall survival (92.5 percent, 95% CI 85.8-96.1) compared with those identified by family history or clinical presentation during the same interval (79.9 [69.5–87.0] and 85.4 percent [71.8–92.8], respectively) . Multivariable analysis revealed that younger age and absence of active infection at the time of HCT, both of which are improved by identification through NBS, were the primary factors driving improvement in overall survival. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis'.)
As of 2022, all state NBS programs in the United States conduct NBS for SCID via measurement of T cell receptor excision circles (TRECs) in dried blood spots , and use of NBS is increasing outside of the US. Infants with SCID have very low or absent TRECs and can be identified by this means prior to onset of any infections. Upon diagnosis, such presymptomatic infants can be protected with immune globulin and prophylactic antimicrobials and promptly treated with allogeneic HCT to achieve optimal survival and immune reconstitution .
Limitations — However, early identification does not always guarantee that patients will remain infection free prior to HCT, since isolation practices differ from center to center, and cytomegalovirus (CMV) may be transmitted to the infant with SCID via breastfeeding during the first weeks of life before the diagnosis is confirmed. In addition, survival in patients with SCID diagnosed clinically following infectious presentations has improved over the years, presumably due to advances in anti-infective supportive care and transplant procedures. Furthermore, rare patients diagnosed by NBS are still at risk for death, either due to infections acquired before HCT or from HCT-related complications. (See 'Direct organ toxicity' below.)
One report from the PIDTC demonstrated that 42 percent of patients in North America diagnosed very early in life due to either NBS or a family history nonetheless developed at least one infection prior to transplant, with 76 percent of the infections occurring after the diagnosis was made and while awaiting HCT . In a cohort of patients transplanted from 2010 to 2014, identification of affected SCID infants with NBS did not improve overall survival compared with patients diagnosed clinically (primarily due to the presence of an opportunistic infection), but survival of all patients was better than in previously reported cohorts .
Other factors — Improvements in other factors, such as donor pools and selection, preparative regimens, and management of infections, are discussed below and in separate topics. (See 'Pretransplant considerations' below and 'Genotype-specific considerations' below and "Donor selection for hematopoietic cell transplantation" and "Preparative regimens for hematopoietic cell transplantation" and "Evaluation for infection before hematopoietic cell transplantation" and "Hematopoietic support after hematopoietic cell transplantation" and "Prevention of graft-versus-host disease".)
PRETRANSPLANT CONSIDERATIONS — The selection of an optimal donor for HCT for a patient with SCID is of critical importance since the other pretransplant decisions regarding stem cell source, conditioning, and graft-versus-host disease (GVHD) prophylaxis strategies are all dependent upon the type of donor and the genotype of the patient (when known) [1,23]. Human leukocyte antigen (HLA) matched related donors are preferred for HCT in patients with SCID, but most patients do not have a matched relative available . However, excellent survival is possible with any donor type if the HCT occurs in the first 3.5 months of life or before the onset of infection [4,14,16]. (See 'Genotype-specific considerations' below.)
Bone marrow was the original source of hematopoietic stem cells (HSCs) for HCT in patients with SCID. Stem cells can also be mobilized from bone marrow niches using agents such as the cytokine granulocyte-colony stimulating factor (G-CSF) and then harvested from peripheral blood by apheresis. HSCs can be obtained in large numbers using this mobilization method and apheresis, but donor cells obtained in this manner typically contain a one log-higher T cell dose and are associated with higher rates of GVHD unless some form of ex vivo T cell depletion is used. Umbilical cord blood (UCB) is another potential source of HSCs. (See "Sources of hematopoietic stem cells".)
Conditioning chemotherapy — SCID is unique amongst all diseases treated with HCT in that the requirement for pretransplant chemotherapy conditioning is controversial and is increasingly tailored to the specific gene defect and the type of donor. A consequence of absence of host T cells in SCID is that there is little or no resistance to incoming grafts for many SCID genotypes. Algorithms have been proposed to help guide decisions regarding conditioning [1,23]. Conditioning can be divided into agents that are mainly immunoablative (ie, cyclophosphamide, fludarabine, and serotherapy such as antithymocyte globulin [ATG] or alemtuzumab) and those that produce some degree of myeloablation or "hematopoietic stem cell space-making," depending upon the dose or exposure delivered (ie, busulfan, melphalan, treosulfan). Peripheral blood myeloid chimerism is a surrogate marker of bone marrow stem cell engraftment. Myeloablation can be further subdivided into regimens designed to completely destroy the host's bone marrow stem cells and replace them with donor cells and those intended to produce a state of stable mixed myeloid chimerism. The latter, often referred to as reduced-intensity conditioning (RIC), is expected to be less toxic in the short and long term compared with fully myeloablative regimens. In one series, survival four years after HCT was 94 percent in the RIC group compared with 58 percent in the myeloablative conditioning group . However, the precise amount of donor stem cells that need to engraft in the recipient's bone marrow for complete and sustained immunologic correction is not fully elucidated. The use of conditioning has resulted in better survival in some , but not all [4,14,20], cohorts.
