Primary Immunodeficiency Research Articles

Neonatal Hemophagocytic Lymphohistiocytosis: Scoping Review and Analysis of 205 Cases

Background: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation and uncontrolled inflammation. Neonatal HLH (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. nHLH is estimated to comprise 10% of familial HLH (fHLH) diagnoses. There have been few, large descriptive studies of nHLH. Objectives: The primary objective of this study was to perform a scoping review and descriptive analysis of published cases of nHLH. The secondary objective of this study was to assess the reporting quality of published nHLH cases. Methods: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age < 30 days. As many as 70 variables were extracted from each case. Frequencies and percentages of variables reported per case in the articles included were provided. Qualitative variables were summarized by frequency and percentage. Quantitative variables which were not approximately normally distributed were summarized with median and interquartile range (IQR). Results: 544 studies were assessed for eligibility. Studies were excluded if they did not discuss nHLH (n=280), aggregated nHLH patient data with all ages (n=83), provided insufficient detail and/or data describing nHLH (n=28), and for other reasons (n=8).205 cases of nHLH from 142 articles were included. Cases were published from 31 countries from 1985-2023. Primary presenting features included fever (38.1%, n=67/176), organomegaly (11.9%, n=21/176) respiratory distress (11.4%, n=20/176), jaundice (4.5%, n=8/176), and signs of bleeding (3.4%, n-6/176). Symptoms began in utero in 20 patients (n=20/161). The median age of symptom onset was day of life (DOL) 3 (IQR: 0-14) (n=141). Median age at diagnosis was DOL 15 (IQR: 6-27) (n=87). The median time from initial evaluation to initiation of HLH therapy was 8 days (IQR: 3-14) (n=53). The frequency of HLH criteria and criteria median values are summarized in Table 1. The median number of diagnostic criteria met by patients were 5/8 (IQR: 4, 6). CNS manifestations were reported in 62.7% of cases (n=64/102). Skin manifestations were reported in 75.4% of cases (n=52/69). Liver injury (67.9%, n=91/134) and/or liver failure (23.9%, n=32/134) were common. Infections were reported in 46.7% of patients (n=70/150). Causes of nHLH included familial/inherited disease (46.8%, n=96/205), infection (26%, n=53), macrophage activation syndrome (2.9%, n=6), primary immunodeficiency (2.9%, n=6), inborn error of metabolism (2.4%, n=5), and malignancy (2%, n=4). Diagnosis was made using clinical and laboratory features (82.4%, n=169/205), gene panel (16.1%, n=33/205), sanger sequencing (1.0%, n=2/205), and ultra-rapid whole genome sequencing (0.5%, n=1/205). Genetic causes of fHLH included mutations in PRF1, STX11, STXBP2, UNC13D, NOCAR-H, and XIAP. The majority of patients (62.7%, n=121/193) died within the period of reporting. The estimated median survival time from nHLH onset of symptoms was 83 days. Only 4.4% (n=9/205) of studies reported complete data to calculate an H-score. Studies reported discernable values for HLH diagnostic variables at the following frequencies: temperature (71.7%), organomegaly (82.9%), hemoglobin (69.3%), thrombocytopenia (82.4%), neutrophils (55.1%), fibrinogen (64.4%), triglycerides (5.5%), hemophagocytosis (73.2%), ferritin (71.2%), low/absent NK cell activity (33.2%), and sIL2R (29.3%). Other clinically relevant variables such as the presence or absence of skin manifestations (33.7%), and CNS manifestations (49.8%) frequently went unreported. There were many cases that made a categorical description of a lab value (e.g., thrombocytopenia) without providing an absolute value (e.g., platelets level). Conclusions: This is the largest aggregated study of nHLH presentations, diagnostic criteria, clinical trajectory, and etiologic diagnoses. Neurologic, dermatologic, and hepatic manifestations occur in the neonatal population. Current reports of nHLH suggest a grim prognosis. Future publications containing data on nHLH should report all clinically relevant variables. Studies looking at multiple patients in aggregate should provide supplemental information with detailed nHLH cases.

