A Case of X-Linked Moesin-Associated Immune Deficiency in a Pediatric Patient

Background: X-Linked Moesin-Associated Immune Deficiency (X-MAID) is a rare severe combined immunodeficiency (SCID) subtype that can present at any age due to its variability. Depending on severity, patients demonstrate failure to thrive, recurrent bacterial and viral infections, and increased susceptibility to varicella zoster. It has been characterized by marked lymphopenia with hypogammaglobulinemia and impaired T-cell migration and proliferation. Case Presentation: This is a report of a Cuban 7-year-old male with poor weight gain and facial dysmorphia. He had a history of recurrent bacterial gastrointestinal infections and pneumonia beginning at 4 months of age. He additionally had 4-6 upper respiratory tract and ear infections annually. While still living in Cuba, he was admitted for a profound EBV infection in the setting of significant leukopenia. A bone marrow biopsy confirmed no malignancy. After he moved to the United States, his laboratory work-up revealed marked leukopenia with low absolute neutrophil and lymphocyte count with low T and B cells, very low immunoglobulin levels IgG, IgA, and IgM, and poor vaccination responses to streptococcus pneumonia, varicella zoster, and SARS-CoV-2. Genetic testing revealed a missense pathogenic variant c.511C>T (p.Arg171Trp) in the moesin (MSN) gene associated with X-MAID. He was managed with Bactrim and acyclovir prophylaxis, and immunoglobulin replacement therapy, and considered for hematopoietic stem cell transplantation. Discussion(s): Diagnosis of X-MAID should be considered in patients with recurrent infections and profound lymphopenia. As with SCID, early diagnosis and intervention is of utmost importance to prevent morbidity and mortality. This case demonstrates the importance of genetic testing in identifying this disease as it may prompt an immunologist to consider HSCT if conservative management is suboptimal. In the current literature, HSCT appears promising, but the long-term outcomes have yet to be described.Copyright © 2023 Elsevier Inc.

AI and the Clinical Immunology/Immunoinformatics for COVID-19

Artificial Intelligence (AI) is contributing to the campaign against the Coronavirus Disease 2019 (COVID-19). Since 2019, more and more AI frameworks and applications in COVID-19 have been proposed, and the recent research has shown that AI is a promising technology because AI can achieve a higher degree of scalability, a more comprehensive and identification of patterns in the vast amount of unstructured and noisy data, accelerated processing power, and strategies to outperform traditional methods in many specific tasks. In this chapter, we focus on the specific AI applications in the clinical immunology/immunoinformatics for COVID-19. More precisely, on one hand, we discuss the application of deep learning in designing SARS-CoV-2 vaccines, and, on the other hand, we discuss the development of a machine learning framework for investigating the SARS-CoV-2 mutations that can help us better respond to the future mutant viruses, including designing more robust vaccines based on such AI approaches. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Persistent Topological Laplacian Analysis of SARS-CoV-2 Variants

Topological data analysis (TDA) is an emerging field in mathematics and data science. Its central technique, persistent homology, has had tremendous success in many science and engineering disciplines. However, persistent homology has limitations, including its inability to handle heterogeneous information, such as multiple types of geometric objects;being qualitative rather than quantitative, e.g., counting a 5-member ring the same as a 6-member ring, and a failure to describe nontopological changes, such as homotopic changes in protein–protein binding. Persistent topological Laplacians (PTLs), such as persistent Laplacian and persistent sheaf Laplacian, were proposed to overcome the limitations of persistent homology. In this work, we examine the modeling and analysis power of PTLs in the study of the protein structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain (RBD). First, we employ PTLs to study how the RBD mutation-induced structural changes of RBD-angiotensin-converting enzyme 2 (ACE2) binding complexes are captured in the changes of spectra of the PTLs among SARS-CoV-2 variants. Additionally, we use PTLs to analyze the binding of RBD and ACE2-induced structural changes of various SARS-CoV-2 variants. Finally, we explore the impacts of computationally generated RBD structures on a topological deep learning paradigm and predictions of deep mutational scanning datasets for the SARS-CoV-2 Omicron BA.2 variant. Our results indicate that PTLs have advantages over persistent homology in analyzing protein structural changes and provide a powerful new TDA tool for data science. [ FROM AUTHOR] Copyright of Journal of Computational Biophysics & Chemistry is the property of World Scientific Publishing Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Structural implications of SARS-CoV-2 Surface Glycoprotein N501Y mutation within receptor-binding domain [499-505]–computational analysis of the most frequent Asn501 polar uncharged amino acid mutations

