Primary Immunodeficiency Research Articles

Comprehensive overview of the current state and impact of cohort studies in newborn screening

Abstract Inborn errors of metabolism (IEM) are a rare and complex group of inherited disorders, typically observed in infants as autosomal recessive or, less commonly, as X-linked recessive conditions. Newborn screening (NBS) for IEMs can significantly improve prognosis and quality of life through early diagnosis and intervention, marking a significant public health achievement. NBS programs vary by country, but generally include tests for a range of metabolic errors, endocrine disorders, primary immunodeficiency disorders, congenital deafness, congenital heart defects, and cystic fibrosis. Integrating mass spectrometry (MS/MS), genetic sequencing, and emerging technologies such as next-generation sequencing into NBS programs represents a substantial advancement in the field of healthcare. These technologies enable early detection, intervention, and the possibility of personalized treatments through gene therapies. Such advancements are poised to shape the future of NBS, potentially enhancing healthcare outcomes for newborns on a global scale. Neonatal screening is the most well-known and widely implemented proactive and preventative pediatric public health initiative worldwide. It encompasses a comprehensive education system, screening, diagnostic confirmation, management, follow-up, and counseling. This article reviews recent advances in newborn metabolic screening, drawing on the results of various clinical trials and pilot studies.

A rare family outbreak of Mycobacterium abscessus infection in immunocompetent fraternal triplets

BackgroundMycobacterium abscessus (M. abscessus) infection is rare in children who were previously healthy, particularly in infants. We present the first report of a family outbreak of M. abscessus infection among immunocompetent infant triplets. MethodsWe reviewed triplets’ demographic data, laboratory tests and imaging examinations to describe their clinical features. We performed whole-exome sequencing to rule out primary immunodeficiency disorders. We used DNA sequencing for M. abscessus subspecies identification. ResultsThe fraternal triplets (triples A, B and C) presented with a 10-day history of cough. Triple A also experienced a brief episode of fever, and triple B had tachypnea. Chest CT scans showed pulmonary masses and nodules in triples A and C, and cavities in triple B. Cultures of sputum and bronchoalveolar lavage fluid from all triplets yielded M. abscessus. Further subspecies identification showed that isolates from triples A and C were M. abscessus subsp. massiliense, and isolates from triple B were M. abscessus subsp. abscessus (MAA). After eight months of combination therapy, the pulmonary lesions of the triplets improved significantly. ConclusionOur study confirms that M. abscessus pulmonary disease can occur in immunocompetent infants. We hypothesize that the simultaneous infection of the triplets may be associated with their prematurity and extensive environmental exposure. This study highlights the importance to include M. abscessus infection in the differential diagnosis of pulmonary masses and/or cavities, regardless of the age of onset or the presence of underlying pathology or susceptible genes.

Peripheral T Cell Development and Immunophenotyping of Twins with Heterozygous FOXN1 Mutations.

The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function FOXN1 variants are associated with T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ T cell reconstitution in these patients is not completely understood, a lower proportion of naive T cells in adults has suggested a role for homeostatic proliferation. In this study, we present an immunophenotyping study of fraternal twins with low TCR excision circles at birth. Targeted primary immunodeficiency testing revealed a heterozygous variant of uncertain significance in FOXN1 (c.1205del, p.Pro402Leufs*148). We present the immune phenotypes of these two patients, as well as their father who carries the same FOXN1 variant, to demonstrate an evolving immune environment over time. While FOXN1 haploinsufficiency may contribute to thymic defects and T cell lymphopenia, we characterized the transcriptional activity and DNA binding of the heterozygous FOXN1 variant in 293T cells and found the FOXN1 variant to have different effects across several target genes. These data suggest multiple mechanisms for similar FOXN1 variants pathogenicity that may be mutation specific. Increased understanding of how these variants drive transcriptional regulation to impact immune cell populations will guide the potential need for therapeutics, risk for infection or autoimmunity over time, and help inform clinical decisions for other variants that might arise.

Infectious Complications in Primary Immunodeficiency Patients Receiving Immunoglobulin Replacement Therapy: 5 Years Experience

Infectious Complications in Primary Immunodeficiency Patients Receiving Immunoglobulin Replacement Therapy: 5 Years Experience

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

AbstractOver 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.

