Manish Butte

Autoimmune and inflammatory manifestations in pediatric patients with primary immunodeficiencies and their importance as a warning sign.

Allergol Immunopathol (Madr). 2020 May 20;:

Authors: Kaplan MY, Ozen S, Akcal O, Gulez N, Genel F

Abstract
INTRODUCTION AND OBJECTIVES: As well as increased susceptibility to infections, autoimmune and inflammatory manifestations also eventuate due to dysregulation of immune system in a substantial proportion of patients with primary immunodeficiency (PID). Autoimmune and inflammatory manifestations can occur prior or after diagnosis of PID. This study aimed to evaluate autoimmune and inflammatory complications among all types of PID patients in childhood and to emphasize the importance of these findings as a warning sign to diagnose PIDs.
METHODS: Medical records of 1036 patients with PID, followed up between 2003 and 2019, were retrospectively screened for occurrence of autoimmunity and inflammation. During this time, demographic features, autoimmune/inflammatory findings and initial time, genetic mutations, laboratory and clinical follow up findings, treatment regimens and outcomes were recorded.
RESULTS: Autoimmune and inflammatory manifestations were observed in 83 patients (10.1%). The median age of autoimmunity initial time was 61.3±53 months. Sixty-seven (80.7%) patients presented with autoimmune and inflammatory manifestations, and these findings had occurred during 16 patients’ (19.3%) follow-up. The most common autoimmune manifestations were autoimmune hematologic (51.8%) and endocrine diseases (26.5%). Fifty patients (60.2%) had a single autoimmune/inflammatory manifestation, however 23 patients (27.7%) had two, eight patients (9.6%) had three and two patients (2.4%) had four different types of autoimmune/inflammatory manifestations. The frequency of autoimmune and inflammatory manifestations in phagocyte defects (56%), combined immune deficiencies (53%) and immune dysregulation diseases (52%) were observed higher than other forms of PIDs. During follow-up 13 (15.7%) patients died.
CONCLUSION: Autoimmune/inflammatory manifestations are associated with high morbidity in patients with PIDs and may precede the diagnosis of PID in childhood. Therefore, physicians must be aware of underlying possible immune deficiency and patients with known PIDs should be evaluated for autoimmune and inflammatory complications.

PMID: 32446782 [PubMed – as supplied by publisher]

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Mutational landscape of severe combined immunodeficiency patients from Turkey.

Int J Immunogenet. 2020 May 22;:

Authors: Firtina S, Yin Ng Y, Hatirnaz Ng O, Kiykim A, Aydiner E, Nepesov S, Camcioglu Y, Sayar EH, Reisli I, Torun SH, Cogurlu T, Uygun D, Simsek IE, Kaya A, Cipe F, Cagdas D, Yucel E, Cekic S, Uygun V, Baris S, Ozen A, Ozbek U, Sayitoglu M

Abstract
Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.

PMID: 32445296 [PubMed – as supplied by publisher]

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Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency.

J Allergy Clin Immunol. 2020 May 19;:

Authors: Lum SH, Selvarajah S, Deya-Martinez A A, McNaughton P, Sobh A, Waugh S, Burton-Fanning S, Newton L, Gandy J, Z ZN, Owens S, Williams E, Emonts M, Flood T, Cant A, Abinun M, Hambleton S, Gennery AR, Slatter M

Abstract
BACKGROUND: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potential life-threatening complication but studies focusing on large cohorts of patients transplanted for primary immunodeficiency (PID) are lacking.
OBJECTIVE: We aimed to study the incidence, risk factors and outcomes of post-HCT AIC and B-lymphocyte function following rituximab.
METHODS: Retrospective study of 502 PID children who were transplanted at our centre between 1987 and 2018.
RESULTS: Thirty-six (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, ATG, acute and chronic GvHD were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (SHR 9.0, 95% CI, 1.50-54.0, p=0.02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin (IVIG) achieved remission in 50% (n=18), additional rituximab led to remission in 25% (n=9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n=5), bortezomib (n=3), mycophenolate mofetil (n=2), splenectomy (n=2), and second HCT (n=3). The mortality of post-HCT AIC reduced from 25% (4/16) prior to 2011 to 5% (1/20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, 4 were in remission with ongoing sirolimus and low dose steroid. Of 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on IVIG replacement, 2 had second HCT and 3 died.
CONCLUSION: The frequency of post HCT AIC in out cohort was 9%, and the most significant risk factors for its occurrence were the presence of GvHD and the use of alemtuzumab.