Long-term reconstitution of B cell, as well as some aspects of T cell, immunity are influenced both by the genetic form of SCID as well as the degree of myeloid chimerism achieved by the conditioning regimens used [20,27,28]. Initial restoration of T cell function is successful for many genotypes of typical SCID without any myeloablation, regardless of donor type [16,17,29]. Specifically, myeloablative chemotherapy is typically unnecessary for T cell engraftment in patients with SCID with B cells (T cell-negative, B cell-positive [T-B+] SCID) such as is seen with defects in interleukin 2 receptor gamma (IL-2RG), Janus kinase 3 (JAK3), or interleukin 7 receptor (IL-7R) [29,30]. On the other hand, patients with SCID lacking B cells (T-B- SCID), such as is seen in patients with defects in recombination-activating gene (RAG) 1/2 or DNA cross-link repair protein 1C (DCLRE1C), have higher rates of T cell engraftment and long-term survival after some degree of myeloablation, although they are at risk for toxic effects of chemotherapy. Patients with leaky SCID and Omenn syndrome also generally require some degree of myeloablative chemotherapy to achieve multilineage engraftment [4-6]. (See 'Reconstitution of immune function' below and 'Long-term prognosis' below and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)
Graft-versus-host disease prophylaxis — Acute GVHD occurs when mature T cells are not entirely removed from the donor source and "contaminate" the graft. These cells may be activated by histocompatibility differences and inflammation and can then mount a cellular immune attack against host tissues . Use of conditioning appears to increase the risk of GVHD . GVHD can be minimized or prevented by processing the donor cells before infusion to remove mature T cells and by prophylactic immunosuppression following HCT. The preference for removing most mature T cells from the graft is a major distinction between stem cell transplantation for immunodeficiency and transplantation for malignancy. The antitumor effect of transferred human leukocyte antigen (HLA) incompatible mature T cells is potentially therapeutic in the setting of malignancy, while the alloreactive effect has no demonstrable benefit for patients with immunodeficiency beyond a difficult-to-measure graft-versus-marrow effect that theoretically might help achieve donor myeloid chimerism. (See "Prevention of graft-versus-host disease" and "Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) in adults", section on 'Graft-versus-leukemia' and "Prevention of graft-versus-host disease", section on 'Introduction'.)
Donor choice — HLA typing to evaluate potential donors should be performed on all available members of the patient's nuclear family as soon as a diagnosis of SCID is established. An HLA-identical sibling is the preferred donor, if available. Alternatives include a matched unrelated donor (URD), a haploidentical parent or other mismatched related donor (MMRD), or a UCB donor. (See "Human leukocyte antigens (HLA): A roadmap" and "Donor selection for hematopoietic cell transplantation" and "Evaluation of the hematopoietic cell transplantation donor".)
Matched related donor (MRD, genoidentical sibling) — Typically, HCT with an HLA-identical (genoidentical) sibling donor results in the most rapid and complete reconstitution of immune function in patients with SCID and carries the most favorable prognosis, with survival rates over 90 percent and approaching 100 percent in modern series [4,14-17,20,30,32-34]. Thus, this is the donor of choice. However, fewer than 20 percent of patients with SCID have an HLA-identical sibling. Outside of the setting of fraternal twins, asymptomatic matched siblings are typically older than the affected patient and therefore presumably unaffected. In addition, beyond a few very rare subtypes, most cases of SCID are autosomal recessive in nature, and there is no issue with haploinsufficiency in donors. Thus, no special screening of sibling donors is needed, although some centers will perform T cell phenotyping for additional confirmation of donor suitability.
Bone marrow is the preferred stem cell source with a matched sibling donor and may be infused without any processing to remove mature T cells. Pretransplant conditioning is not indicated for most patients with typical SCID receiving HLA-identical HCT from a sibling donor, although some have advocated for its use in certain genotypes, such as RAG1/RAG2 deficiency [4,14,32]. The risk of histocompatibility-associated GVHD is fairly low at approximately 25 percent for Grades II to IV and 5 percent for Grades III to IV [14,32]. Thus, some centers do not give pharmacologic GVHD prophylaxis in this setting. Theoretically, a graft-versus-marrow effect occurring in the absence of chemotherapy may help achieve donor myeloid engraftment, as is noted in almost 50 percent of matched sibling donor HCTs . Conversely, some centers elect to use short-term GVHD prophylaxis with matched sibling donors since patients who develop acute GVHD may have thymic damage that predisposes to the develop of chronic GVHD [35-37]. Thus, the question of whether to use GVHD prophylaxis for MRD HCT remains unanswered. (See 'Graft-versus-host disease' below.)
Some patients may also have nonsibling relatives who are HLA matched (also called a phenoidentical donor) because autosomal-recessive forms of SCID often occur in patients with constrained genetic diversity because of consanguinity or a limited ancestral population. In general, although data are sparse, it appears that outcomes are not as good in this setting as with matched sibling donors, perhaps due to differences in nontested minor histocompatibility antigens .
Mismatched related donor (MMRD, haploidentical parent or other) — Another donor option is an HLA MMRD, usually a haploidentical parent [4,14,16,17,30,38,39]. The prognosis following haploidentical HCT in SCID is slightly less favorable than that with HLA-identical sibling transplants but has significantly improved from past eras. Reported survival ranges are approaching 90 percent [4,15-17,40]. T cell function and cellular immunity typically recover within three to six months after transplantation with the use of T cell-depleted cells.
Both biologic parents have at least 50 percent identity ("haploidentical") with their offspring and may be suitable donors, although the mother is often preferred over the father because of the frequent persistence of maternally transferred lymphocytes detectable in the circulation of infants with SCID [14,41] (see "HLA-haploidentical hematopoietic cell transplantation", section on 'Non-inherited maternal HLA antigens'). Because it implies a state of tolerance to maternal cells, this transplacental maternal engraftment (TME) may facilitate engraftment of additional maternal stem cells. However, in one series, TME was not associated with improved survival or less need for second transplant . In addition, patients with TME had higher rates of post-HCT acute GVHD, possibly due to the presence of subclinical GVHD prior to HCT. The use of serotherapy in the conditioning regimen partially abrogated this risk .