Charting a course for global progress in PIDs by 2030 - proceedings from the IPOPI global multi-stakeholders' summit (September 2023).

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders' Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what's next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management. Discussion also covered the complexities of PID diagnosis, addressing issues such as global diagnostic disparities, the integration of patient-reported outcome measures, and the potential of artificial intelligence to increase PID diagnosis rates and to enhance diagnostic precision. These proceedings outline the outcomes and recommendations arising from the 2023 IPOPI Global Multi-Stakeholders' Summit, offering valuable insights to inform future strategies in PID management and care. Integral to this initiative is its role in fostering collaborative efforts among stakeholders to prepare for the multiple challenges facing the global PID community.

Paving the way in implementation of SCID newborn screening in developing nations: feasibility study and strategies to move forward in Malaysia.

Early diagnosis and effective management of Primary immunodeficiency diseases (PIDs), particularly severe combined immunodeficiency (SCID), play a crucial role in minimizing associated morbidities and mortality. Newborn screening (NBS) serves as a valuable tool in facilitating these efforts. Timely detection and diagnosis are essential for swiftly implementing isolation measures and ensuring prompt referral for definitive treatment, such as allogeneic hematopoietic stem cell transplantation. The utilization of comprehensive protocols and screening assays, including T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), is essential in facilitating early diagnosis of SCID and other PIDs, but their successful application requires clinical expertise and proper implementation strategy. Unfortunately, a notable challenge arises from insufficient funding for the treatment of PIDs. To address these issues, a collaborative approach is imperative, involving advancements in technology, a well-functioning healthcare system, and active engagement from stakeholders. The integration of these elements is essential for overcoming the existing challenges in NBS for PIDs. By fostering synergy between technology providers, healthcare professionals, and governmental stakeholders, we can enhance the efficiency and effectiveness of early diagnosis and intervention, ultimately improving outcomes for individuals with PIDs.

Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort

AbstractNeutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Proof-of-concept study evaluating humoral primary immunodeficiencies via CJ:KREC ratio and serum BAFF level

Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children’s hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.

Evans syndrome: Disease awareness and clinical management in a nation-wide ITP-NET survey.

Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.

Opening SCID newborn screening for novel exon genetic variants through whole-exome sequencing in China

BackgroundSevere combined immunodeficiency (SCID) is the most fatal form of inherited primary immunodeficiency disease. Known molecular defect mutations occur in most children with SCID. MethodsHerein, we report Adenosine Deaminase-SCID (ADA-SCID) using whole-exome sequencing (WES), explore exome mutational landscape and significance for 17 SCID samples, and verify the mutated exon genes using the Gene Expression Omnibus (GEO) datasets. A total of 250 patients, who were hospitalized at the Neonatal Intensive Care Unit (NICU) of The Seventh Medical Center of the PLA General Hospital for 3 years (from 2017 to 2020), were screened for SCID. We collected mutated genes from the WES data of 17 SCID children. GSE609 and GSE99176 cohorts were used to identify the expressions of mutated exon genes and molecular features in SCID. Gene set variation analyses (GSVA) and correlation analyses were performed. ResultsThe detection rate with approximately 6.8 % (17/250) of SCID is high in the NICU. A total of 16 genes were identified among 17 SCID samples, of which the Top 2 genes (MUC6 and RP11-683L23.1) might be crucial in the progression of SCID with 94 % mutation frequency. Furthermore, CNN2 and SCGB1C1 had significant co-mutations and may cooperate to affect SCID development. Importantly, the phylogenetic tree classification results of 17 SCID samples are more correlated to MUC6 with the most significant mutations. Expression profiles of seven mutated genes and five mutated genes were documented in GSE609 and GSE99176 cohorts based on microarray, respectively. Several immune-related pathways were significantly enriched, and Foxd4, differing from the other four mutated genes, was inversely correlated with the GSVA-enriched pathway. ConclusionDue to its high detection rate (6.8%) and fatality rate (100%), the inclusion of SCID in newborn screening (NBS) is urgent for children in China. The WES successfully identified several common exonic variants (e.g., MUC6) and depicted the feature of mutations and evolution, which will help develop new diagnostic methods for SCID.