A Global Study of Novel Agents in Paediatric and Adolescent Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma (Glo-BNHL)

Overview Glo-BNHL is an adaptive prospective international academic-led multicentre platform clinical trial designed to evaluate the efficacy and safety of the most promising novel agents as monotherapy or in combination with existing therapies for the treatment of children, adolescents, and young adults with relapsed or refractory (r/r) B-cell Non-Hodgkin Lymphoma (B-NHL). A direct output of the second ACCELERATE multi-stakeholder Paediatric Strategy Forum (Pearson, 2019), Glo-BNHL was designed in collaboration with patient advocates, is supported by the Regulatory Authorities, and the intent is for trial data to support filing for marketing authorisation. Rationale Outcomes for r/r paediatric B-NHL are extremely poor with long term cure rates lower than 30%. Glo-BNHL fulfils the critical need for a single collaborative global approach to find new treatments for these rare patients for whom current therapy is inadequate. It allows for a rational approach to investigating the array of potentially promising agents currently in development for adults. The classes of agents currently prioritised for inclusion in Glo-BNHL are: Treatment Arm I: bispecific antibodies (BsAbs)Treatment Arm II: antibody-drug conjugates (ADCs) combined with standard chemotherapyTreatment Arm III: chimeric antigen receptor (CAR) T-cell products A robust systematic assessment of each asset is undertaken before a decision to include in the platform is made (published separately). Population Glo-BNHL will enrol participants in ≥45 sites in 18 countries spanning Europe, Asia, North America and Australasia. Eligible patients are aged ≤25 years with radiologically or histologically proven relapsed (≥ first) or refractory B-NHL with evaluable disease, adequate organ function, negative pregnancy test, agreement to use effective contraception and written informed consent. Key exclusion criteria include recent stem cell transplant, craniospinal radiation or investigational treatment, on-going moderate or severe acute toxicities, uncontrolled infection or primary immunodeficiency. Patients may be enrolled into any of the available treatment arms for which they are eligible. Statistical Design In this rare population we anticipate global enrolment of 30 patients per year. The Bayesian design enables initial cohorts of 15 patients to be meaningfully evaluated. A transition analysis will estimate with ≥80% certainty whether the true efficacy of the treatment exceeds the pre-defined target response rate. Agents demonstrating sufficient promise will be further evaluated in an expansion stage, following discussion with regulators to clarify data requirements to enable subsequent approval of the agent. Confirmatory analyses of all evaluable patients will estimate with ≥95% certainty whether the true efficacy exceeds the target response rate (“GO”). During both initial and expansion stages patients will be closely monitored, with regular interim futility analyses employed, allowing a treatment arm to stop early if there is very little probability of efficacy (“NoGO”). Outcome measures Primary outcomes measures are occurrence of an objective response after 12 weeks of treatment (Treatment Arm I), occurrence of complete response within a maximum of three cycles of treatment (Treatment Arm II) and occurrence of an objective response following CAR T-cell infusion (Treatment Arm III). Secondary outcome measures include event-free survival, progression-free survival, overall survival time, best overall response, duration of response, adverse events, pharmacokinetic profile and pharmacodynamics markers. Treatment Treatment Arm I: Odronextamab (Regeneron) - a human CD20xCD3 bispecific antibody - monotherapy will be given as an intravenous infusion weekly for 12 weeks, then at a decreasing frequency until progression or up to two years for responding patients. Treatment Arm II: Loncastuximab tesirine (ADC Therapeutics) - a humanised CD19-targeting monoclonal antibody with PBD dimer cytotoxin - will be given as an intravenous infusion with each cycle of modified R-ICE chemotherapy (rituximab, ifosfamide, carboplatin, etoposide and dexamethasone) for up to three cycles. Treatment Arm III: product negotiations are on-going Conclusion Glo-BNHL addresses an urgent unmet clinical need through an innovative trial design serving as a paradigm for evaluation of novel agents in very rare diseases.

Dosing Strategy of Immunoglobulin (IgG) Replacement Therapies in Obese and Overweight Patients with Primary Immunodeficiency Diseases (PIDDs): A Meta-Analysis of Clinical Trials.

