J Clin Immunol. 2021 Jun 8. doi: 10.1007/s10875-021-01068-6. Online ahead of print.
NO ABSTRACT
PMID:34101091 | DOI:10.1007/s10875-021-01068-6
Powered by WPeMatico
Stanford Alliance for Primary Immunodeficiency
Stanford University
By Manish Butte
J Clin Immunol. 2021 Jun 8. doi: 10.1007/s10875-021-01068-6. Online ahead of print.
NO ABSTRACT
PMID:34101091 | DOI:10.1007/s10875-021-01068-6
Powered by WPeMatico
By Manish Butte
Immunol Invest. 2021 Jun 7:1-12. doi: 10.1080/08820139.2021.1933516. Online ahead of print.
ABSTRACT
Objective: Wiskott Aldrich Syndrome is an X-linked primary immunodeficiency disorder characterized by microthrombocytopenia, severe immunodeficiency, and eczema. To define clinical-laboratory features, genetic defects (known/novel) of 23 patients of Wiskott Aldrich Syndrome/X-linked Thrombocytopenia (WAS/XLT) cohort, establish relationships between molecular defects and clinical features if present, evaluate patients who underwent hematopoietic stem cell transplantation (HSCT) and did not.Methods: Qualitative analysis from patients’ hospital files and Sanger sequencing for molecular diagnosis was performed. Twenty-two WAS patients and one XLT patient were included in the study.Results: The median age of diagnosis was 15 months (2.5-172 months). The most common symptom was otitis media and all patients had microthrombocytopenia. Autoimmune findings were detected in 34.7% (8 patients) of the patients; three patients (13%) had positive anti-nuclear antibody (ANA), three patients (13%) hemolytic anemia, one patient autoimmune neutropenia, two patients vasculitis, and one patient demyelinating polyneuropathy. Nine of the 23 (39,1%) patients had HSCT with nearly 90% success. We identified 13 different mutations in our cohort; seven were novel.Conclusions: HSCT is the only curative treatment for WAS. The study confirms that early diagnosis is very important for the success of therapy, so we must increase awareness in society and physicians to keep an eye out for clues. Our study cohort and follow-up period are not sufficient to establish phenotype-genotype correlation, so a larger cohort from various centers with longer follow-up will be more decisive.
PMID:34098853 | DOI:10.1080/08820139.2021.1933516
Powered by WPeMatico
By Manish Butte
Pediatr Allergy Immunol. 2021 Jun 7. doi: 10.1111/pai.13571. Online ahead of print.
ABSTRACT
BACKGROUND: Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers’ knowledge regarding which patients to test and barriers to accessing sequencing.
METHODS: Here we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014-2019. Data was abstracted from a chart review and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients.
RESULTS: We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow-up and prognosis.
CONCLUSION: This paper expands the paucity of literature on genetically confirmed IEIs in North America, and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort.
PMID:34097760 | DOI:10.1111/pai.13571
Powered by WPeMatico
By Manish Butte
Mult Scler. 2021 Jun 7:1352458520963896. doi: 10.1177/1352458520963896. Online ahead of print.
ABSTRACT
BACKGROUND: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regulator of T-cell activation and promotes self-tolerance.
CASE: We report the first case of biopsy-proven central nervous system inflammatory demyelination in the context of primary immunodeficiency and a novel CTLA-4 variant.
CONCLUSION: This case has significant implications for the development of novel treatments for autoimmune conditions including multiple sclerosis and further emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors in those with a history of inflammatory demyelination.
PMID:34097529 | DOI:10.1177/1352458520963896
Powered by WPeMatico
By Manish Butte
Pharmacoepidemiol Drug Saf. 2021 Jun 7. doi: 10.1002/pds.5302. Online ahead of print.
ABSTRACT
PURPOSE: Most European influenza vaccine strategies target individuals at higher risk of complications, which include, among others, individuals aged ≥65 years and with chronic conditions. These individuals not only have a high-risk of post-infection complications but also could have lower capacity of acquiring adequate vaccine-induced protection. As such, chronic conditions and age could modify the effect of vaccines. This study aimed at assessing the potential effect modification of influenza vaccine effectiveness (IVE) by age and chronic conditions.
