Research progress of primary immunodeficiency disease with hyper IgE syndrome / 中华实用儿科临床杂志

The hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.The JOB syndrome due to heterozygous loss-of-function mutations in the signal transduction and transcription activator-3(STAT3) gene is the prototype of HIES.However, several other immunodeficiency disorders with the phenotype of HIES have been identified over the past decade.This study aims to review these disorders and their molecular mechanisms, aiming to improve the understanding of this rare disease.

Observation of efficacy of allogeneic hematopoietic cell transplantation using unrelated cord blood or haploidentical donors in children with primary immunodeficiency diseases / 中华实用儿科临床杂志

Objective:To evaluate the efficacy of allogeneic hematopoietic cell transplantation(allo-HSCT) using unrelated cord blood or haploidentical donors in the treatment of children with primary immunodeficiency diseases (PID).Methods:The clinical data of 60 children with PID admitted to Chinese People′s Liberation Army General Hospital-Sixth Medical Center from April 2014 to October 2019 were retrospectively analyzed, including 56 cases of chronic granulomatous disease, 2 cases of severe combined immunodeficiency disease, 1 case of high-IgM syndrome and 1 case of severe congenital neutropenia.All patients underwent allo-HSCT, including 12 cases receiving the transplantation from unrelated cord blood (UCB group) and 48 cases from haploidentical donors combined with a third party unrelated cord blood (haploid group). Among these patients, there were 59 males and 1 female, with a median age of 3.4 years.All patients received a myeloablative conditioning regimen based on Busulfan.The prophylaxis of acute graft versus host disease (aGVHD) was performed based on Cyclosporine.In the UCB group, the median dose of mononuclear cells and CD 34+ cells was 0.67×10 8/kg and 0.51×10 6/kg recipient body weight, respectively; In the haploid group, bone marrow and peripheral stem cells from haploid donors were infused on day 01 and day 02, respectively.The third party cord blood was infused 4 hours before bone marrow infusion.The median dose of mononuclear cells and CD 34+ cells of bone marrow and peripheral stem cells from haploid donors was 9.97×10 8/kg and 5.12×10 6/kg recipient body weight, respectively.Kaplan-Meier method was used to analyze the overall survival rate. Results:The median day to neutrophil and platelet engraftment was 13.0 days and 23.5 days, respectively.The rate of complete donor chime-rism was shown 30.0 days after transplantation.There was no case with primary engraftment failure, and 1 case with secondary engraftment failure.The incidence of grade Ⅰ-Ⅱ and grade Ⅲ-Ⅳ aGVHD was 43.3% and 15.5%, respectively.The incidence of chronic graft versus host disease with limited skin type was 6.7%, while that with extensive type was 1.1%.The median follow-up period was 818 days.There were 6 death cases, among which, 5 cases died from infection and 1 case died from heart failure.The total mortality related to transplantation was 11.9%.A total of 53 cases survived without diseases.The estimated 5-year failure free survival and overall survival rate was 83.9% and 88.1%, respectively.Conclusion:The efficacy of allo-HSCT in the treatment of children with PID using unrelated cord blood and haploidentical donors is favorable.

Clinical features and diagnostic progress of activated phosphoinositide 3-kinase δ syndrome / 中国综合临床

Activated phosphoinositide 3-kinase δ syndrome(APDS) is an autosomal dominant inherited primary immunodeficiency disease that is caused by mutations in PIK3CD or PIK3R1 genes leading to overactivation of the PI3Kδ signaling pathway, first reported by Angulo et al in 2013. The clinical manifestations of the disease are recurrent respiratory tract infections, benign lymph node hyperplasia, autoimmune diseases, lymphoma and so on. Although most patients develop the disease in childhood, there are also reports of adult onset and asymptomatic patients. In addition, the immunophenotype of activated phosphoinositide 3-kinase δ syndrome is changeable, usually the IgA levels are reduced, the IgM levels can be normal or elevated, and the IgG levels are variable, so it is easy to be misdiagnosed at first diagnosis. There is no unified diagnostic standard at present, and timely genetic testing is required to confirm the diagnosis.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome / 中国当代儿科杂志

OBJECTIVES@#To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).@*METHODS@#A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT.@*RESULTS@#After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04).@*CONCLUSIONS@#Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

Advances in phenotyping activated phosphoinositide 3-kinase-delta syndrome type 1 and type 2 / 国际儿科学杂志

Activated phosphoinositide 3-kinase-delta syndrome(APDS) is a rare autosomal dominant primary immunodeficiency disease.According to mutation types, APDS is divided into two types, APDS1 and APDS2.APDS1 patients have more susceptibility to develop bronchiectasis, sinusitis, hepatomegaly, splenomegaly, asthma, autoimmune or inflammatory diseases, and are more frequently infected with Streptococcus pneumoniae and Haemophilus influenzae, while APDS2 patients are more prone to get pneumonia, eye infection, and lymphadenopathy, malignancy, neurological and growth retardation.Among the immunological features, the T cell count of APDS1 is significantly low, and APDS2 is more obvious to appear elevated IgM levels.Rapamycin is beneficial for both types of APDS, and Leniolisib is better tolerated in patients with APDS1.This article reviews the differences in pathogenesis, clinical manifestations, immunological characteristics, and treatment between APDS1 and APDS2 to improve the understanding by clinicians.