The current dosing strategy of immune globulin products for the treatment of primary immunodeficiency diseases (PIDDs) in the USA is based on total body weight (BW). The aim of our study was to assess the relationship between dose and trough level, and to determine whether an alternative dosing strategy should be considered for patients who are overweight or obese. We analyzed data in a total of 533 patients from 11 studies. We modeled the relationship between trough level and dose per week using a linear mixed model. We used an over-dispersed Poisson model to model the relationship between infection and trough level. In these analyses, we then combined the study-specific treatment effects using a random-effect or fixed-effect model. The mean administered dose per week was 9.77, 14.00, or 18.17g in patients who were normal weight, overweight, or obese, respectively. Compared with a patient of normal weight, a 1g increase in dose per week in a patient who was overweight was associated with a smaller increase in the trough level, 0.08g/L less (95%CI -0.14 to -0.03g/L), and a 1g increase in dose per week in a patient who was obese was associated with a much smaller increase in trough level, 0.01g/L less (95%CI -0.07 to 0.06g/L). Last, for a 1unit (g/L) increase in trough level, the expected number of infections remained the same, with a multiplicative factor of 1.01 (95%CI 0.98-1.04). Overall, we found no compelling evidence to justify a reconsideration of the current dosing strategy based on total BW for patients with PIDDs who are overweight or obese.

Evaluation of Psychiatric Symptomatology, Quality of Life, and Caregiver Burden in Mothers and Children with Primary Immunodeficiency

Background: The present study aimed to evaluate the quality of life, depression, and anxiety scores of children with primary immunodeficiency (PID) and depression, anxiety scores, and the caregiving burden of their mothers. Methods: A total of 149 children aged 2-18 years and their mothers were included in the present study, along with 125 healthy children and their mothers as a control group. The Pediatric Quality of Life Inventory (PedsQL), Child Depression Inventory (CDI), and Screening for Child Anxiety-Related Emotional Disorders (SCARED) questionnaire were used based on the views of children and their mothers. The Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Temperament Evaluation of Memphis, Pisa, Paris, San Diego Autoquestionnaire (TEMPS-A), and Zarit Caregiver Burden Scale (ZCB) were used for the mothers. Results: According to children and their mothers, the scores of the PedsQL were lower than that of the control group (P < 0.05). In addition, according to the views of children and mothers, we found that PID children had higher depression and anxiety scores than healthy children (P < 0.05). The depression and anxiety levels of mothers in the patient group were also significantly higher than those in the control group (P = 0.05 and P = 0.001). Conclusion: Statistically, we found significantly lower psychosocial health summary scores and total scale score levels from the subclass of PedsQL in the patient group than in the control group. According to the views of both children and mothers, we observed that PID children had higher depression and anxiety scores than healthy children. It was also found that the BDI and BAI values in case of mothers in the patient group were significantly higher than those in the control group.

Difficult Cases in Primary Immunodeficiency

Difficult Cases in Primary Immunodeficiency

Unsupervised and Supervised Machine Learning to Identify Variability of Tumor-Educated Platelets and Association with Pan-Cancer: A Cross-National Study

Cancer can educate platelets by altering transcriptome profiles. However, the exact education mechanism remains unclear, and the variability of tumor-educated platelet (TEP) transcriptome has not been investigated. In this study, we aimed to build a stratification system for TEP based on machine learning (ML) data-driven patterns and platelet transcriptome profiles. This study included platelet samples from 1,628 cancer participants from European and United States populations, including 18 different and most prevalent types of cancer. Gaussian mixture model (GMM) was used to identify robust clusters and similar education pattern. While extreme gradient boosting (XGBoost) was used to precisely predict the clusters. Three clusters were eventually identified. The cluster results showed robustness and generality, reflected by comparable patterns of important gene expression, cancer type prevalence, and biological annotation across derivation, evaluation and validation cohorts. Cluster 1 (n = 346), mainly participated in drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, and glutathione metabolism. Cluster 2 (n = 538) mainly participated in ribosome, spliceosome, and primary immunodeficiency. Cluster 3 (n = 744) mainly participated in gap junction and focal adhesion. Based on this novel cluster system, further observational study can investigate the association between these clusters and cancer progression, prognosis, cancer associated thrombosis, treatment resistance (both chemotherapy and immunotherapy), and immune cell infiltration. Overall, in this study, we built the first pan-cancer TEP stratification system based on data-driven patterns of ML and platelet transcriptional profiles. These clusters could help us better understand the variability of the pan-cancer education mechanism.

