Field Of Primary Immunodeficiencies Research Articles

Transition practice for primary immunodeficiency diseases in Southeast Asia: a regional survey.

With increased diagnostic capabilities and treatment modalities in the field of primary immunodeficiencies (PID), many pediatric patients survive beyond childhood and experience a change of care to the adult-oriented healthcare system. Unfortunately, the transition pathways for PID are less clearly defined, resulting in deterioration of quality of care in adulthood. Hence, this is the first regional study to address PID clinicians' opinions on practices and challenges of transition care in 7 Southeast Asia (SEA) countries. We adopted a cross-sectional study design through an online survey platform to enquire opinions of transition practices from expert representatives in 7 SEA countries. Regionally, 3 out 7 countries reported having no practice of transition care. Among cited challenges were reluctant adaptation by patients and caregivers to unfamiliarized adult healthcare systems, inadequate ratio of adult immunologists to patients and lack of facilities for transfer. Our study provides evidence to advocate policy makers on the importance of standardized integration of transition practice towards betterment of transiting PID patients into adulthood.

Autoinflammatory undifferentiated syndrome

Identification of primary immunodeficiencies (PID), distinction of their nosological forms and timely admoinistered therapy for this disorders frepresent topical problems of modern immunology. According to the PID registry of the National Association of Experts in the Field of Primary Immunodeficiencies (NAEPID), as of 2021, 3617 cases of this disease were diagnosed in Russian Federation (RF). The prevalence of PID in Russian Federation is 2.48 per 100,000 population. Currently, autoinflammatory syndromes (AIS) comprise rare, genetically determined disorders. According to the NAEPID registry data, of the PID register, 541 cases of autoinflammatory syndrome (AIS) were registered in the Russian Federation (2021). Timely diagnosis of AIS is especially important in young children who have similar phenotypic signs, in order to reduce the number of deaths and prevent disability. According to the PID registry, the median diagnostic delay in Russia is 27 months. The purpose of this work is to update information about the autoinflammatory syndrome that clinicians may encounter, e.g., pediatricians, rheumatologists, hematologists and other specialists. This syndrome requires a complex differential diagnostic algorithm for clinicians and is often subject to multidisciplinary approach, involving specialists of different profile. This article describes a clinical case of a 3-year-old child S. with a diagnosis of Primary immunodeficiency: autoinflammatory syndrome, undifferentiated. The patient was diagnosed since the age of 5 months, when periodic rises in body temperature to febrile values were registered once a month. Later on, the fever episodes were observed 2 times a month. The diagnosis was made at the place of residence as secondary immunodeficiency virus-associated state (CMV infection). CMV viremia was canceled against the background of ongoing treatment, but the inflammatory attacks persisted. Molecular genetic studies did not reveal any defects. In view of poor response to NSAID therapy and prednisone prescribed at a dose of 1-1.5 mg/kg/day, he was admitted to the Dmitry Rogachev Research Medical Cemter. The child was finally diagnosed with PID, and therapy was initiated with a selective competitive inhibitor of TNFa etanercept at a dose of 0.8 mg/kg/day once a week. Hence, the autoinflammatory syndrome in children is difficult to diagnose and select therapy, and it may be unfavorable prognostically.

Hereditary angioedema. Clinical guidelines. (D84.1)

Hereditary angioedema is a rare, potentially life-threatening genetic disease that manifests with skin and mucous/submucosal swelling that occurs under the influence of bradykinin. The clinical guidelines for hereditary angioedema (code for the International Statistical Classification of Diseases and Related Health Problems D84.1) were developed in December 2020 by the Russian Association of Allergology and Clinical Immunology, Association of Medical Geneticists, National Association of Experts in the Field of Primary Immunodeficiencies, Union of Pediatricians of Russia. In December 2020, the project was approved at a meeting of the Scientific and Practical Council of the Ministry of Health of the Russian Federation (December 10, 2020 No. 743/12).
 The clinical guidelines are devoted to optimizing the clinical care of patients with hereditary angioedema. The topic is relevant owing to the under-diagnosis of hereditary angioedema and insufficient awareness of doctors of various specialties about this problem, as well as the difficulties in managing this category of patients. The clinical guidelines contain information about the epidemiology, etiology, classification, pathogenesis, and common clinical manifestations of hereditary angioedema. Thus, the paper described actual diagnostic approaches and differential diagnosis of hereditary angioedema and established its diagnostic criteria. Medical care algorithms to patients with hereditary angioedema at the prehospital and hospital stages are also described. The principles of pharmacotherapy, including long-term prophylaxis, short-term prophylaxis, and acute therapy, for hereditary angioedema are also presented. Treatment regimens are stratified according to patients age and gender. Non-drug measures for the prevention hereditary angioedema attacks are considered. Sections were also added in the edition of the new clinical guidelines of hereditary angioedema. Clinical guidelines for hereditary angioedema are intended for practicing doctors of all specialties, students and teachers of medical universities, residents, graduate students of medical universities.

