Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency that is universally fatal in infancy unless immune reconstitution is achieved by hematopoietic stem ...cell transplantation, gene therapy, or enzyme replacement. Published long-term clinical follow-up is limited for transplanted patients with SCID.
To characterize the long-term outcomes of patients with SCID treated at a single center.
We examined the clinical outcomes of 177 successive SCID infants given allogeneic bone marrow over 38 years without pretransplant chemotherapy or post-transplant graft-versus-host disease prophylaxis. A total of 90% received T-cell-depleted haploidentical parental marrow. Clinical status was assessed by questionnaires delivered by mail or electronically. Molecular type of SCID, demographics, and type, date and age of transplant were obtained from a database.
Eighty-eight questionnaires were completed for survivors ranging in age from 2 to 38 years. Survival remained higher in those transplanted before 3.5 months of age. Half of the cohort remained on immunoglobulin replacement. Health conditions reported included rashes, anxiety, depression, warts, and mouth ulcers. Most reported that these were transient, self-resolving issues. Attention-deficit/hyperactivity disorder, warts, and learning disabilities were reportedly more prevalent than in the general population. Most reported having no active concerns about their health. We found substantial scholastic achievement, with half of adult patients reporting college attendance. Most patients had a healthy body mass index.
Overall, our findings are consistent with those in the last update in 2009 in this population. Age at transplant remains a key variable in survival.
Objective To determine long-term health benefits of nonablative bone marrow transplantation for severe combined immunodeficiency (SCID), we investigated our cohort of 161 related donor bone ...marrow–transplanted patients with SCID. Only 16 (10%) had HLA-identical donors. Study design All 124 survivors were sent questionnaires about their current clinical statuses. Details from clinic visits were also compiled. One hundred eleven patients (90%) were reached. We compared outcomes of patients transplanted before and after 3.5 months of life and by molecular defect. Results The overall survival rate was 77%, but the rate for the 48 infants transplanted in the first 3.5 months of life was 94%, compared with 70% for the 113 transplanted after 3.5 months ( P = .002). Twenty-eight (76%) of the 37 deceased patients died of viral infections present at diagnosis. One or more clinical problems were reported to have been present in the past 2 years in 71 (64%) of the survivors, although 95 (86%) were considered healthy by their families. Conclusions Most patients with SCID transplanted with related donor marrow without pretransplant chemotherapy have done well in the long term, but those transplanted at <3.5 months of age had a superior survival rate, a lower rate of clinical problems, less need for booster transplants, and better nutritional status.
Background Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. ...Objective We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. Methods We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n = 37) or MSDs (n = 66). Results Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P < .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versus-host disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients ( P < .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P < .001). Conclusion Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy.
Interactions between oceanic and atmospheric processes within coral reefs can significantly alter local-scale (< km) water temperatures, and consequently drive variations in heat stress and bleaching ...severity. The Scott Reef atoll system was one of many reefs affected by the 2015–2016 mass coral bleaching event across tropical Australia, and specifically experienced sea surface temperature anomalies of 2 °C that caused severe mass bleaching (> 60%) over most of this system; however, the bleaching patterns were not uniform. Little is known about the processes governing thermodynamic variability within atolls, particularly those that are dominated by large amplitude tides. Here, we identify three mechanisms at Scott Reef that alleviated heat stress during the marine heatwave in 2016: (1) the cool wake of a tropical cyclone that induced temperature drops of 1.3 °C over a period of 8 days; (2) air–sea heat fluxes that interacted with the reef morphology during neap tides at one of the atolls to reduce water temperatures by up to 2.9 °C; (3) internal tidal processes that forced deeper and cooler water (up to 2.7 °C) into some sections of the shallow reefs. The latter two processes created localized areas of reduced temperatures that led to lower incidences of coral bleaching for parts of the reef. We predict these processes are likely to occur in other similar tide-dominated reef environments worldwide. Identifying locations where physical processes reduce heat stress will likely be critical for coral reefs in the future, by maintaining communities that can help facilitate local recovery of reefs following bleaching events that are expected to increase in frequency and severity in the coming decades.
Identification of the molecular etiologies of primary immunodeficiencies has led to important insights into the development and function of the immune system. We report here the cause of combined ...immunodeficiency in 4 patients from 2 different consanguineous Qatari families with similar clinical and immunologic phenotypes. The patients presented at an early age with fungal, viral, and bacterial infections and hypogammaglobulinemia. Although their B- and T-cell numbers were normal, they had low regulatory T-cell and NK-cell numbers. Moreover, patients' T cells were mostly CD45RA+-naive cells and were defective in activation after T-cell receptor stimulation. All patients contained the same homozygous nonsense mutation in IKBKB (R286X), revealed by whole-exome sequencing with undetectable IKKβ and severely decreased NEMO proteins. Mutant IKKβ(R286X) was unable to complex with IKKα/NEMO. Immortalized patient B cells displayed impaired IκBα phosphorylation and NFκB nuclear translocation. These data indicate that mutated IKBKB is the likely cause of immunodeficiency in these 4 patients.
•A nonsense mutation in IKBKB caused the absence of IKKβ and a lack of T- and B-cell activation through their antigen receptors.•IKKβ is not necessary for development of T or B lymphocytes but is important for their activation and for the development/function of NK cells.
We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and ...immunodeficiency.
We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.
All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).
Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)
Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular ...genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.
Purpose
Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified ...(PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi.
Methods
We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data.
Results
Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2–3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred.
Conclusion
Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.
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