Difficult Cases in Primary Immunodeficiency

Difficult Cases in Primary Immunodeficiency

A case series of pneumonia beyond usual infections in children

Pneumonia is the most common cause of mortality in under-five children worldwide. Largely, viral pneumonia is the most common cause of pneumonia in children across all age groups. We need to think outside the jukebox while dealing with cases of recurrent or persistent pneumonia. A few uncommon causes of persistent or recurrent pneumonia are primary or secondary immunodeficiencies, airway anomalies, infection with Mycobacterium tuberculosis complex, aspiration pneumonia, and severe gastroesophageal reflux. We present a few uncommon presentations of pneumonia in children, which can pose a significant diagnostic challenge in a resource-limited setting.

Too much of a good thing: a review of primary immune regulatory disorders.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical 'primary immunodeficiency' as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research.

Application of a pattern-based approach to histological diagnosis in very early onset IBD (VEO-IBD) in a multicentric cohort of children with emphasis on monogenic disease with IBD-like morphology.

Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before the age of 6 years, encompassing both 'pure' IBD, such as ulcerative colitis (UC) and Crohn's disease (CD) and monogenic diseases (MDs), the latter often involving genes associated with primary immunodeficiencies. Moreover, histological features in gastrointestinal (GI) biopsies in MD can also have IBD-like morphology, making differential diagnosis difficult. Correct diagnosis is fundamental, as MDs show a more severe clinical course and their inadequate/untimely recognition leads to inappropriate therapy. Biopsy samples from the lower and upper GI tract of 93 clinically diagnosed VEO-IBD children were retrospectively selected in a multicentre cohort and histologically re-evaluated by 10 pathologists blinded to clinical information. Each case was classified according to morphological patterns, including UC-like; CD-like; enterocolitis-like; apoptotic; eosinophil-rich; and IBD-unclassified (IBD-U). Nine (69%) MD children showed IBD-like morphology; only the IBD-U pattern correlated with MD diagnosis (P = 0.02) (available in 64 cases: 51 non-MD, true early-onset IBD/other; 13 MD cases). MD patients showed earlier GI symptom onset (18.7 versus 26.9 months) and were sent to endoscopy earlier (22 versus 37 months), these differences were statistically significant (P < 0.05). Upper GI histology was informative in 37 biopsies. The diagnosis of the underlying cause of VEO-IBD requires a multidisciplinary setting, and pathology, while being one of the fundamental puzzle pieces, is often difficult to interpret. A pattern-based histological approach is therefore suggested, thus aiding the pathologist in VEO-IBD reporting and multidisciplinary discussion.

Features of the pre-analytical stage in quantitative determination of TREC/KREC in peripheral blood

The use of dried blood spots (DBS) obtained from the heels of infants has many advantages over the collection of whole blood samples. DNA extracted from DBS can be used to detect genetic diseases by PCR, which has contributed to the development of population-based newborn screening worldwide. Since January 2023, the list of identified diseases includes a group of primary immunodeficiencies (PIDs), associated with the absence or decrease in the levels of T and/or B lymphocytes, determined as part of screening by the levels of TREC and KREC molecules in peripheral blood, respectively. Quantitative analysis requires special attention to biological material. The aim is to evaluate the impact of the preanalytical step on the quantitative analysis of TREC/KREC levels in peripheral blood.The material included 5219 DBS obtained from infants on days 3-4 of life, as well as DBS prepared from the whole blood of 100 apparently healthy individuals aged 18 to 29 years. A comparative analysis of the TREC/KREC molecules number in correctly and incorrectly collected DBS from newborns and adults, as well as depending on the volume of applied blood, was carried out by RT-PCR using test systems to assess the levels of TREC and KREC in peripheral blood. DBS quality was assessed visually.In the first months of the project, a significant number of incorrectly taken samples were identified – over a third of all DNA maps received for each corresponding month. As a result of additional training of medical staff, the amount of incorrectly collected material decreased to a level not exceeding 1% of all monthly samples collected. When using DNA extracted from DBS with application errors, the majority of samples (64% for newborns, 78% for adults) failed to obtain a result. In the remaining cases, the results obtained were significantly lower than the normal levels of TREC/KREC determined in the same samples with correct DBS collection (all p &lt; 0.0001, 95% CI). The volume of blood used when correctly applied to Guthrie cards did not affect the results obtained, TREC and KREC levels were comparable; when comparing the medians calculated for each group of samples, no significant differences were identified (p &gt; 0.05).When quantitatively analyzing TREC/KREC levels in peripheral blood, correctly taken material is fundamental importance to obtain reliable indicators, primarily to exclude false-positive results. To minimize errors in the preanalytical stage, additional training of medical personnel is necessary to control and/or correct errors.