There is not a uniform approach to the administration of conditioning when MMRDs are used, other than as noted below for specific genotypes (see 'Genotype-specific considerations' below), but it is under study in natural history protocols, such as those of the Primary Immune Deficiency Treatment Consortium (PIDTC) [4,14]. RIC regimens or immunoablative approaches are increasingly used to eliminate natural killer (NK) cells (when present) [4,14,38]. Historically, most centers performing MMRD transplants have used some form of ex vivo T cell depletion, but there are no uniform guidelines across all centers.
The development of methods for removing mature lymphocytes, but not stem cells, from hematopoietic cell grafts was a major breakthrough, permitting the use of HLA nonidentical donors with a drastically reduced rate of GVHD.
One early method used soybean lectin agglutination followed by rosetting with sheep red blood cells to remove mature B and T cells [16,17,43,44]. Another early method directly treated the donor bone marrow cells with the monoclonal antibody alemtuzumab and complement [29,30]. Mature lymphocyte numbers may also be significantly decreased by positively selecting for CD34+ hematopoietic progenitor cells on columns that bind these cells while mature T cells and other cells are then washed away. After release from the column, CD34-enriched cells are infused into the recipient . While all of these methods are no longer routinely practiced, they are important to be aware of when considering historical reports, including patients transplanted in prior decades.
Newer approaches to ex vivo T cell depletion negatively select out alpha-beta T cell receptor (TCR) T cells (and B cells), while leaving in gamma-delta TCR T cells and NK cells in order to provide some early protection from viral infections [46,47]. These ex vivo approaches can be performed on either bone marrow or peripheral blood stem cells (PBSCs). PBSCs are often used because very high cell doses can be achieved, which may speed T cell recovery .
Another approach under investigation is in vivo T cell depletion via infusion of unmodified bone marrow from an MMRD, followed several days later by killing T cells activated by the HLA-incompatibility differences with high-dose cyclophosphamide . This approach uses less specialized and costly resources than ex vivo T cell depletion strategies. However, it requires posttransplant pharmacologic GVHD prophylaxis, exposes infants to additional alkylating chemotherapy (with associated risk of late effects), and can produce a cytokine release syndrome . (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Proposed mechanisms'.)
Matched unrelated donor (URD) — A third donor option is a matched URD identified from among adult volunteers registered in the National Marrow Donor Program and other affiliated donor programs. URDs are a widely available source of HLA closely matched hematopoietic cells in the United States, particularly for White individuals. Molecular typing by DNA sequencing of histocompatibility genes, which has now replaced serologic typing, has led to better matches and a lower incidence of GVHD. (See "Donor selection for hematopoietic cell transplantation".)
Earlier surveys suggested that survival after URD HCT was lower than survival after HLA-identical sibling donor HCT. Subsequent data suggest that the survival rates are converging [4,14,50]. As an example, one study reviewed 94 patients with SCID who underwent various types of HCT at two centers between 1990 and 2004. Survival rates of patients with URD HCT were slightly lower than those of patients with HLA-identical donors (81 and 92 percent, respectively) . Similarly, URD recipients receiving no conditioning did worse than similarly treated HLA-matched sibling recipients, with five-year survival rates of 71 percent versus 92 percent .
Certain approaches may alter these survival rates. Patients in one study who received serotherapy (eg, antithymocyte globulin [ATG] or alemtuzumab) prior to URD HCT had 100 percent survival . However, selection of conditioning regimen may be confounded by other patient factors, such as concurrent infections or degree of HLA matching of available donors. In addition, most studies analyze survival by time from HCT, which introduces a bias in favor of patients receiving an HCT from an HLA-matched sibling, since it takes at least an additional month from the time of SCID diagnosis to locate a URD, during which time previous infections may worsen and additional infections may develop [14,38].
The best approach for transplanting cells from matched URDs has not been determined but is under study in the natural history protocols of the PIDTC [4,14]. Although patients with defects in IL2RG, adenosine deaminase (ADA), IL7R, and even the Artemis DCLRE1C may engraft URD T cells without significant chemotherapy exposure, some of these patients may continue to require immune globulin replacement because of poor B cell engraftment [32,51]. Nonmyeloablative or RIC regimens and serotherapy (antithymocyte globulin [ATG] or alemtuzumab) are increasingly used to eliminate NK cells and prevent infused donor lymphocytes from causing GVHD [4,14].
Umbilical cord blood donor (UCB) — UCB contains a relatively high concentration of HSCs and can be used unmodified as a source of HSCs for transplantation. (See "Collection and storage of umbilical cord blood for hematopoietic cell transplantation" and "Sources of hematopoietic stem cells", section on 'Umbilical cord blood'.)
One relatively large, retrospective comparison showed a similar rate of T cell engraftment and somewhat more GVHD in recipients of unrelated UCB donor HSC in comparison with MMRD transplantation . Five-year survival rates were similar for both groups (57 and 62 percent, respectively) . However, the PIDTC studies have consistently shown lower, albeit not statistically significant, overall survival with UCB grafts compared with MMRD or adult URD grafts (two-year overall survival 100, 96, 90, and 81 percent for MRD, MMRD, URD, and UCB donor transplants, respectively) [4,14]. The etiology of this lower survival is unclear but raises concerns that standard approaches to UCB HCT for other diseases may be suboptimal for patients with SCID and may require additional honing to make this an equally attractive option compared with MMRD or adult URD. Most patients receiving UCB HCT have received fairly intensive conditioning regimens, reflecting experience with high rejection rates in patients with other disorders undergoing this type of HCT. Careful attention to serotherapy dosing may improve UCB HCT outcomes .