Progress of screening for primary immunodeficiency diseases in neonates / 中国小儿急救医学

Primary immunodeficiency disease (PID) is a disease that seriously affects children′s life and health.Early identification and timely intervention can significantly improve prognosis.Some PIDs appear clinical warning symptoms in neonatal period, which help clinicians to carry out early recognition.However, there are still great challenges in early detection of PIDs.At present, there are PID screening methods based on dried blood spots, including TREC screening for SCID and other T lymphocytopenia diseases, KREC screening for XLA and other B-lymphocytopenia diseases, and multiplex protein profiling screening for complement and phagocyte deficiencies.With the development of gene sequencing, next generation sequencing(NGS) has a good prospect in the application of newborn PID screening.Therefore, it is urgent to establish screening process of Chinese newborn PID.This review elaborated on the progress of newborn PID screening.

Clinical and genetic characteristics and differential diagnosis in children with autosomal dominant hyper-IgE syndrome / 中华实用儿科临床杂志

Objective:To summarize the clinical features of children with autosomal dominant hyper-IgE syndrome (AD-HIES) and the differential diagnosis of hyper-IgE syndrome and allergic diseases as well.Methods:All clinical data, including general information, clinical features, and genetic changes, from 7 children with AD-HIES who were diagnosed in Beijing Children′s Hospital Affiliated to Capital Medical University from April 2016 to June 2020 were analyzed retrospectively.The diagnostic criteria are based on the National Institutes of Health′s (NIH)′s hyper-IgE syndrome score and combined with the results of gene detection, shown as follows: (1) NIH score over 40, with signal transducer and activator of transcription 3 gene ( STAT3) pathogenic mutation; (2) NIH score between 20 and 40, with reported STAT3 pathogenic mutation; (3) NIH score less than 20 points was excluded. Results:There were 3 males and 4 females.The onset age of 7 cases was within 2 months after birth, and the mean age at diagnosis was 3 years old.All seven cases had recurrent skin or lung infections, with 4 cases having skin and lung infections, 1 case of skin abscesses at the BCG vaccination site, and 2 cases without skin infection suffering from recurrent pneumonia.The mean onset age of skin abscess in 5 cases was 1.5 years, and pus culture of 3 cases were Staphylococcus aureus.Four cases developed bullae and 6 cases had lung infections.Four cases had otitis media, and oral thrush was seen in 4 cases.One case of skin and lung infection developed liver abscess and sepsis.Seven cases had eczema, which was disco-vered in the neonatal period for 6 cases.Four cases had the symptoms of eczema for the first visit.Two cases had food allergy, and 1 case had recurrent wheezing within 1 year old.The serum IgE level and blood eosinophil count in 7 children were elevated.All children had heterozygous pathogenic mutations in STAT3.Six patients had de novo mutations.There were 6 different mutation sites.The 4 mutation sites were reported: c.1145G>A, c.1144C>T, and c. 1699A>G were missense mutations, and c. 1139+ 5G>A was splicing mutation.Two mutation sites had not been reported: c.1031A>C was missense mutation, and c. 2050G>T was nonsense mutation.The pathogenic grade of them were likely pathogenic, and the NIH score of 2 cases were above 40 score, which was consistent with the clinical diagnosis of hyper-IgE syndrome. Conclusions:Eczema is a common and early clinical manifestation of hyper-IgE syndrome, along with elevated IgE levels and eosinophil counts that need to be differentiated from allergic diseases.On the contrary, it often had recurrent skin abscesses or pneumonia, which was prone to bullae.The clinical manifestations of young children were atypical, and genetic testing was helpful for early diagnosis.

Mutation of CTLA-4 causes primary immunodeficiency disease: One case report / 中国免疫学杂志

The main biological function of cytotoxic T cell-associated protein 4 (CTLA-4) is to suppress the T cell response and suppress the immune response, and its mutation will cause a series of immune related abnormalities. This case reports a rare case of onset of lymphocytosis, immune hemolysis, repeated infection, and other similar symptoms of autoimmune lymphoproliferative syndrome which caused by CTLA4 Exon2 c. 151 C＞T mutation. Sequencing validation was performed to clarify the source of gene mutation. We review the pathogenesis of CTLA4 and new progress in treatment in this case, and the follow-up treatment for the patient was prospected.