Profile of 208 patients with inborn errors of immunity at a tertiary care center in South India.

Primary immune deficiencies or inborn errors of immunity (IEI) are a heterogeneous group of disorders that predispose affected individuals to infections, allergy, autoimmunity, autoinflammation and malignancies. IEIs are increasingly being recognized in the Indian subcontinent. Two hundred and eight patients diagnosed with an IEI during February 2017 to November 2021 at a tertiary care center in South India were included in the study. The clinical features, laboratory findings including microbiologic and genetic data, and treatment and outcome details were analyzed. The diagnosis of IEI was confirmed in a total of 208 patients (198 kindreds) based on relevant immunological tests and/or genetic tests. The male-to-female ratio was 1.8:1. Of the 208 patients, 72 (34.6%) were < 1yr, 112 (53.8%) were 1-18years, and 24 (11.5%) were above 18years. The most common IEI in our cohort was SCID (17.7%) followed by CGD (12.9%) and CVID (9.1%). We also had a significant proportion of patients with DOCK8 deficiency (7.2%), LAD (6.2%) and six patients (2.8%) with autoinflammatory diseases. Autoimmunity was noted in forty-six (22%) patients. Molecular testing was performed in 152 patients by exome sequencing on the NGS platform, and a genetic variant was reported in 132 cases. Twenty-nine children underwent 34 HSCT, and 135 patients remain on supportive therapy such as immunoglobulin replacement and/or antimicrobial prophylaxis. Fifty-nine (28.3%) patients died during the study period, and infections were the predominant cause of mortality. Seven families underwent prenatal testing in the subsequent pregnancy. We describe the profile of 208 patients with IEI, and to the best of our knowledge, this represents the largest data on IEI from the Indian subcontinent reported so far.

CRISPR-Cas9 engineering of the RAG2 locus via complete coding sequence replacement for therapeutic applications

RAG2-SCID is a primary immunodeficiency caused by mutations in Recombination-activating gene 2 (RAG2), a gene intimately involved in the process of lymphocyte maturation and function. ex-vivo manipulation of a patient’s own hematopoietic stem and progenitor cells (HSPCs) using CRISPR-Cas9/rAAV6 gene editing could provide a therapeutic alternative to the only current treatment, allogeneic hematopoietic stem cell transplantation (HSCT). Here we show an innovative RAG2 correction strategy that replaces the entire endogenous coding sequence (CDS) for the purpose of preserving the critical endogenous spatiotemporal gene regulation and locus architecture. Expression of the corrective transgene leads to successful development into CD3+TCRαβ+ and CD3+TCRγδ+ T cells and promotes the establishment of highly diverse TRB and TRG repertoires in an in-vitro T-cell differentiation platform. Thus, our proof-of-concept study holds promise for safer gene therapy techniques of tightly regulated genes.

Unraveling the impact of primary immunodeficiency disorders on the microbiota of dental caries in children through 16S rRNA gene-based metagenomic analysis.

Dental caries is a frequently occurring and multifactorial chronic disease in children resulting from the interaction of cariogenic bacteria and host susceptibility. The aim of this study was to elucidate the impacts of primary immunodeficiency disorders (PIDs) on microbiota of dental caries in children by 16S rRNA gene-based metagenomic analysis. Enrolled in this study were 15 children with primary PID with caries (PID group) and 15 healthy children with caries as a control (CG). The DMFT index, saliva flow rate, and buffering capacity of each participant were assessed before the metagenomic analyses were conducted. For taxonomic profiling, the reads were obtained by high-throughput sequencing of the V3-V4 hypervariable region of 16S rRNA. The DMFT score, saliva flow rate, and buffering capacity of the groups were similar. The flow rate and buffering capacity had no correlation with the number of species with 95% confidence. The metagenomic analysis resulted in the identification of 2440 bacterial species in all of the samples. Among the 50 most prevalent species present at ≥1% relative abundance, Prevotella melaninogenica and Prevotella salivae were differentially more abundant in the PID group. The PID group and CG showed similar species richness and evenness, but 4 of the 5 samples with the highest Shannon-Weiner and Inverse Simpson indices belonged to the PID group. The Spearman test results for correlation of the species in the PID subgroups showed that Prevotella oris had a positively correlated relationship with both Scardovia wiggsiae and Saccharibacteria genera incertae sedis. This study provided insight into the caries microbiota of children with immunodeficiency diseases. Differentially abundant species, novel bacterial associations, and unique bacterial species were disclosed in the PID samples, indicating the role of the immune system in altering the caries microbiota. The prominent bacterial species and associations in the PID group should be suspected in regard to their link with present or future diseases.