PMID: 32442647 [PubMed – as supplied by publisher]

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Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity.

Clin Genet. 2020 May 22;:

Authors: Suspitsin EN, Guseva MN, Kostik MM, Sokolenko AP, Skripchenko NV, Levina AS, Goleva OV, Dubko MF, Tumakova AV, Makhova MA, Lyazina LV, Bizin IV, Sokolova NE, Gabrusskaya TV, Ditkovskaya LV, Kozlova OP, Vahliarskaya SS, Kondratenko IV, Imyanitov EN

Abstract
Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of non-syndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C > T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, X-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C > T (p.R257*), NBN c.657del5, DCLRE1C c.103C > G (p.H35D), NLRP12 c.1054C > T (p.R352C) and c.910C > T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity. This article is protected by copyright. All rights reserved.

PMID: 32441320 [PubMed – as supplied by publisher]

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Malignancy post-hematopoietic stem cell transplant in patients with primary immunodeficiency.

Expert Rev Clin Immunol. 2020 May 22;:1-19

Authors: Lum SH, Slatter MA

Abstract
INTRODUCTION: Hematopoietic cell transplantation (HCT) is a curative treatment for an expanding number of primary immunodeficiencies (PIDs). Malignancies are more common in patients with PID than in the general population, and this review will discuss whether a successful HCT is expected to abolish or alter this risk. Second malignancy post HCT for a malignant disease is well known to occur, but generally less expected in patients transplanted for PID.
AREAS COVERED: This article reviews recently published literature focusing on the pattern of malignancy in children with PID, incidence, and risk factors for developing malignancy post-HCT for PID and possible strategies to reduce the risks.
EXPERT OPINION: Survival post HCT for PID has improved dramatically in the last 20 years and the genomic revolution has led to an expanding number of indications. To improve long-term quality of life attention needs to focus on late effects, including the possibility of malignancy occurring more frequently than expected in the general population, understand the risks and improve the process of transplantation in order to minimize them. Further studies are needed.

PMID: 32441164 [PubMed – as supplied by publisher]

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Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3+ T cells in a patient with IPEX syndrome.

Joint Bone Spine. 2020 May 10;:

Authors: Boschetti G, Sarfati M, Fabien N, Flourié B, Lachaux A, Nancey S, Coury F

Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.

PMID: 32438064 [PubMed – as supplied by publisher]

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Screening for primary immunodeficiency diseases by next-generation sequencing in early life.

Clin Transl Immunology. 2020 May;9(5):e1138

Authors: Sun J, Yang L, Lu Y, Wang H, Peng X, Dong X, Cheng G, Cao Y, Wu B, Wang X, Zhou W

Abstract
Objective: We aimed to use next-generation sequencing (NGS) for the early diagnosis of primary immunodeficiency diseases (PIDs) and define its effects on medical management for an infant cohort in early life.
Methods: A single-centre study was conducted from November 2015 to April 2018. Infants less than 3 months old with infections or abnormal white blood cell counts were enrolled in the study. Gene variants were analysed by NGS, and once a mutation was found in a PID-associated gene, the immune functions associated with this mutation were detected. The diagnosis rate of PIDs in the cohort was the main outcome. The patients received corresponding management and follow-up treatments.
Results: Among 2392 patients who were genetically tested with NGS, 51 infants were diagnosed with PIDs. Seven types of PIDs were detected, and the most common (25/51, 49%) were combined immunodeficiencies with associated or syndromic features. Thirty-five patients (68.6%) were cured or had improved outcomes after being diagnosed with PID. The NGS cost was US$280 per case.
Conclusions: This study not only highlighted the potential of NGS to rapidly deliver molecular diagnoses of PIDs but also indicated that the prevalence of PIDs is underestimated. With broader use, this approach has the potential to alter clinical strategies.