RECONSTITUTION OF IMMUNE FUNCTION — Thymic T cell output is restored following HCT for SCID and peaks in one to two years. Recovery of B cell function is less consistent after HCT and does not occur in a substantial fraction of patients, especially if space-making chemotherapy conditioning is not administered.
T cells — Following HCT, T cell precursors develop from donor stem cells and repopulate the native thymus, a previously vestigial organ in patients with SCID. Thymic T cell development can be monitored by measuring T cell receptor excision circles (TRECs) in the blood. Newly formed T cells also display the "naïve" cell surface marker isoform of CD45RA. (See "Newborn screening for inborn errors of immunity", section on 'Overview of TREC screening test'.)
Timing of T cell reconstitution — It takes at least 12 to 16 weeks to generate new T cells from donor hematopoietic stem cells (HSCs). However, a few mature donor T cells derived from precommitted lymphoid progenitors may begin to appear in the circulation after approximately three to six weeks, with larger numbers developing subsequently . Mature T cells may appear even earlier, expanding two weeks after HCT in unconditioned infants with SCID who have received an unmanipulated human leukocyte antigen (HLA) identical graft from a family donor that contains mature T cells. Grafts from unrelated donors (URDs) and mismatched related donors (MMRDs) often take longer to show rising T cell numbers, probably due to the more stringent in vivo or ex vivo T cell depletion used to prevent graft-versus-host disease (GVHD). However, these expanding mature T cells may provide some immediate immune reconstitution, even before de novo generation of T cells from donor-derived stem cells occurs.
Biomarkers of long-term outcomes — Early recovery of absolute CD4 T cell counts and naïve (CD4/CD45RA+) T cell counts at 6 and 12 months predicts long-term survival . Patients with CD4 counts >500 or CD4/CD45 counts >200 had nearly 100 percent survival, while those with lower counts were at elevated risk for late mortality, suggesting that some such patients may benefit from preemptive repeat HCT to enhance T cell reconstitution. However, the optimal biomarkers for proposing a repeat HCT are not fully elucidated. Some candidates include T cell exhaustion markers and T cell receptor (TCR) beta repertoire .
Enhancement of T cell reconstitution — Some aspects of T cell reconstitution may be enhanced with the use of reduced-intensity or myeloablative conditioning . One study reported higher total CD3 counts and higher median CD4+CD45RA+ naïve helper T cell counts , while another also reported higher naïve T cell counts . However, many patients who did not receive conditioning also had excellent T cell counts. Additional research is needed to sort out which subsets of patients will do well without conditioning from those who definitively benefit from it in terms of immune reconstitution and survival.
Decline in T cell counts and function — Thymic T cell output peaks one to two years after HCT and begins to decline thereafter. In the optimal post-HCT state, T cell reconstitution (including thymic output, clonal diversity, and T cell function) is maintained long term at levels similar or equal to normal healthy controls . In individuals without a history of SCID, a decline in new T cell production in the thymus and in T cell function occurs progressively from birth up to age 80 years, after which age data are limited. T cell decline in transplanted patients with SCID, some of whom have now been followed for over 30 years, is often not associated with clinical deterioration or increased occurrence of infections. However, relatively few studies have assessed the very long-term durability of T cell function in patients with SCID post-HCT.
One such study of 83 patients from a single center who received unconditioned identical or haploidentical transplants showed a peak in thymic T cell output at one to two years posttransplant and then a decline over 14 years . However, a report nine years later of the same cohort with additional patients found that the decline in thymic T cell output seen initially was not observed to a greater degree in the 115 patients followed longer term than in age-matched control individuals . In other long-term follow-up studies previously discussed, T cell counts and function were stable over an approximately 15-year follow-up period [55,57]. In the latter studies, many transplants were preceded by myeloablation.
Mixed T cell chimerism — Some degree of mixed hematopoietic chimerism is common after HCT [4,14,16,29,30,58,59]. T cells are 90 to 100 percent donor derived in almost all cases of successful HCT for SCID. One exception is patients with natural killer cell-positive (NK+) SCID, who are more likely to have mixed T cell chimerism (mean donor T cells 78 percent in one series compared with 98 percent for NK- SCID) and poorer long-term recovery of CD4+ T cell immunity . This is probably because many patients with mutations in RAG1/2 are somewhat "leaky," allowing production of a small amount of dysfunctional host T cells if complete myeloablation is not achieved.
B cells — Recovery of B cell function is less consistent after HCT for SCID and does not occur in a substantial fraction of patients [4,14,16,28-30]. Pretransplant conditioning increases, but does not assure, the posttransplant development of B cell function [4,14]. For most genetic forms of SCID, particularly IL2RG- or JAK3-deficient T-B+NK- SCID and for T-B- SCID, there is no B cell function without engraftment of donor B cells, since host B cell function is intrinsically abnormal in X-linked and JAK3-deficient SCID and absent in T-B- SCID. However, B cells are intrinsically normal in SCID defects limited to the T cell lineage (eg, interleukin 7 receptor [IL-7R] deficiency; CD3 delta, epsilon, or zeta chain deficiencies; and CD45 deficiency). In these types of SCID, host B cells can produce protective antibodies when helper T cells are restored by HCT .