The aim of this study was to evaluate the impact of the most frequent Asn501 polar uncharged amino acid mutations upon important structural properties of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Surface Glycoprotein RBD–hACE2 (human angiotensin-converting enzyme 2) heterodimer. Mutations N501Y, N501T and N501S were considered and their impact upon complex solubility, secondary motifs formation and intermolecular hydrogen bonding interface was analyzed. Results and findings are reported based on 50 ns run in Gromacs molecular dynamics simulation software. Special attention is paid on the biomechanical shifts in the receptor-binding domain (RBD) [499-505]: ProThrAsn(Tyr)GlyValGlyTyr, having substituted Asparagine to Tyrosine at position 501. The main findings indicate that the N501S mutation increases SARS-CoV-2 S-protein RBD–hACE2 solubility over N501T, N501 (wild type): (Formula presented.), (Formula presented.). The N501Y mutation shifts (Formula presented.) -helix S-protein RBD [366-370]: SerValLeuTyrAsn into π-helix for t > 38.5 ns. An S-protein RBD [503-505]: ValGlyTyr shift from (Formula presented.) -helix into a turn is observed due to the N501Y mutation in t > 33 ns. An empirical proof for the presence of a Y501-binding pocket, based on RBD [499-505]: PTYGVGY (Formula presented.) 's RMSF peak formation is presented. There is enhanced electrostatic interaction between Tyr505 (RBD) phenolic -OH group and Glu37 (hACE2) side chain oxygen atoms due to the N501Y mutation. The N501Y mutation shifts the (Formula presented.) hydrogen bond into permanent polar contact;(Formula presented.);(Formula presented.). © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Persistent chemosensory dysfunction in COVID-19 patients: a deep dive into the psychophysical and genetic characterisation of an Italian cohort

Background/Objectives: Chemosensory dysfunction is a hallmark of SARS-CoV-2 infection;nevertheless, the genetic factors predisposing to long-term smell and taste loss are still unknown. This study aims to identify candidate genes possibly involved in persistent smell/taste loss through Whole Genome Sequencing (WGS) analysis of a large cohort of 130 fully characterised Italian individuals, previously diagnosed with COVID-19. Method(s): DNA of all analysed patients was used to perform WGS analysis, and a detailed personal anamnesis was collected. Moreover, orthonasal function was assessed through the extended Sniffin' Sticks test, retronasal function was tested with 20 powdered tasteless aromas, and taste was determined with validated Taste Strips. Self-reported smell and taste alterations were assessed via Visual Analog Scales plus questionnaires. Result(s): The clinical evaluation allowed to classify the patients in two groups: 88 cases affected by persistent smell dysfunction (median age, 49) and 42 controls (median age, 51). Among cases, 26.1% (n = 23) were functionally anosmic and 73.9% (n = 65) were hyposmic. Within cases, 77 underwent the taste strip test: 53.2% (n = 41) presented hypogeusia and 46.8% (n = 36) were normogeusic. Preliminary WGS results on a first subset of 76 samples confirmed the important role of UGT2A1 gene, previously described as involved in smell loss. Interestingly, we identified a nonsense variant (rs111696697, MAF 0.046) significantly associated with anosmia in males (p-value: 0.0183). Conclusion(s): Here, for the first time a large cohort of patients, fully characterised through a comprehensive psychophysical evaluation of smell and taste, have been analysed to better define the genetic bases of COVID-19-related persistent chemosensory dysfunction.