Challenges in understanding host genetics and severity of community-acquired pneumonia.

This study found no association of the top two associated FER variants with severity of community-acquired pneumonia. Precise characterisation of phenotypes may be required in order to unravel the genetic mechanisms predisposing to poor outcome in sepsis. https://bit.ly/3jc9SmR

Primary Immunodeficiencies With Defects in Innate Immunity: Focus on Orofacial Manifestations.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as “inborn errors of immunity” due to the association between a wide range of immune dysregulation-related clinical features and the “prototypic” increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.

Autoimmunity and immunodeficiency.

Advances in genomics and animal models of human disease have enabled the discovery of mechanisms important for host immunity and self-tolerance. Here, we summarize conceptual and clinical discoveries identified from 2018 to 2019 in the field of primary immunodeficiencies and autoimmunity. Three new primary immunodeficiencies with autoimmunity were identified and the clinical phenotypes of NFKB1 haploinsufficiency and RASGRP1 deficiency were expanded. A diversity of novel mechanisms leading to autoimmunity associated with primary immunodeficiencies (PIDs) was reported, including pathways important for the metabolism and function of regulatory T cells and germinal B cells, the contribution of neutrophil extracellular traps to plasmacytoid dendritic cell activation and the influence of commensal bacteria on the generation of autoantibodies. With regard to therapeutic developments in the field, we highlight the use of janus kinase inhibitors for immune dysregulation associated with gain-of-function variants in STAT1 and STAT3, as well as the risks of persistent hypogammaglobulinemia associated with rituximab treatment. Mechanistic studies of PIDs with autoimmunity elucidate key principles governing the balance between immune surveillance and self-tolerance.

Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies.

The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The first patients to demonstrate sustained benefit and prolonged cure from the primary genetic defect following allogeneic haematopoietic stem cell transplantation were patients with primary immunodeficiencies. Although primary immunodeficiency patients began the modern era of haematopoietic stem cell transplantation, the history is nevertheless short-in answer to the question “what is the long term outcome of patients transplanted for primary immunodeficiencies?” we often have to say that we do not know. We believe that most patients who undergo haematopoietic stem cell transplantation for primary immunodeficiencies should live a normal lifespan with a fully corrected immune system. We are now beginning to understanding long term outcomes, the relationship to the underlying genetic defect, age, and pre-morbid condition of the patient at time of transplantation, stem cell source and donor, and effect of pre-transplant cytoreductive chemotherapy conditioning. The long term consequences of post-transplant complications such as graft vs. host disease, veno-occlusive disease, or immune dysregulation are also being recognized. Additionally, some genetic defects have a systemic distribution, and we are learning the natural history of these defects once the immunodeficiency has been removed.

Gene therapy for primary immunodeficiencies.

Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long-lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of severe combined immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious. It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years.

The European Society for Immunodeficiencies (ESID) registry 2014.

The current European Society for Immunodeficiencies (ESID) registry was established 10 years ago in 2004, when the system was moved from a paper-based to an online system. The purpose of the registry is to collect data on European patients with primary immunodeficiencies (PIDs) and their treatment, with the aim of building an easily accessible database for use by physicians and researchers.

Improving care, education, and research: the Asian primary immunodeficiency network

The field of primary immunodeficiencies (PIDs) is marked by continuous discoveries in the mechanisms of disease, genetic etiologies, and treatments. A widening gap between cutting-edge scientific research and its translation to clinical practice is noticeable. To narrow this gap, collaborative networks must be made that bring together a critical mass of specialists to share the knowledge required for the next innovations. In this paper, we describe the current status of the Asian primary immunodeficiency network, which links 40 hospitals in China and Southeast Asia. Over the past 10 years, genetic studies performed on more than 500 patients have led to genetic confirmation of primary immunodeficiency in 272 patients, as well as generating cohort studies that have provided unique phenotypic observations. The network has a dynamic capacity to accommodate priorities and interests of collaborating units, from consultations and genetic testing to scientific research involving next-generation sequencing technologies.

Gene therapy for primary adaptive immune deficiencies

Gene therapy has become an option for the treatment of 2 forms of severe combined immunodeficiency (SCID): X-linked SCID and adenosine deaminase deficiency. The results of clinical trials initiated more than 10 years ago testify to sustained and reproducible correction of the underlying T-cell immunodeficiency. Successful treatment is based on the selective advantage conferred on T-cell precursors through their expression of the therapeutic transgene. However, "first-generation" retroviral vectors also caused leukemia in some patients with X-linked SCID because of the constructs' tendency to insert into active genes (eg, proto-oncogenes) in progenitor cells and transactivate an oncogene through a viral element in the long terminal repeat. These elements have been deleted from the vectors now in use. Together with the use of lentiviral vectors (which are more potent for transducing stem cells), these advances should provide a basis for the safe and effective extension of gene therapy's indications in the field of primary immunodeficiencies. Nevertheless, this extension will have to be proved by examining the results of the ongoing clinical trials.