B cell function may take a few years to normalize and may never be sufficient to discontinue immune globulin replacement therapy, even if there is a significant fraction of donor B cells in the circulation. After HLA-identical HCT, the rate of reconstitution of B cell function is approximately 60 percent for T-B- SCID and 90 percent for T-B+ SCID (table 1) [30,32]. After MMRD HCT, the rate of reconstitution of B cell function is approximately 40 percent for T-B- SCID and 70 percent for T-B+ SCID . These rates depend upon the approach to conditioning used in terms of the amount of myeloid chimerism achieved.
Patients should be monitored for signs of donor B cell development over the first three to five years after HCT. Measurements of immunoglobulin A (IgA) and immunoglobulin M (IgM) antibody synthesis and specific IgM antibodies to isohemagglutinins are informative even in patients receiving immune globulin (IgG) replacement therapy. Monitoring should continue on a regular basis at least every few years even after B cell function is adequate to stop immune globulin replacement therapy because, in rare patients, B cell function may potentially deteriorate after a number of years, requiring reinstitution of immune globulin replacement therapy. (See "Immune globulin therapy in inborn errors of immunity" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)
COMPLICATIONS BEFORE AND AFTER HCT — Complications before, during, and following HCT include infections, toxicity from cytoreductive chemotherapy, graft rejection, graft-versus-host disease (GVHD), and posttransplant lymphoproliferative disease. The incidence of these adverse events varies with the type of HCT, conditioning regimen, and underlying disease.
Infections — Historically, in the absence of newborn screening (NBS), most infants with SCID had one or more pre-HCT infections, many of which were still active at the time of HCT or which may have resulted in death before HCT could be performed [4,14]. Many of the deaths that occur before or relatively soon after HCT are caused by infections that may have been acquired prior to transplantation [16,29,30]. (See "Evaluation for infection before hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Overview of infections following hematopoietic cell transplantation" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
The most common organisms include cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus. Additional important viral pathogens include respiratory syncytial virus, parainfluenza, enteroviruses, hepatitis viruses, and herpes simplex viruses . Chronic diarrhea due to norovirus has been seen in all types of SCID patients . Severe diarrhea can be caused by inadvertent administration of live-attenuated rotavirus vaccine to infants with SCID . Similarly, live polio vaccination has caused paralytic polio, and disseminated infection with Bacillus Calmette-Guérin (BCG), a live-attenuated mycobacterium related to Mycobacterium tuberculosis, is prominent in areas outside of the United States where this vaccine is routinely administered to newborns .
Active monitoring for viral infection/reactivation by polymerase chain reaction (PCR) is key to initiating preemptive treatment, particularly in patients with CMV or EBV infection prior to transplantation. Diagnosis by serologic testing is inappropriate since infants with SCID are unable to mount antibody responses and may have positive IgG titers reflecting maternally transferred or exogenously administered IgG.
One option for treatment of some viral infections (including CMV, EBV, and adenovirus) both pre- and post-HCT is adoptive transfer of virus-reactive T cells . This approach is used to reconstitute antiviral immunity with a low risk of inducing alloreactivity.
The various types of infections that commonly occur post-HCT, including viral, bacterial, and fungal infections, are discussed in greater detail separately. (See "Overview of infections following hematopoietic cell transplantation".)
Posttransplant lymphoproliferative disease — EBV-mediated posttransplant lymphoproliferative disease is a potential serious complication of HCT. The risk is greatest in EBV-inexperienced patients receiving an HCT with T cell depletion from a matched unrelated donor (URD) or human leukocyte antigen (HLA) mismatched related donor (MMRD) who has experienced past EBV infection . (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
Graft rejection — Graft rejection arises when sufficient immune function remains for the recipient to mount a cellular immune response against donor major and minor histocompatibility molecules. Many subtypes of SCID (such as IL2RG and JAK3 deficiencies) have extremely low risks of graft rejection, while others (especially leaky forms of RAG1/2 deficiency) are fully capable of rejecting donor cells via either small numbers of residual host T cells or functional natural killer (NK) cells. Rejection may be overcome by "conditioning" the host (immunoablation) with chemotherapy to destroy immunocompetent cells and by attempting major histocompatibility matching between donor and recipient. Immunoablation with chemotherapy is preferred over irradiation in patients with primary immunodeficiency because the use of irradiation for conditioning in infants and young children is associated with a greater potential negative impact on neurocognitive development . However, the optimal agents for immunoablation are not fully elucidated. As an example, fludarabine is commonly used to eliminate residual T cells but has limited effect on NK cells. When graft rejection does occur, it is typically managed with second transplant from either the original donor or a different donor . (See "Donor selection for hematopoietic cell transplantation" and "Preparative regimens for hematopoietic cell transplantation" and 'Conditioning chemotherapy' above and 'Donor choice' above.)
Direct organ toxicity — Significant morbidity and mortality may result from the pretransplant chemotherapy itself, especially when myeloablative agents are used. The most common myeloablative agent used in the United States is busulfan. Measurement of busulfan levels, with dose adjustment as needed so as not to exceed planned exposure levels, is advised since metabolism of busulfan can vary greatly, especially in young infants . Overexposure to busulfan is associated with high rates of hepatic sinusoidal obstructive syndrome (SOS) and transplant-related mortality, especially in very young children . In one study of 29 infants with SCID who received myeloablative conditioning, fatal SOS was seen in 7 percent of patients . In Europe, treosulfan has been increasingly used to replace busulfan since it appears to have lower risks of SOS . (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)
Unexplained pulmonary failure is also a common cause of death . The etiology of this is likely multifactorial, with possibilities including unrecognized infections due to detection failure with conventional testing , alloreactivity , and directly induced damage from conditioning agents .