A case of primary immunodeficiency with immune dysregulation: features of clinical manifestation and diagnostic difficulties

A case of primary immunodeficiency with immune dysregulation: features of clinical manifestation and diagnostic difficulties

Disseminated BCG in primary immunodeficiency

Disseminated BCG in primary immunodeficiency

Autophagy-related molecular clusters identified as indicators for distinguishing active and latent TB infection in pediatric patients

BackgroundAutophagy is crucial for controlling the manifestation of tuberculosis. This study intends to discover autophagy-related molecular clusters as biomarkers for discriminating between latent tuberculosis (LTBI) and active tuberculosis (ATB) in children through gene expression profile analysis. MethodsThe expression of autophagy modulators was examined in pediatric patients with LTBI and ATB utilizing public datasets from the Gene Expression Omnibus (GEO) collection (GSE39939 and GSE39940).ResultsIn a training dataset (GSE39939), patients with LTBI and ATB exhibited the expression of autophagy-related genes connected with their active immune responses. Two molecular clusters associated with autophagy were identified. Compared to Cluster 1, Cluster 2 was distinguished through decreased adaptive cellular immune response and enhanced inflammatory activation, according to single-sample gene set enrichment analysis (ssGSEA). Per the study of gene set variation, Cluster 2’s differentially expressed genes (DEGs) played a role in synthesizing transfer RNA, DNA repair and recombination, and primary immunodeficiency. The peak variation efficiency, root mean square error, and area under the curve (AUC) (AUC = 0.950) were all lowered in random forest models. Finally, a seven-gene-dependent random forest profile was created utilizing the CD247, MAN1C1, FAM84B, HSZFP36, SLC16A10, DTX3, and SIRT4 genes, which performed well against the validation dataset GSE139940 (AUC = 0.888). The nomogram calibration and decision curves performed well in identifying ATB from LTBI.ConclusionsIn summary, according to the present investigation, autophagy and the immunopathology of TB might be correlated. Furthermore, this investigation established a compelling prediction expression profile for measuring autophagy subtype development risks, which might be employed as possible biomarkers in children to differentiate ATB from LTBI.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.

The effects of nanoplastics and microcystin-LR coexposure on Aristichthys nobilis at the early developmental stages

Nanoplastics (NPs) and microcystin-LR (MC-LR) are two common and harmful pollutants in water environments, especially at aquafarm where are full of plastic products and algae. It is of great significance to study the toxic effects and mechanisms of the NPs and/or MC-LR on fish at the early stage. In this study, the embryo and larvae of a filtering-feeding fish, Aristichthys nobilis, were used as the research objects. The results showed that the survival and hatching rates of the embryo were not significantly affected by the environmental concentration exposure of these two pollutants. Scanning electron microscopy (SEM) observation displayed that NPs adhered to the surface of the embryo membrane. Transcriptomic and bioinformatic analyses revealed that the NPs exposure activated neuromuscular junction development and skeletal muscle fiber in larvae, and affected C5-Branched dibasic acid metabolism. The metabolic and biosynthetic processes of zeaxanthin, xanthophyll, tetraterpenoid, and carotenoid were suppressed after the MC-LR exposure, which was harmful to the retinol metabolism of fish. Excessive production of superoxide dismutase (SOD) was detected under the MC-LR exposure. The MC-LR and NPs coexposure triggered primary immunodeficiency and adaptive immune response, leading to the possibility of reduced fitness of A.nobilis during the development. Collectively, our results indicate that environmental concentration NPs and MC-LR coexposure could cause toxic damage and enhance sick risk in A.nobilis, providing new insights into the risk of NPs and MC-LR on filtering-feeding fish.

New coronavirus infection SARS-CoV-2 in adult patients with inborn errors of immunity