Gene diagnostic method for primary immunodeficiency disease based on targeted panel sequencing / 上海交通大学学报（医学版）

Objective · To design and build a high-throughput sequencing approach based on targeted panel sequencing (TPS) using for the primary immunodeficiency disease (PID) diagnosis. Methods · By reviewing the literature and querying the relevant databases to determine the known diseasecausing genes of PID, capture probes using for the TPS were designed and customized for all exons and flanking sequences of these genes. A child suspected with PID was diagnosed by the customized TPS. Results · The PID sequencing panel contains a total of 100 known pathogenic genes. The sequencing data of the patient has 16414298 reads. The average coverage depth is 157 X, 98.35% of the target region sequencing depth is greater than 20 X, and 99.97% of the target region sequencing depth is greater than 1 X. Finally, a heterozygous nonsense mutation was found in the exon 2 of the CXCR4 gene (c.1000C>T, p.Arg334*) in the child. The results of Sanger sequencing confirmed the variation in the child and showed that his parents were wildtype at the corresponding sites, indicating the mutation is de novo. Conclusion · This study established a high-throughput sequencing diagnostic approach for PID, with which a case of WHIM syndrome was successfully diagnosed.

Progress of diagnosis and treatment for Wiskott-Aldrich syndrome / 中华实用儿科临床杂志

Wiskott-Aldrich syndrome (WAS) is due to the mutation of the WAS gene on the X chromosome,which has both features of primary immunodeficiency disease (PID) and congenital hereditary hematopoietic disease.Although the clinical manifestations of classic WAS were more obvious,the related gene (WAS) and its protein product (WASP) have the value of diagnosis,but due to the low incidence,and there were significant differences in the severity of clinical symptoms of the patients,so WAS is easily misdiagnosed.This article through collecting and analyzing the recent years of research progress of literature data and the clinical reports,and combined with the author＇s previous experience in the diagnosis and treatment,to induct the main points of diagnosis and treatment for WAS.

Vaccine immunization in children with primary immunodeficiency diseases / 中华实用儿科临床杂志

Primary immunodeficiency diseases (PID)are a heterogeneous group of congenital and genetically determined conditions caused by one or more defects of innate and/or adaptive immunity,which are a common retarding factor of vaccines immunization.The infections,however,play a major role in the final prognosis of most PID.The immune response after the vaccine injection may be impaired in some PID cases,even no protection is evoked.Moreover,some disease caused by the live vaccine virus or bacteria strains could occur after immunization.The contents of this paper is to introduce the consensus of the vaccine immunization based on the category of PID,immunization of the contacts and other concerns.

Establishment of Chinese patient online database and registry system for primary immunodeficiency diseases / 中华实用儿科临床杂志

Primary immunodeficiency disease (PID) are rare diseases caused by inherent defects of the immune system,the main clinical manifestations are increased susceptibility to infections,autoimmune diseases and malignancies.For such rare diseases,it's essential to establish national patient online database for collaborative studies.By using hypertext preprocessor (PHP) and MySQL,the database and registration system are successfully set up,and itcould complete inquiries for the information saving,export,query,retrieval,backup etc.This database includes patient's information on the diagnosis,clinical manifestations,laboratory examinations,treatments.Through communication and information-sharing between multiple centers,it creates a basis for nationwide research on PID.

STAT1 mutations associated with primary immunodeficiency diseases / 国际儿科学杂志

STAT1 plays a central role in multiple intracellular signal transduction pathways.STAT1 gene mutations have led to four types primary immunodeficiency disease,including.autosomal recessive (AR) complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant (AD) STAT1 deficiency,and AD gain of STAT1 activity.The first three diseases due principally to the impairment of IFN-γ-mediated and/or IFN-α/β-mediated immunity.Different from common primary immunodeficiency diseases,AD gain of STAT1 function probably due to an enhancement of IFN-a/b-mediated immunity.This article reviews the pathogenesis,clinical manifestations,diagnosis and treatments of inborn errors of human STAT1 immunity.

Progress of innate immunity defect disease / 国际儿科学杂志

Pritnaiy immunodeficiency diseases can be divided into eight diseases, including defects in innate immunity. According to new literature,defects in innate immunity involves seven diseases which are all resulted from gene mutation. Three diseases have a correlation with NF-κB signaling pathway. Different from common primary immunodeficiency diseases, two diseases have a correlation with virus infection. Defects in innate immunity play an important role in primary immunodeficiency diseases. But it can't make a definite diagnosis because of incompletely understanding.

Detection and Diagnosis of Primary Immunodeficiency Diseases / 소아과

Primary immunodeficiency diseases result from innate defects of immune system. As a consequence, recurrent viral, bactrial, fungal, and protozoal infections of varying severity ensue. Although primary immunodeficiency diseases are relatively rare, intensive study of these disorder has expanded our understanding of immunity. Recent progress in immunobiology and genetics has identified the causes of many of the primary immunodeficiency diseases. Diagnosis and therapy can as a result be more specific and effective. Appreciation of the genetic nature of a host immunologic defect makes possible family counseling, carrier detection and prenatal diagnosis. A high index of suspicion and prompt diagnosis of patients with primary immunodeficiency diseases can led to lifesaving treatment or significant improvement in quality of life. Therefore, it is critical for the primary care provider to maintain an index of suspicion for immunodeficiency.