Poliomyelitis alert on Tunisian borders: response and challenges

Abstract Introduction Poliomyelitis, which disappeared in Tunisia 30 years ago, should be the second disease to be eradicated after smallpox. However, a few endemic foci persist and its recent detection in some regions is causing great concern. On January 11, 2023, Tunisia received an alert with the notification of 2 polio cases in Algeria, the second of which was detected in November 2022 at about 400 KM from Tunisia. The objective of this study is to describe the results of the investigations following this alert as well as the prevention and response measures triggered. Methods We conducted an active search for acute flaccid paralysis (AFP) cases in all governorates and a retrospective search for possible unreported AFP cases hospitalized from November 1, 2022. Vaccination coverage was verified for catch-up if incomplete vaccination. Surveillance of poliovirus shedding in patients with primary immunodeficiencies (PIDs) was also conducted as well as other public health measures. Results As of April 20, 2023, 38 AFP cases have been reported through active search. Retrospective hospital-based surveillance has revealed 31 cases. In addition, 3142 children with deficient vaccination were identified, distributed differently by region. All of them were caught up with Inactivated polio vaccine (IPV). A total of 90 PIDs were followed up. The replacement of the Oral polio vaccine (OPV) dose at 6 months by IPV in the national immunization schedule as well as a request for verification of the possibility of using the new OPV2 in Tunisia and of the required requirements were made. Conclusions The risk of poliomyelitis resurgence in our country is not negligible. Sustained vigilance is necessary, particularly through ensuring high vaccination coverage and effective surveillance to rapidly detect any imported case. This is essential in view of the global context and the existence of outbreaks especially in certain African countries with which several exchanges and migratory flows remain. Key messages • The Poliomyelitis alert on Tunisian borders in January 2023 is a real threat, that should also be taken into consideration by neighboring countries. • Sustained vigilance is necessary, particularly through effective surveillance and appropriate vaccination strategy.

Exploring the Significance of Immune Checkpoints and EBV Reactivation in Antibody Deficiencies with Near-Normal Immunoglobulin Levels or Hyperimmunoglobulinemia.

This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein-Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies.

Case of newly diagnosed primary immunodeficiency at age 65

Low awareness of doctors of various specialties about such an initial defect in immunity as hereditary angioedema leads to poor detection of this disease, as a result of which patients often receive ineffective drugs for a long time and are at risk of developing life-threatening complications.&#x0D; A clinical case was presented of a patient whose diagnosis of hereditary angioedema was first established at the age of 65 despite a long history of edema. There were no urticarial rashes. For edema for 3 years, the patient took Loratadine, systemic glucocorticosteroids were repeatedly administered. In addition, for many years she was worried about abdominal syndrome with an episode rate of up to several times a week, for the purpose of stopping which she used Tempalgin. There is a burdened family history of angioedema. This hospitalization was due to the development of edema of the lower lip and left cheek, the appearance of which is associated with a bite of the inner side of the cheek in sleep, there was no effect from the use of systemic glucocorticosteroids and antihistamines. The examination revealed a decrease in both the amount and functional activity of the C1-inhibitor, thus, hereditary angioedema of type I was diagnosed. Genetic examination revealed a previously undescribed variant of mutations in the SERPING1 gene.&#x0D; The pathogenesis of edema in hereditary angioedema is due to the accumulation of bradykinin, therefore, the use of glucocorticosteroids and antihistamines is ineffective. Currently, there are modern highly effective and safe means, both for stopping and for the prevention of such edema.&#x0D; It is important to inform specialists of various profiles about this disease and the principles of its therapy.

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.