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies.

The field of primary immunodeficiencies (PIDs) is one of several in the area of clinical immunology that has not been static, but rather has shown exponential growth due to enhanced physician, scientist and patient education and awareness, leading to identification of new diseases, new molecular diagnoses of existing clinical phenotypes, broadening of the spectrum of clinical and phenotypic presentations associated with a single or related gene defects, increased bioinformatics resources, and utilization of advanced diagnostic technology and methodology for disease diagnosis and management resulting in improved outcomes and survival. There are currently over 200 PIDs with at least 170 associated genetic defects identified, with several of these being reported in recent years. The enormous clinical and immunological heterogeneity in the PIDs makes diagnosis challenging, but there is no doubt that early and accurate diagnosis facilitates prompt intervention leading to decreased morbidity and mortality. Diagnosis of PIDs often requires correlation of data obtained from clinical and radiological findings with laboratory immunological analyses and genetic testing. The field of laboratory diagnostic immunology is also rapidly burgeoning, both in terms of novel technologies and applications, and knowledge of human immunology. Over the years, the classification of PIDs has been primarily based on the immunological defect(s) ("immunophenotype") with the relatively recent addition of genotype, though there are clinical classifications as well. There can be substantial overlap in terms of the broad immunophenotype and clinical features between PIDs, and therefore, it is relevant to refine, at a cellular and molecular level, unique immunological defects that allow for a specific and accurate diagnosis. The diagnostic testing armamentarium for PID includes flow cytometry - phenotyping and functional, cellular and molecular assays, protein analysis, and mutation identification by gene sequencing. The complexity and diversity of the laboratory diagnosis of PIDs necessitates many of the above-mentioned tests being performed in highly specialized reference laboratories. Despite these restrictions, there remains an urgent need for improved standardization and optimization of phenotypic and functional flow cytometry and protein-specific assays. A key component in the interpretation of immunological assays is the comparison of patient data to that obtained in a statistically-robust manner from age and gender-matched healthy donors. This review highlights a few of the laboratory assays available for the diagnostic work-up of broad categories of PIDs, based on immunophenotyping, followed by examples of disease-specific testing.

Revisiting human primary immunodeficiencies

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations.

Primary Immunodeficiencies: A Field in Its Infancy

A paradigm shift is occurring in the field of primary immunodeficiencies, with revision of the definition of these conditions and a considerable expansion of their limits. Inborn errors of immunity were initially thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leukocyte subsets and resulting in multiple, recurrent, opportunistic, and fatal infections in infancy. A growing number of exceptions to each of these conventional qualifications have gradually accumulated. It now appears that most individuals suffer from at least one of a multitude of primary immunodeficiencies, the dissection of which is helping to improve human medicine while describing immunity in natura.

Phagocyte immunodeficiencies and their infections

Primary immunodeficiencies (PIDs) primarily affecting the phagocytes (neutrophils and macrophages) typically predispose patients to infections. However, one of the most clinically important features of these disorders is their relatively narrow spectrum of disease-specific infections. Invasive aspergillosis in the absence of immune suppression is essentially seen only in chronic granulomatous disease; disseminated nontuberculous mycobacterial infection in the absence of immune suppression is seen predominantly in patients with defects of the IFN-γ/IL-12 axis. In contrast, infections that are relatively common in some of the PIDs affecting the lymphoid system (Pneumocystis jiroveci and Streptococcus pneumoniae) are extremely uncommon in PIDs affecting phagocytes. Therefore careful attention to the microbiology laboratory early in the course of evaluation of a patient with recurrent infections and suspected of having a PID will help steer the workup in the appropriate direction. Over the last few years, there have been major advances in the molecular and cellular understandings of PIDs affecting phagocytes. As the field of PIDs becomes broader and more clinical and molecular definition becomes available, it is increasingly important to be able to identify likely pathways for investigation early in the evaluation. Here we have updated some of the more rapidly evolving aspects of PIDs affecting phagocytes, with a special emphasis on the associated microbiology.

Immunodeficiencies of genetic origin

Progress in genetics and the use of new molecular biological tools have resulted in major advances in the field of primary immunodeficiencies over the past two years, including the discovery of new genes. Interest is focused on primary immunodeficiencies as a series of models for the study of development and function of the immune system, as discussed at a recent workshop *