BACKGROUND: Diagnosis and treatment of COVID-19 in patients with primary immunodeficiency, or inborn errors of immunity, are often challenging. AIM: Description of the COVID-19 course and therapy of adult patients with primary immunodeficiency treated in medical organizations of Moscow Healthcare Department. MATERIALS AND METHODS: We analyzed a cohort of 68 patients over 18 years (median ― 35 years) with primary immunodeficiency; 91% of patients have primary immunodeficiency with predominantly antibody deficiencies. Altogether 90 cases of the new СOVID-19 were analyzed: in 68 cases infection occurred for the first time, in 22 cases it recurred. The duration of the disease ranged from 3 to 80 days. Duration of PCR-positivity ranged from 0 to 59 days, median 8 days. RESULTS: Patients with Wuhan and Delta strains had more severe inflammatory signs according to C-reactive protein and lactate dehydrogenase, in patients with Wuhan lung involvement on CT-scam was larger. In demonstrated group of patients higher C-reactive protein correlated with larger lung involvement, longer duration of the disease and PCR-positivity, significant lymphopenia also correlated with higher C-reactive protein. To our data regularity of intravenous immunoglobulin therapy and IgG trough level didn’t correlate with infection severity and duration of the disease and virus-carriage. Indirectly, the change in the spectrum of medicine used in patients of the analyzed group coincided with the virus strain evolution. Anti-inflammatory therapy was mainly presented by dexamethasone and antagonists to interleukin 6 or its receptor (anti-IL-6): 55% and 73% for Wuhan, 63% and 50% for Delta, 17% and 39% for Omicron. Then, preference was gradually given to the target anti-cytokine medicine. Etiotropic antiviral therapy was more often used to treat infection caused by Wuhan and Delta strains ― 32% and 38%, respectively (in 17% for Omicron). With shifting toward immunotherapy by specific against COVID-19 immunoglobulins and monoclonal antibody to SARS-CoV-2: 5% and 9% for Wuhan, 0% and 75% for Delta, 48% and 83% for Omicron, respectively. Immune and etiotropic therapy was not carried out in Wuhan in 39%, in Delta in 43%, in Omicron in 41% of cases. The overall mortality rate from COVID-19 in the analyzed group was 3%. CONCLUSION: Patients with primary immunodeficiency represent a vulnerable group to the SARS-CoV-2 virus with a high risk of not only severe, but also a protracted and undulating course of infection, what must be taken into account for the correct interpretation of the patient's condition and the timely administration of the appropriate therapy.

Chronic Septic Granulomatosis Revealed in Adulthood by Respiratory Manifestations

Chronic septic granulomatosis is a rare genetic disease that affects the immune system. It is characterized by a primary immune deficiency that makes it more difficult for phagocytic cells (such as polymorphonuclear neutrophils, eosinophils, monocytes, and macrophages) to eradicate some harmful bacteria and fungi. It is considered an orphan disease because it affects less than 0.05% of a given population.

Peculiar features of intravenous immunoglobulins application in rheumatic diseases

Intravenous immunoglobulins (IVIG) are the most commonly used immunobiological agents produced from donor blood. They were first used in the mid-twentieth century for the treatment of primary immunodeficiencies. Later, they were successfully used to treat a variety of autoimmune, inflammatory and other diseases. There are currently a growing number of basic and clinical studies looking at the mechanism of action and efficacy of different doses of IVIG. At the same time, much remains unclear, contradictory, and some data are mutually exclusive.

АНАЛИЗ КАЧЕСТВА ЖИЗНИ, СВЯЗАННОГО СО ЗДОРОВЬЕМ, У ДЕТЕЙ И ВЗРОСЛЫХ С ПЕРВИЧНЫМИ ИММУНОДЕФИЦИТАМИ В РОССИЙСКОЙ ФЕДЕРАЦИИ

Primary immunodeficiencies (PIDs) accompany patients lifelong therefore assessing the quality of life and developing methods to improving it are of a particular importance. The purpose of this research was to assess the health-related quality of life in patients with PIDs among the Russian population and to compare the results obtained v. worldwide data. Materials and methods used: a single-center cross-sectional survey study was conducted in patients with PIDs in Oct. 2020-Feb. 2021. Patients below the age of 18 y/o had filled the PedsQL 4.0 questionnaire to provide data on psychosocial functioning, a total score was then calculated on the scales of emotional, social and role functioning. Adult patients had completed the EQ-5D-5L questionnaire that included the “mobility, self-care, activities of daily living, pain and discomfort, anxiety and depression” domains. Each question had five answer options and also included a 100-point visual analogue scale for subjective assessment of health. Results: EQ-5D-5L showed significant deviations on the “Anxiety/Depression” scale (Me 2.5). The least affected area was “Self-Care” (1.0 on average). On average, the subjective assessment of one's own health was satisfactory 70.04 points out of 100. On the other hand, PedsQL showed the lowest scores in the “emotional functioning” and “functioning in kindergarten/school” scales, the average ones were in those related to physical functioning and the highest in the social functioning domains.