Graft-versus-host disease — Despite methods noted above to prevent it (see 'Graft-versus-host disease prophylaxis' above), Grade II to IV acute GVHD still afflicts approximately 20 percent of patients with SCID, and approximately 8 percent develop severe Grade III to IV disease [4,14]. In addition, chronic GVHD, which can last for years and significantly impair quality of life, affects approximately 15 percent of patients with SCID posttransplant [4,14,57]. Acute and chronic GVHD may also be directly responsible for posttransplant mortality in approximately 2 percent of transplants [4,14]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)
Autoimmunity — Autoimmunity, particularly autoimmune hemolytic anemia, is another potential complication of HCT . It occurs more frequently after nonmyeloablative than myeloablative conditioning. The most common cause is the passenger lymphocyte syndrome, in which the donor B cells produce antibodies against the recipient's red blood cell antigens due to minor ABO blood group incompatibility. (See "Pretransfusion testing for red blood cell transfusion" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Transplantation'.)
LONG-TERM PROGNOSIS — The long-term prognosis of HCT for SCID has improved with advances in early diagnosis with newborn screening (NBS), high-resolution tissue typing, refinement and tailoring of conditioning regimens (especially for T cell-negative, B cell-negative [T-B-] SCID), use of reduced-intensity conditioning (RIC), depletion of donor lymphoid cells, supportive care, early detection and treatment of viral infections, and graft-versus-host disease (GVHD) management [4,14,29,57,74].
Late effects — Despite improved long-term prognosis, survivors of HCT are still at risk for the development of late effects of conditioning or its absence . One study in children less than two years of age at HCT (20 percent with congenital immunodeficiency) who received high-dose busulfan prior to an umbilical cord blood (UCB) transplant found that 98 percent had at least one significant late effect, including dental problems, short stature, cognitive deficits, pulmonary dysfunction, and abnormal pubertal development .
Detailed information was reported on the general medical and immunologic health of 40 children who were alive at least five years after HCT for severe T cell immunodeficiencies :
●Most had normal T and B cell numbers and function. However, recovery of B cell function was seen more consistently in patients who had received conditioning regimens prior to transplant, a finding that has been confirmed by the Primary Immune Deficiency Treatment Consortium (PIDTC) [14,20].
●Significant infections still occurred in 13 percent of patients after the first year posttransplant.
●Thirteen percent had short stature, and 18 percent were underweight.
●Endocrine abnormalities, most commonly autoimmune thyroid disease, occurred in 18 percent.
●Severe neurologic abnormalities were seen in 10 percent.
Longer-term follow-up in a larger cohort was reported in another study that retrospectively analyzed outcome after HCT in 90 patients with SCID followed for a median of 14 years (range 2 to 34 years) . At the time of the report, 71 percent of the 82 living patients did not require any form of treatment. However, nearly one-half of the 90 patients had experienced clinically significant issues at least two years after HCT. Risk factors for late complications included nongenoidentical donors and radiation-sensitive forms of SCID such as Artemis/DCLRE1C deficiency. These issues included:
●Late mortality (9 percent)
●Chronic GVHD (11 percent)
●Autoimmune and inflammatory complications (13 percent)
●Poor T or B cell reconstitution requiring a booster unconditioned or second conditioned HCT (12 percent)
●Chronic human papillomavirus infection (26 percent)
●Prolonged requirement for nutritional support (20 percent)
●Growth failure (15 percent)
Neurocognitive consequences — As long-term data become available, one emerging issue is that HCT in children with severe primary immunodeficiencies is associated with behavioral abnormalities and decreased neurocognitive function [12,34,74,77-79]. In one study, patients with severe primary immunodeficiencies who had undergone HCT had lower intelligence quotient (IQ) scores (85, 95% CI 81.0-90.0) than the population average (100) . They also had lower IQ scores compared with unaffected matched siblings (90 versus 118). Reasons for this are not proven but may include sequelae of infections that occurred during immune compromise, late effects of chemotherapy or irradiation used for conditioning, effects of prolonged hospitalization, and multisystem abnormalities.
In the absence of NBS for SCID, some infants have had encephalitis or meningitis as a presenting illness and suffer lasting sequelae from that infection or from other causes of anoxic brain injury  (see "Bacterial meningitis in children older than one month: Treatment and prognosis"). Children with SCID can also have extended periods of illness and prolonged hospitalizations with secondary social isolation. Late effects of chemotherapy (and, in earlier HCTs, radiation) are hard to tease out but are becoming better known in cancer patients.
Decreased cognitive function is a direct consequence of the genetic defect in some types of SCID. HCT does not correct associated nonhematopoietic abnormalities in primary immunodeficiencies in which expression of the defective gene is not restricted to the immune system. Thus, continued and progressive symptoms are observed posttransplant in these conditions. Examples include impaired cognitive function in patients with adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiencies and an increased rate of deafness in ADA deficiency . Impaired cognition is also seen in some patients with DNA ligase 4 deficiency and nonhomologous end-joining protein 1 (Cernunnos) deficiency (table 1). (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)
Improvements in overall survival and recognition that many SCID patients have significant late effects have led to questioning whether survival alone is a sufficient endpoint for studies evaluating post-HCT outcomes. One proposed endpoint is neurologic event-free survival, in which severe neurocognitive events are taken into account, although it fails to capture problems such as ongoing infections, requirement for intravenous immune globulin (IVIG), chronic GVHD, pulmonary damage, and other potential late effects of HCT . However, using this endpoint, it is clear that early diagnosis and HCT can potentially spare much of the severe neurocognitive events caused by devastating pre-HCT infections.