PMID: 32431812 [PubMed]

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Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.

Front Immunol. 2020;11:831

Authors: Sharifinejad N, Jamee M, Zaki-Dizaji M, Lo B, Shaghaghi M, Mohammadi H, Jadidi-Niaragh F, Shaghaghi S, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G

Abstract
Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.

PMID: 32431715 [PubMed – in process]

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Delivery of subcutaneous immunoglobulin by rapid “push” infusion for primary immunodeficiency patients in Manitoba: a retrospective review.

Allergy Asthma Clin Immunol. 2020;16:34

Authors: Walter G, Kalicinsky C, Warrington R, Miguel M, Reyes J, Rubin TS

Abstract
Background: Both intravenous and subcutaneous human immune globin G (IgG) replacement (IVIG and SCIG, respectively) reduce severe infection and increase serum IgG levels in primary immune deficiency disorder (PIDD) patients who require replacement. SCIG can be administered either with the aid of an infusion pump, or by patients or caregivers themselves, using butterfly needles and a syringe (“SCIG push”). SCIG offers advantages over IVIG, including higher steady state IgG levels, improved patient quality of life indicators, and decreased cost to the healthcare system, and for these reasons, SCIG has been increasingly used in Manitoba starting in 2007. We sought to determine the effectiveness of SCIG push in our local adult PIDD population.
Methods: We conducted a retrospective chart review of all adult patients enrolled in the SCIG push program in Manitoba, Canada from its inception in November 2007 through September 2018. We included patients who were naïve to IgG replacement prior to SCIG, and those who had received IVIG immediately prior. We collected data regarding serum IgG levels, antibiotic prescriptions, hospital admissions, and adverse events during a pre-defined period prior to and following SCIG initiation. Statistical significance was determined via two-tailed t-test.
Results: 62 patients met inclusion criteria, of whom 35 were on IVIG prior and 27 were IgG replacement naïve. SCIG push resulted in an increase in serum IgG levels in those naïve to IgG replacement, as well as in those who received IVIG prior. SCIG push also resulted in a statistically significant reduction in number of antibiotic prescriptions filled in the naïve subgroup, and no significant change in antibiotics filled in the IVIG prior group. 8/62 PIDD patients (12.9%) left the SCIG program during our review period for varying reasons, including side-effects.
Conclusions: In a real-life setting, in the Manitoba adult PIDD population, SCIG push is an effective method of preventing severe infections, with most patients preferring to continue this therapy once initiated.

PMID: 32426003 [PubMed]

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Successful reconstitution of leukocyte adhesion defect after umbilical cord blood stem cell transplant.

Cent Eur J Immunol. 2020;45(1):117-121

Authors: Chakraborty S, Gupta D, Thakral D, Bakhshi S, Kumar P, Kabra SK, Lodha R, Mitra DK

Abstract
Leukocyte adhesion deficiencies (LADs) are a type of primary immunodeficiencies characterized by delayed detachment of the umbilical cord, impaired wound healing, leukocytosis, and recurrent infections. The disease is caused by genetic defects affecting different steps in the process of leukocyte adhesion cascade such as rolling, integrin activation, and adhesion of leukocytes, resulting in the impairment of leukocyte trafficking. Till date, three types of LAD have been documented: type I, II and III. Type I LAD is caused by congenital defect in the β2 integrin receptor complex CD11/CD18 on the cell surface of leukocytes, which results in impaired leukocytes connection to endothelial cells and migration. Type II LAD is caused by defect in the fucose metabolism resulting in the absence of fucosylated selectin ligands on neutrophils and impaired rolling phase of the leukocyte adhesion cascade. Type III LAD is caused by mutations in the kindlin-3 gene resulting in defective integrin activation. In this article, we present a review of literature for type I LAD, and successful treatment of patient using umbilical cord blood stem cell transplantation.

PMID: 32425689 [PubMed]

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