METHODS: We used eight-season data from the Portuguese vaccine effectiveness study. Every season, physicians at primary care units recruited patients with influenza-like illness. Clinical data and swabs were collected for Reverse Transverse Polymerase Chain Reaction (RT-PCR) detection of influenza. Trivalent inactivated IVE was estimated as 1 – odds ratio (OR) of being vaccinated in cases (RT-PCR positive for influenza) versus negative controls. ORs were obtained using a multivariable conditional logistic regression model, paired by week of onset within each season. Confounders were assessed by designing a specific causal diagram. Age (< 65 or ≥ 65 years) and chronic conditions (diabetes, cardiovascular disease, chronic renal disease, chronic hepatic disease, obesity, chronic respiratory disease, and congenital or acquired immunodeficiency) were studied as effect modifiers by including an interaction term in the regression models. Significance was established at 5%.
RESULTS: Point estimates indicate a higher IVE in the chronic condition strata compared to that in the no chronic condition strata. Regarding age, different results were obtained considering the virus type and (sub)type. When comparing the ≥65 years of age strata with the <65 years of age strata, we observed a higher IVE against A(H1N1)pdm09, an equal IVE against A(H3N2) and a lower IVE against B virus. However, all interaction terms were statistically insignificant, and this may be due to a small sample size.
CONCLUSION: The potential effect modification of age or chronic condition was not observed within our study. This article is protected by copyright. All rights reserved.
PMID:34096151 | DOI:10.1002/pds.5302
Powered by WPeMatico
By Manish Butte
Front Immunol. 2021 May 21;12:665621. doi: 10.3389/fimmu.2021.665621. eCollection 2021.
ABSTRACT
Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.
PMID:34093558 | PMC:PMC8176954 | DOI:10.3389/fimmu.2021.665621
Powered by WPeMatico
By Manish Butte
Pediatr Transplant. 2021 Jun 6:e14063. doi: 10.1111/petr.14063. Online ahead of print.
ABSTRACT
BACKGROUND: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases.
METHODS: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID.
RESULTS: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients.
CONCLUSIONS: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.
PMID:34092004 | DOI:10.1111/petr.14063
Powered by WPeMatico
By Manish Butte
Sci Immunol. 2021 Jun 4;6(60):eabd3774. doi: 10.1126/sciimmunol.abd3774.
ABSTRACT
Although CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3+CD8+ T cells. FoxP3+CD8+ Treg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGFβ, and retinoic acid contributed to the generation of gut-tropic CCR9+CD103+FoxP3+CD8+ Tregs Last, CD103-deficient CD8+ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3+CD8+ Treg function. Our results describe a role for FoxP3+CD8+ Tregs in cross-tolerance in the intestine for which development requires intestinal cDC1.
PMID:34088744 | DOI:10.1126/sciimmunol.abd3774
Powered by WPeMatico
By Manish Butte
J Allergy Clin Immunol. 2021 Jun 1:S0091-6749(21)00886-1. doi: 10.1016/j.jaci.2021.05.028. Online ahead of print.
ABSTRACT
BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.
OBJECTIVE: To describe NRH prevalence, associated features and impact in patients with XLA.
METHODS: Medical records of all XLA patients referred to the NIH between 1994 and 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher’s exact test and Mann-Whitney test were used for statistical comparisons.
RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent at least one liver biopsy of whom 6 (29% of NIH XLA cohort) were NRH+. The median age at NRH diagnosis was 20y (17-31). Among patients who had liver biopsies, alkaline phosphatase (ALP) levels were only increased in NRH+ patients (p=0.04). Persistently low platelet count (<100k/μL for more than 6 months), mildly to highly elevated hepatic venous pressure gradient (HVPG) and either hepatomegaly and/or splenomegaly were present in all NRH+ patients. In opposition, persistently low platelet counts were not seen in NRH- patients, and hepatosplenomegaly only observed in one NRH- patient. HVPG was normal in the only NRH- patient tested. All-cause mortality was higher among NRH+ patients (5/6, 83%) than in the rest of the cohort (1/15, 7% among NRH- and Unknown patients, p=0.002).
CONCLUSION: NRH is an underreported, frequent and severe complication in XLA, which is associated with increased morbidity and mortality.
PMID:34087243 | DOI:10.1016/j.jaci.2021.05.028
Powered by WPeMatico
By Manish Butte
Front Immunol. 2021 May 14;12:667727. doi: 10.3389/fimmu.2021.667727. eCollection 2021.
NO ABSTRACT
PMID:34084169 | PMC:PMC8168433 | DOI:10.3389/fimmu.2021.667727
Powered by WPeMatico