GENOTYPE-SPECIFIC CONSIDERATIONS — Due to the rarity of the disease, patients with combined defects in their T and B cells have traditionally been lumped into the general grouping of SCID and analyzed together. However, there is increasing recognition that different genotypes of SCID (table 1) may require different approaches to HCT and have distinct outcomes and complications [1,20]. Historically, broad groupings have been applied. As an example, data demonstrate that mortality appears to be higher in infants with natural killer-positive (NK+) SCID compared with NK- SCID (survival rates of 62 versus 87 percent, respectively, in one series) . Unfortunately, this sort of grouping obscures the fact that there are important biologic differences among the various genotypes that produce NK+ SCID. Studies are attempting to separately examine outcomes based upon actual genotypes so as to best understand the optimal approach to HCT for specific patients .
IL2RG and JAK3 — Patients with these genotypes have the lowest barrier to engraftment of donor cells because they typically lack both T cells and NK cells. Thus, these patients are often transplanted without any conditioning chemotherapy, regardless of donor source [32,81]. However, this typically results in a state of split chimerism, where there is only engraftment of donor T cells, while all other hematopoietic cells remain of host origin. These patients will typically continue to require lifelong gammaglobulin replacement if not conditioned, since the host B cells of patients with deficiencies in interleukin 2 receptor gamma chain (IL2RG) and Janus kinase 3 (JAK3) are intrinsically defective [28,55]. These patients also have higher reported rates of papillomavirus infections, which may be due to abnormal signaling in keratinocytes, a defect that is not corrected by HCT [55,57] or due to failure of NK cell development in unconditioned HCTs . (See "X-linked severe combined immunodeficiency (X-SCID)", section on 'Treatment' and "Severe combined immunodeficiency (SCID) with JAK3 deficiency", section on 'Hematopoietic cell transplantation'.)
ADA — Patients with adenosine deaminase (ADA) deficiency are unique in that a pegylated enzyme is available for replacement, which provides at least partial removal of excess purine intermediates that are toxic to lymphocytes, thereby restoring immunity. Thus, HCT is less urgent for these patients . The defect in purine metabolism appears to lead to inflammation (eg, elevated transaminases) and increased susceptibility to certain conditioning chemotherapies, which may translate to lower survival in patients receiving conditioning . However, these patients are potentially able to reject donor cells, especially if human leukocyte antigen (HLA) mismatched, since ADA deficiency rarely results in complete absence of lymphocytes . Outcomes following allogeneic HCT are worse for ADA patients compared with most other genetic subtypes in some , but not all , cohorts. Finally, a significant number of patients with ADA deficiency have long-term neurocognitive abnormalities that are not corrected by HCT. The risk factors for this are not fully understood . (See "Adenosine deaminase deficiency: Treatment and prognosis".)
RAG1/2 — Patients with defects in recombination-activating genes 1 and 2 (RAG1, RAG2) can present in a myriad of ways depending upon the degree that the specific mutation affects protein function. This can range from typical SCID missing most T and B cells to leaky SCID with some number of partially functional T cells to patients whose T cells have a propensity to being autoreactive, which manifests as Omenn syndrome . They have normal numbers of NK cells, which means their immune systems are fully capable of mediating rejection of donor cells, especially if they are class I HLA mismatched [18,39,60]. Hence, immunoablative conditioning is typically required except when a matched sibling donor is available. In addition, there are data suggesting that long-term T cell reconstitution and survival are improved when some degree of myeloablative conditioning is used . If conditioning is not used, these patients typically continue to have low to absent B cells and a need for long-term immune globulin replacement therapy . (See "T-B-NK+ SCID: Management", section on 'Hematopoietic cell transplantation'.)
Artemis (DCLRE1C) — Patients with defects in DNA cross-link repair protein 1C (DCLRE1C), also known as Artemis, fail to produce a critical component of the nonhomologous end joining complex, which is a minor component of the DNA repair system within all cells in the body. Thus, these patients have an increased sensitivity to ionizing radiation and alkylating chemotherapy, which manifests as a significantly increased risk of late effects when these agents are used [80,87]. Unfortunately, some degree of conditioning is often needed for optimal immune reconstitution and survival because these patients have fully functional NK cells, similar to patients with defects in RAG1/2 . Hence, these patients have the most urgent need for the development of novel "space-making" agents, which mediate their effects through a mechanism other than the creation of double-stranded DNA breaks. Serotherapy such as antithymocyte globulin (ATG) and alemtuzumab may potentially eliminate some NK cells , but NK cells appear to be resistant to killing by the nonalkylator fludarabine . Overall, survival for this subtype of SCID is worse than others . (See "T-B-NK+ SCID: Management", section on 'Hematopoietic cell transplantation'.)
IL7R, CD3 subunits, and CD45 — Patients with defects in interleukin 7 receptor (IL7R) present with both B cells and NK cells. The requirement for conditioning is less clear, despite the presence of NK cells (like patients with RAG1/2 SCID). In addition, the B cells of these patients are intrinsically functional when given adequate T cell support, unlike patients with defects in IL2RG or JAK3. Therefore, an unconditioned approach with split chimerism can potentially produce a complete recovery of both T and B cells . The published experience with CD3 subunit and CD45 defects is very sparse. However, they are expected to behave similarly to patients with IL-7R mutations . (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'Interleukin 7 receptor alpha chain (CD127) deficiency' and "Severe combined immunodeficiency (SCID): Specific defects", section on 'CD45 deficiency' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'CD3 deficiency'.)
Reticular dysgenesis — Mutations in mitochondrial adenylate kinase 2 (AK2) produce a severe form of SCID with agranulocytosis and sensorineural deafness. These patients require some degree of myeloablative conditioning in order to correct the agranulocytosis . (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'Reticular dysgenesis'.)
