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Long term outcomes of severe combined immunodeficiency: therapy implications.

ABSTRACT: Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has improved following hematopoietic stem cell transplantation (HCT) with the best outcomes seen following use of a matched sibling donor. However, questions remain regarding the optimal alternative donor source, appropriate use of conditioning and the impact of these decisions on immune reconstitution and other late morbidities. Areas covered: The currently available literature reporting late effects after HCT for SCID and use of alternative therapies including enzyme replacement, alternative donors and gene therapy are reviewed. A literature search was performed on Pubmed and ClinicalTrials.gov using key words 'Severe Combined Immunodeficiency', 'SCID', 'hematopoietic stem cell transplant', 'conditioning', 'gene therapy', 'SCID newborn screening', 'TREC' and 'late effects'. Expert commentary: Newborn screening has dramatically changed the clinical presentation of newborn SCID. While the majority of patients with SCID survive HCT, data regarding late effects in these patients is limited and additional studies focused on genotype specific late effects are needed. Prospective studies aimed at minimizing the use of alkylating agents and reducing late effects beyond survival are needed. Gene therapy is being developed and will likely become a more commonly used treatment that will require separate consideration of survival and late effects.

SUBMITTER: Heimall J

PROVIDER: S-EPMC6019104 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Long term outcomes of severe combined immunodeficiency: therapy implications.

Heimall Jennifer J Cowan Morton J MJ

Expert review of clinical immunology 20170923 11

<h4>Introduction</h4>Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has improved following hematopoietic stem cell transplantation (HCT) with the best outcomes seen following use of a matched sibling donor. However, questions remain regarding the optimal alternative donor source, appropriate use of conditioning and the impact of these decisions on immune reconstitution and other ...[more]

PMID: 28918671

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Project description:The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Project description:The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.

Project description:Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for ~7.5 months to clear the infection. Stool samples (collected 2013-2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histo-blood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. In conclusion, long term infection with norovirus in a patient with severe CVID led to the evolution of a unique norovirus strain with amino acid substitutions in immunodominant epitopes, but conservation within HBGA binding pockets. Regularly administered SCIg, IVIg, and ~7.5-month ribavirin treatment failed to clear the infection.

Project description:BackgroundThe long-term effect of coronavirus disease 2019 (COVID-19) acute treatments on postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is unknown. The CONTAIN-Extend study explores the long-term impact of COVID-19 convalescent plasma (CCP) therapy on postacute sequelae of SARS-CoV-2 infection (PASC) symptoms and general health 18 months following hospitalization.MethodsThe CONTAIN-Extend study examined 281 participants from the original CONTAIN COVID-19 trial (CONTAIN-RCT, NCT04364737) at 18 months post-hospitalization for acute COVID-19. Symptom surveys, global health assessments, and biospecimen collection were performed from November 2021 to October 2022. Multivariable logistic and linear regression estimated associations between the randomization arms and self-reported symptoms and Patient-Reported Outcomes Measurement Information System (PROMIS) scores and adjusted for covariables, including age, sex, race/ethnicity, disease severity, and CONTAIN enrollment quarter and sites.ResultsThere were no differences in symptoms or PROMIS scores between CCP and placebo (adjusted odds ratio [aOR] of general symptoms, 0.95; 95% CI, 0.54-1.67). However, females (aOR, 3.01; 95% CI, 1.73-5.34), those 45-64 years (aOR, 2.55; 95% CI, 1.14-6.23), and April-June 2020 enrollees (aOR, 2.39; 95% CI, 1.10-5.19) were more likely to report general symptoms and have poorer PROMIS physical health scores than their respective reference groups. Hispanic participants (difference, -3.05; 95% CI, -5.82 to -0.27) and Black participants (-4.48; 95% CI, -7.94 to -1.02) had poorer PROMIS physical health than White participants.ConclusionsCCP demonstrated no lasting effect on PASC symptoms or overall health in comparison to the placebo. This study underscores the significance of demographic factors, including sex, age, and timing of acute infection, in influencing symptom reporting 18 months after acute hypoxic COVID-19 hospitalization.

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Long term outcomes of severe combined immunodeficiency: therapy implications.

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Long term outcomes of severe combined immunodeficiency: therapy implications.

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