KNOWLEDGE AND SKILLS OF NURSES REGARDING ORPHAN DISEASES

Introduction. The role of the nurse in providing comprehensive and individualized care to patients with rare diseases is one ofthe key roles. Nurses work closely with physicians and patients and play an educational role for patients and their families, facilitating coordination, monitoring and continuity of care. Therefore, nurses should have a certain range of knowledge and skills regarding the most common rare diseases.The aim of research was to determine the knowledge and skills of nurses regarding some specifi c rare diseases.Material and methods. An anonymous and voluntary survey of nurses was conducted at the regional children’s clinical hospitalfrom April to May 2023. A total of 63 nurses from the hospital participated in the survey. The questionnaire consisted of 27 questions related to the sociodemographic data of the respondents and rare diseases. The most common rare diseases encountered in the practice of nurses at the hospital were primary immunodefi ciencies (PID), spina bifi da (SB), cystic fi brosis, and juvenile idiopathic arthritis.The research results are presented in the form of descriptive statistics. Comparisons of frequency parameters were made using the Chi-square test. Diff erences between parameters were considered statistically signifi cant at p&lt;0.05. Statistical analysis of the survey results was performed using the statistical package STATISTICA 10.0 and Microsoft Excel 2003 spreadsheet editor.The research and the publication of the materials were approved by the Bioethics Committee of the I. Horbachevsky Ternopil National Medical University (protocol № 73 dated 03.04.2023).The study was conducted within the framework of the research project of the Department of Children’s Diseases with PediatricSurgery of the I. Horbachevsky Ternopil National Medical University “Improvement of methods of diagnostics, treatment and rehabilitation of the most common children’s diseases”, registration number 0122U000039.Results. The majority of respondents were female (96.8%), between the ages of 31 and 50 (63.5%), and employed in the hospitalsetting (90.5%). Most were experienced workers with more than 20 years of experience (52.4%). Overall, the majority of respondents (71.0%) correctly identifi ed which diseases are rare. The percentage of correct answers regarding knowledge of rare diseases ranged from 47.9% for PID to 77.5% for SB, while correct answers regarding skills ranged from 41.3% for SB to 63.0% for PID. Overall, nurses demonstrated better knowledge than skills regarding rare diseases (p=0.0003). The most problematic issues were that HIV/AIDS was classifi ed as PID (31.7%), lack of knowledge about standards of neurogenic bladder control in children with SB (49.2%), unfamiliarity with the technique of subcutaneous immunoglobulin administration (87.3%), and bowel cleansing procedures in children with SB (95.2%), as well as infection control in patients with cystic fi brosis (66.1%).Conclusion. The study revealed a lack of awareness among nurses regarding certain rare diseases. The lowest level of knowledge was found for primary immunodefi ciencies. There is a need to improve nurses’ knowledge and skills regarding rare diseases, which can improve the quality of care for rare disease patients and their families. The development of educational interventions for nurses can help to increase their awareness of rare diseases.

The effectiveness of Omalizumab in the treatment of Hyper-IgE syndrome: A case report

BACKGROUND - Hyper-immunoglobulin E (IgE) syndrome (HIES) is a rare primary multisystem immunodeficiency disorder with an incidence of one case per million population. It is characterized by elevated serum IgE levels, dermatitis, recurrent skin and lung infections, skeletal abnormalities such as scoliosis, and distinctive facial features. Moreover, the clinical manifestations may include vascular, dental, joint, and brain abnormalities. Treatment for HIES predominantly targets symptom relief. Omalizumab, a monoclonal antibody, works by inhibiting the binding of free IgE to receptors on effector cells, consequently reducing the release of inflammatory mediators and alleviating some cutaneous and respiratory symptoms of HIES. To date, according to our understanding, no treatment protocol for HIES patients exists in Jordan. To fill this gap, we report our experience using omalizumab and intravenous immunoglobulin (IVIG) in treating the first documented case of HIES in Jordan. CASE PRESENTATION - We present the case of an 18-year-old male patient who had been diagnosed with HIES since infancy. The patient had been subjected to multiple treatment trials, but none proved effective. In our treatment protocol, 150 mg of omalizumab was administered subcutaneously every 2 weeks, later increasing to 300 mg. Following this treatment, the eczema symptoms and eosinophil count showed a marked reduction. The patient’s IgE level decreased from 21,800 IU/ml in 2011 and 2,039 IU/ml in 2019 to 764 IU/ml in 2022, with treatment commencing in the latter year. CONCLUSION - The combined use of omalizumab and IVIG therapies demonstrated efficacy in reducing the elevated IgE levels and symptom severity in our patient. There is a need for more case studies to report clinical findings in the management of HIES