EXPERIMENTAL APPROACHES TO HCT — In addition to the conventional approaches to HCT noted above, as well as transplantation of autologous gene-corrected cells (see "Overview of gene therapy for inborn errors of immunity"), there are several experimental approaches worth noting.
Nonchemotherapy-based myeloablation — One approach used monoclonal antibody-based conditioning using anti-CD45 and alemtuzumab (anti-CD52) to eliminate host hematopoietic cells and immune cells, respectively, in combination with reduced doses of immunoablative chemotherapeutic agents . Such a regimen was used successfully in children with primary immunodeficiencies who were under one year of age, had pre-existing organ toxicity, and/or had DNA repair defects, all of which are factors associated with increased toxic side effects of alkylating agents such as busulfan used for conditioning, although achieved myeloid chimerism was quite variable.
An alternate approach uses a monoclonal antibody targeted to CD117 (c-kit), which in mouse models of SCID facilitates bone marrow stem cell engraftment (approximately 10 to 15 percent) . A humanized version of anti-CD117 is in clinical trials for patients with SCID. If anti-CD117 is unable produce a sufficient degree of donor hematopoietic stem cell (HSC) bone marrow engraftment or if the effect is not sustained, potential next steps are to combine it with an anti-CD47 (a "don't-eat-me" signal on HSCs) monoclonal antibody, which, in mouse SCID models, produces donor myeloid chimerism in the 45 to 60 percent range  or to conjugate it to a toxin . These approaches are predicted to have significantly less long-term organ toxicity than high-dose chemotherapy.
Domino transplantation — Domino transplantation refers to sequential transplantation in which a first affected sibling undergoes successful HCT and then acts as a functionally human leukocyte antigen (HLA)-matched donor for subsequent affected siblings. There is limited published experience with families with multiple children affected by immunodeficiency in which one child received a mismatched related donor (MMRD) transplant and then served as a bone marrow donor for another HLA-identical child [96,97]. Small reports suggest that there may be lower rates of graft-versus-host disease (GVHD) and more rapid immune reconstitution in the second child using this approach. The primary recipient may tolerize and functionally HLA match the original HLA-mismatched donor cells.
In utero transplantation — In utero hematopoietic cell transplantation (IUHCT) has been performed in an attempt to reduce the possibility of graft rejection by taking advantage of the immunologic immaturity of the fetus [98-103]. However, IUHCT is controversial since fetal loss is possible. In addition, it is not clear that outcomes are superior to what is routinely achieved when infants are diagnosed with SCID in the neonatal period and protected from infections while awaiting HCT and immune reconstitution [17,104]. Furthermore, split chimerism is common with IUHCT for SCID, with generally only T cells engrafting . Thus, it may be best to wait to test, diagnose, and treat in the newborn period if termination of a potentially affected pregnancy is not under consideration.
The first IUHCT for X-linked SCID was performed in 1995 . Paternal bone marrow cells were enriched for HSCs and infused into the fetus intraperitoneally in utero at 16, 17, and 18 weeks of gestation . The infant was born at term and appeared healthy, with normal cellular and humoral immune function at 11 months of age. IUHCT has been performed for other forms of SCID, including T cell-negative, B cell-positive, natural killer cell-positive (T-B+NK+) SCID due to IL7R deficiency and T-B-NK+ SCID due to recombination-activating gene (RAG) mutations . Findings in a mouse model of X-linked SCID suggest that more rapid and sustained B and T cell reconstitution is achieved with IUHCT using lymphoid-primed multipotent progenitors rather than HSCs .
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)".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")
●Hematopoietic cell transplantation for severe combined immunodeficiency – Hematopoietic cell transplantation (HCT) is the only potentially curative, nonexperimental therapy available for patients with severe combined immunodeficiency (SCID) (table 1). Although trials of gene therapy for several forms of SCID have produced promising results, none are US Food and Drug Administration (FDA) approved. (See 'Introduction' above and "Overview of gene therapy for inborn errors of immunity".)
●Survival – Early diagnosis through population-wide newborn screening (NBS) and early transplantation in the absence of infectious complications appear to improve HCT outcomes. Survival rates have also continued to improve due to advances in the methods of preparing hosts and donor cells and improvements in supportive and adjuvant therapies. (See 'Factors associated with improved survival' above and 'Genotypes and HCT' above.)
●Genotype and pretransplant considerations – Approaches to donor choice, stem cell source, graft-versus-host disease (GVHD) prophylaxis, and conditioning are increasingly driven by the underlying genotype. (See 'Pretransplant considerations' above and 'Genotype-specific considerations' above.)
●Reconstitution of immune function – Thymic T cell output is restored following HCT for SCID and peaks in one to two years. Recovery of B cell function is less consistent after HCT and does not occur in a substantial fraction of patients, especially if chemotherapy conditioning is not administered. (See 'Reconstitution of immune function' above.)
●Complications – Complications following HCT include infections, posttransplant lymphoproliferative disease, graft rejection, direct organ toxicities, GVHD, and autoimmunity. The incidence of these adverse events varies with the type of HCT and underlying disease. (See 'Complications before and after HCT' above.)
●Long-term prognosis – The long-term prognosis of HCT for primary immunodeficiency has improved, but challenges remain. Children with SCID post-HCT may be predisposed to decreased neurocognitive function and behavioral abnormalities. In addition, HCT does not correct associated nonhematopoietic abnormalities in primary immunodeficiencies in which expression of the defective gene is not restricted to the immune system. (See 'Long-term prognosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, 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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