Diagnosis Of Primary Immune Deficiencies Research Articles

European flow cytometry quality assurance guidelines for the diagnosis of primary immune deficiencies and assessment of immune reconstitution following B cell depletion therapies and transplantation.

Over the last 15 years activity of diagnostic flow cytometry services have evolved from monitoring of CD4 T cell subsets in HIV-1 infection to screening for primary and secondary immune deficiencies syndromes and assessment of immune constitution following B cell depleting therapy and transplantation. Changes in laboratory activity in high income countries have been driven by initiation of anti-retroviral therapy (ART) in HIV-1 regardless of CD4 T cell counts, increasing recognition of primary immune deficiency syndromes and the wider application of B cell depleting therapy and transplantation in clinical practice. Laboratories should use their experience in standardization and quality assurance of CD4 T cell counting in HIV-1 infection to provide immune monitoring services to patients with primary and secondary immune deficiencies. Assessment of immune reconstitution post B cell depleting agents and transplantation can also draw on the expertise acquired by flow cytometry laboratories for detection of CD34 stem cell and assessment of MRD in hematological malignancies. This guideline provides recommendations for clinical laboratories on providing flow cytometry services in screening for immune deficiencies and its emerging role immune reconstitution after B cell targeting therapies and transplantation.

Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease

Background. X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus.Clinical case description. Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed.Conclusion. XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease.

Analysis of IFN-γR1 (CD119) and IL-12Rβ1 (CD212) Deficiency by Flow Cytometry

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare primary immune deficiency (PID). IL-12Rβ1 deficiency is the most frequently observed of more than 16 genetic defects that have been identified for MSMD. Genetic and immunological tests are remarkable in the diagnosis of PID. In this study, it was aimed to determine the expression of IFN-γR1 and IL-12Rβ1 in patients with MSMD, their relatives, and healthy individuals and to evaluate the importance of flow cytometry as a fast and reliable method in the diagnosis of MSMD. IFN-γR1 and IL-12Rβ1 expression levels were analyzed in 32 volunteers including six patients, six relatives, and 20 healthy individuals. The normal range of IFN-γR1 and IL-12Rβ1 levels among healthy individuals were determined. IL-12Rβ1 expression level in lymphocytes was found to be low in one patient's relative, and less than 1% in three patients and in one patient's relative. It was observed that the IL-12Rβ1 expression levels of the patient with STAT1 deficiency were increased compared to the healthy individuals. No difference was found in the expression levels of IFN-γR1 and IL-12Rβ1 in one patient, but IFN-γR1 expression was decreased in one patient compared to healthy individuals. Our results show that the determination of IL-12Rβ1 and IFN-γR1 deficiencies by flow cytometry can be used as a rapid and reliable method for the diagnosis of MSMD. The use of this method as a screening test will enable early diagnosis especially in patients whose genetic diagnosis has not been confirmed and clinically compatible with MSMD. In addition, it is thought that IL-12Rβ1 and IFN-γR1 range data obtained from healthy individuals will be considered as a reference source in routine and research studies to be conducted with MSMD.

Investigation of primary immune deficiency after severe bacterial infection in children: A population-based study in western France

BackgroundInfectious diseases are still an important cause of morbidity and mortality in high-income countries and may preferentially affect predisposed children, especially immunocompromised children. We aimed to evaluate the frequency of recommended immunological tests in children with community-onset severe bacterial infection (COSBI) admitted to a pediatric intensive care unit. We also assessed the frequency and described the typology of diagnosed primary immune deficiency (PID). MethodsWe conducted a retrospective observational epidemiological study in six university hospitals in western France. All children from 1 month to 16 years of age admitted to hospital for bacterial meningitis, purpura fulminans, or meningococcal disease between August 2009 and January 2014 were included. We analyzed the frequency, type, and results of the immunological tests performed on children with meningitis, purpura fulminans, or a meningococcemia episode. ResultsAmong the 143 children included (144 episodes), 84 (59%) and 60 (41%) had bacterial meningitis and purpura fulminans or meningococcemia, respectively: 72 (50%) had immunological tests and 8% had a complete immunological investigation as recommended. Among the 72 children examined for PID, 11 (15%) had at least one anomaly in the immunological test results. Two children had a diagnosis of PID (one with C2 deficit and the other with C8 deficit) and seven other children had possible PID. Thus, the prevalence of a definite or possible diagnosis of PID was 12% among the children examined. ConclusionPID is rarely investigated after COSBI. We raise awareness of the need for immunological investigations after a severe infection requiring PICU admission.

Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran

IntroductionThe prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients. ObjectiveTo examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease. MethodsThis descriptive cross-sectional study was carried out during the years 2015–2016 in Ali Asghar (AS) Clinic and Hospital. Two hundred patients with suspected primary immune deficiency disease were eligible for inclusion in the study. Multivariable logistic regression analysis was used to determine the relation between findings. ResultsIn this study, the majority of suspected cases of immunodeficiency were males (57%) with a mean age of 3.33±2.89 years. Twenty-one (10.5%) patients were diagnosed with immunodeficiency disease. The mean diagnostic delay among primary immune deficient patients was 2.05±1.7 years. There was a significant relationship between having parental consanguinity (OR=2.68, 95% CI: 1.07–6.70), allergies (OR=5.03, 95% CI: 1.13–22.31), vaccine adverse effects (OR=9.31, 95% CI: 1.24–69.96) and primary immune deficiency diagnosis. No association was observed between age (OR=0.98, 95% CI: 0.84–1.14), gender (OR=0.99, 95% CI: 0.39–2.47), immune deficiency scoring (OR=0.68, 95% CI: 0.31–1.45) and primary immune deficiency diagnosis. ConclusionTen warning sign scoring system is of less value to consider a patient suspected of having primary immune deficiency. There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.

Identifying Primary Immune Deficiencies in Patients with Autoimmune Cytopenias

Objective: The purpose of this study is to increase awareness and improve diagnosis of primary immune deficiency (PID) in the heterogenous group of patients with autoimmune cytopenia (AIC) by identifying clinical characteristics and laboratory biomarkers that distinguish PID patients from patients with AIC alone. This is especially relevant in genetically-defined PIDs which may be resistant to conventional therapy and mechanism-based treatment approach is required. Evans syndrome, defined by multi-lineage autoantibodies (two or more positive anti-platelet, anti-neutrophil, or direct Coombs test) is a known risk factor for PID; therefore we also investigate the incidence of PID in a broad cohort of AIC patients with single and multi-lineage cytopenias. Methods: Patients with autoimmune cytopenias (autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), or autoimmune neutropenia (AIN)) were referred to our Immune Dysregulation clinical team and prospectively enrolled in the study period of 2016-2019. Detailed immune phenotyping (IgG, IgA, IgM, lymphocyte subsets, vaccine titers, lymphocyte proliferation to mitogens/antigens), serum lipopolysaccharide (LPS) and autoantibodies were measured and/or collected by chart review and genetic testing for PID was pursued. Results: From 2016 to 2019, 78 patients were enrolled to our study. The patients were predominantly children (ages 1-82 years, average age 16.82 years). Of 78 patients with AIC, 48 (61%) were diagnosed with underlying PID based on immune phenotyping and/or genetic testing. Of 39 patients with genetic testing to date, 19 (49%) have been diagnosed with genetically-defined PID (pathogenic variants in CTLA-4, NFKB1, ALPS-related genes, WAS, POLE-1, PI3K, CYBB, or 22q11 [partial DiGeorge syndrome]); the remainder were classified as combined immune deficiency or common variable immune deficiency based on immune phenotyping; an additional two patients were classified as ALPS based on clinical history/flow cytometry/family history of ALPS. Lymphocyte subsets (CD4+ T, CD8+ T, CD19+ B, CD56+ NK) and immune globulins (IgG, IgA, IgM) tended to be lower in AIC-PID patients vs AIC-only (p<0.05). Evans syndrome was more commonly found in AIC-PID patients (13/31, 42%) compared to AIC-only (4/42, 10%). LPS was significantly elevated in the serum of AIC patients compared to healthy controls (mean 719 vs 87 pg/mL, p<0.001). Excluding partial DiGeorge syndrome patients (average LPS 222pg/mL), LPS levels were significantly higher in genetically-defined untreated PID patients (average 1463 pg/mL) vs. other PID (average 444 pg/mL) (p=0.02) or patients with AIC alone (average 667 pg/mL) (p=0.03). Studies are ongoing on specific subsets that are linked to immune dysregulation (T-regulatory cells, double negative T cells, T follicular helper cells). Conclusions: An unexpectedly high fraction of patients with AIC were identified with underlying PID in our Immune Dysregulation program. Routine basic immune evaluation with immunoglobulin levels and lymphocyte subsets expedited diagnosis of PID. Genetic evaluation distinguished a group of patients with AIC-PID and highly elevated LPS level, reflecting high bacterial load, and this may distinguish them from the rest of patients with AIC. The source of bacterial LPS can be multifactorial and is yet to be determined. Our studies continue focusing on biomarkers that can be applied to the heterogenous group of patients with AIC. This will allow early detection and timely initiation of targeted therapies. Disclosures No relevant conflicts of interest to declare.

Now Is the Time to Use Molecular Gene Testing for the Diagnosis of Primary Immune Deficiencies

The discovery of chromosomes, genes, and DNA in the early 20th century paved the way for the development of techniques to examine the role of these elements in disease pathogenesis. Since the start of the 21st century, genetic testing and particularly next-generation sequencing has allowed for a rapid rate of gene disease associations for a broad range of primary immunodeficiency patients. At the same time, biologic and small molecule-based therapies targeting specific molecular pathways have been developed and are being applied clinically and in research settings to treat genetically defined immunodeficiencies. In recent years, both the American Academy of Allergy Asthma and Immunology and the Clinical Immunology Society have recommended the use of genetic testing for diagnosis, therapy guidance, and genetic counseling in patients with clinical symptoms of primary immunodeficiency.

Neurologic Involvement in Primary Immunodeficiency Disorders.

The nervous system may be affected in primary immune deficiency (PID) syndromes through infectious, autoimmune, neoplastic mechanisms, or as a primary feature of the syndrome. However certain neurologic problems do not conform to these etiopathogenetic groups. We retrospectively examined PID patients seen in neurology consultation between 2014 and 2017 in order to determine the spectrum of nervous system involvement. Among patients with confirmed neurologic problems (n = 35), common manifestations were encephalopathy and global developmental/cognitive delay. In 13 (37%) instances, the neurologic signs had no apparent relation with a treatment-related, infectious, or vascular complication and were considered as primary findings: acquired microcephaly, central nervous system malformation, or peripheral neuropathy. The diagnosis of PID was made after, and based on, the neurologic manifestation in 6 of 35 (17%) patients. Neurologic presentation may constitute the initial manifestation in some types of primary immune deficiency.

Клинический случай синдрома Луи-Бар в сочетании с эпилепсией у подростка

В статье приведен случай собственного многолетнего клинического наблюдения синдрома Луи-Бар (врожденной атаксии-телеангиэктазии) в сочетании с эпилепсией у девочки 15 лет. Отмечены особенности течения и манифестации клинических признаков синдрома Луи-Бар, сочетание с эпилепсией и полиорганностью поражений у данного пациента. Приведенный случай демонстрирует сложность ранней диагностики первичных иммунодефицитных состояний у детей в сочетании с патологией нервной системы. Для своевременной верификации диагноза необходим тщательный анализ клинико-анамнестических данных в сочетании с дифференциальным поиском причин рецидивирования инфекционных заболеваний у детей с неврологической патологией.

Primary Immune Deficiencies - Principles of Care

Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders caused by ineffective, absent or an increasing number of gain of function mutations in immune components, mainly cells and proteins. Once recognized, these rare disorders are treatable and in some cases curable. Otherwise untreated PIDs are often chronic, serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or facilities for diagnosis, and management of PIDs is complex. This document was prepared by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive principles of care for PIDs. These include the role of specialized centers, the importance of registries, the need for multinational research, the role of patient organizations, management and treatment options, the requirement for sustained access to all treatments including immunoglobulin therapies and hematopoietic stem cell transplantation, important considerations for developing countries and suggestions for implementation. A range of healthcare policies and services have to be put into place by government agencies and healthcare providers, to ensure that PID patients worldwide have access to appropriate and sustainable medical and support services.

Examining the use of ICD-9 diagnosis codes for primary immune deficiency diseases in New York State.

To use International Classification of Disease Codes (ICD-9) codes to investigate primary immune deficiency (PID) in New York State. We investigated the diagnosis of Primary Immune Deficiency (PID) in New York State (NYS) using the Statewide Planning and Research Cooperative System (SPARCS) database, a comprehensive data reporting system that collects ICD-9 codes for each patient hospitalized in NYS. From 2000-2004 there were 13,539,358 hospitalizations for 4,777,295 patients; of these, 2,361 patients (0.05 %) were diagnosed with one or more of the ICD-9 codes for PID. Antibody defects were the most common diagnoses made. The PID population had significantly more Caucasians, and fewer African American or Hispanic subjects compared to the general population. Subjects with PID codes were younger, had longer hospitalizations, were less likely to have Medicare and more likely to have Medicaid or Blue Cross insurance. Most hospitalizations were due to respiratory and infectious diseases. Most patients resided in the most populous counties, Kings, New York and Queens, but the distribution of home zip codes was not proportional to county populations. These data provide useful information on incidence and complications of selected PID diagnoses in one large state.

Increased Diagnosis of Primary Immune Deficiency and IgE to Galactose 1,3-alpha-galactose in Northwest Arkansas

Increased Diagnosis of Primary Immune Deficiency and IgE to Galactose 1,3-alpha-galactose in Northwest Arkansas

Déficits immunitaires primitifs de révélation tardive

Primary immune deficiencies (PID) are characterized by a failure of the immune system that is not explained by any infectious, neoplastic, or iatrogenic cause. The diagnosis of PID should be considered in cases of severe or recurrent infections but also in cases with granulomatosis, autoimmune diseases, hemophagocytic syndrome, lymphoproliferative disorders, or even some solid tumors. The onset of PID may be late, most often in adulthood. Nonetheless, late onset may also mean in the first years rather than months of life or in adolescence rather than early childhood. In adults, the diagnosis of PID cannot be considered before acquired immunodeficiencies--far more frequent--are ruled out. Factors affecting the late onset of PID are not known.

Spectrum of primary immune deficiency at a tertiary care hospital

To report various primary immune deficiencies diagnosed in children at a tertiary care hospital, their clinical manifestations and laboratory profile. Case records of children diagnosed to have primary immunodeficiency disorders over a period of 24 months at a tertiary care hospital in northern India were evaluated. Twenty-seven children (M: F=3.5: 1) with mean age of 5.4 +/- 4.6 yrs (2 mo-16 yr) were diagnosed to have primary immunodeficiency. Thirteen children had chronic granulomatous disease (CGD), 4 had severe combined immunodeficiency (SCID), 4 had hypogammaglobulinemia, 2 had Ataxia telangiectasia, and one each had DiGeorge syndrome, Wiskott Aldrich syndrome, hyper IgM syndrome and leukocyte adhesion defect. Common mode of presentation were recurrent/ persistent pneumonia in 19, recurrent/ persistent diarrhea in 10, deep seated abscesses in 8, allergy in 3, disseminated tuberculosis infection in 2, extensive fungal infections in 2 and 1 each of disseminated cytomegalovirus (CMV) infection, disseminated BCG disease, otitis media and meningitis. Family history of sibling deaths was elicited in 2 families. Infectious agents were isolated in 16 cases. From a single center 27 patients with primary immune deficiency could be identified by chart review, suggesting need for high index of suspicion for diagnosis of primary immune deficiency in India. Though the exact prevalence is not known there is need to make a registry to document the magnitude of problem of these disorders.

Diagnostic des déficits immunitaires primitifs à l’âge adulte

The molecular bases of approximately one hundred primary immune deficiencies (PID) have been identified over the last 15 years. In adults, the diagnosis of PID cannot be evoked before ruling out acquired immunodeficiencies, which are far more frequent. The search for specific PIDs may be oriented by the type of agent responsible for severe and/or recurrent infection. More rarely, other clinical manifestations such as granulomatosis, autoimmune manifestations, hemophagocytic syndrome, lymphoproliferation, or solid tumors may also lead to the identification of PID.

IMMUNEDEFICIENCY IN FEMALE SIBLINGS

Although the familial occurrence of primary immunedeficiencies is not uncommon, the occurrence of immunedeficiencies among female family members is unusual. Most cases of familial immunedeficiencies occur in male siblings and usually obey an x-linked recessive mode of determination.Data are presented on two sisters with identical primary immunedeficiencies. One sister presented with recurrent otitis, pyoderma, and H. influenzae ventriculitis. The second sister presented with what appeared to be pauciarticular rheumatoid arthritis. Both sisters had identical findings of decreased concentrations of IgG and IgA, normal concentrations of IgM, deficient antibody production, and absent lymphoid follicles and germinal centers in their lymph nodes, in the presence of normal cell-mediated immunity. These data are consistent with the diagnosis of primary immunedeficiency with hyper-IgM (dysgammaglobulinemia, type I) appearing for the first time in sisters. Chromosomal analysis revealed both sisters to have normal female karyotypes and study of the family pedigree failed to reveal consanguinity. This immunedeficiency probably represents a previously undescribed autosomal recessive form of primary immunedeficiency with hyper-IgM.