IRF2BP2 mutation with autoimmune enteropathy, immune deficiency, and respiratory failure

Case history: We present the case of a 31-year-old Hispanic male with history of recurrent bronchiectasis, invasive aspergillosis, and severe persistent asthma, who is now status post lung transplant for end-stage lung disease. He initially presented at 7 years of age with diarrhea, failure to thrive, and nearly absent immunoglobulin levels (IgG < 33 mg/dL, IgA < 7 mg/dL, IgM = 11 mg/dL, IgE = 4 IU/dL) necessitating IVIG treatment. Small intestinal biopsy showed villous atrophy consistent with autoimmune enteropathy. Sweat chloride was reported as indeterminate (44 me/dL). Initial WBC, platelet, and T- and NK-cell counts were within normal range, and B-cell count and percentage were borderline low. Most recently, he was found to have increased immature B-cell count (CD21low), decreased memory B-cells, and poor pneumococcal vaccine antibody response. Patient has been hospitalized numerous times with increasingly severe bronchiectasis, pneumonitis, and COVID-19 infections twice despite vaccination, leading to respiratory failure and lung transplantation. Family history is negative for immune deficiency and lung diseases. Discussion(s): Of these 3 VUSs (see the table), the one in IRF2BP2 has the most pathogenic potential due to its autosomal dominant inheritance, its location in a conserved domain (Ring), and previous case reports of pathogenic variants at the same or adjacent alleles 1-3. Baxter et al reported a de novo truncating mutation in IRF2BP2 at codon 536 (c.1606CinsTTT), which is similar to our patient's mutation. This patient was noted to have an IPEX-like presentation, with chronic diarrhea, hypogammaglobulinemia, and recurrent infections. Variant Functional Prediction Score for our variant predicts a potentially high damage effect. There are 2 other case reports of heterozygous mutations in loci adjacent to this allele;one (c.1652G>A)2 with a similar clinical phenotype to our patient and the other (C.625-665 del)3 with primarily inflammatory features and few infections. Impact: This case highlights a variant in IRF2BP2 associated with severe hypogammaglobulinemia, recurrent pulmonary infections, and autoimmune enteropathy. [Table presented]Copyright © 2023 Elsevier Inc.

A New Registry for Genetic Diagnosis of Inborn Errors of Immunity within the Military Health System

Genotypic definition of monogenic inborn errors of immunity (IEIs) continues to accelerate with broader access to next generation sequencing, underscoring this aggregated group of disorders as a major health burden impacting both civilian and military populations. At an estimated prevalence of 1 in 1200 individuals, IEIs affect ~8,000 patients within the Military Health System (MHS). Despite access to targeted gene/exome panels at military treatment facilities, most affected patients never receive a definitive genetic diagnosis that would significantly improve clinical care. To address this gap, we established the first registry of IEI patients within the MHS with the goal of identifying known and novel pathogenic genetic defects to increase diagnosis rates and enhance clinical care. Using the registry, a research protocol was opened in July 2022. Since July we have enrolled 75 IEI patients encompassing a breadth of phenotypes including severe and recurrent infections, bone marrow failure, autoimmunity/autoinflammation, atopic disease, and malignancy. Enrolled patients provide blood and bone marrow samples for whole genome, ultra-deep targeted panel and comprehensive transcriptome sequencing, plus cryopreservation of peripheral blood mononuclear cells for future functional studies. We are also implementing and developing analytical methods for identifying and interrogating non-coding and structural variants. Suspected pathogenic variants are adjudicated by a clinical molecular geneticist using state-of-the-art analysis pipelines. These analyses subsequently inform in vitro experiments to validate causative mutations using cell reporter systems and primary patient cells. Clinical variant validation and return of genetic results are planned with genetic counseling provided. As a proof of principle, this integrated genetic evaluation pipeline revealed a novel, candidate TLR7 nonsense variant in two adolescent brothers who both endured critical COVID-19 pneumonia, requiring mechanical ventilation and extracorporeal membrane oxygenation. Our protocol is therefore poised to greatly enrich clinical genetics resources available in the MHS for IEI patients, contributing to better diagnosis rates, informed family counseling, and targeted treatments that collectively improve the health and readiness of the military community. Moreover, our efforts should yield new mechanistic insights on immune pathogenesis for a broad variety of known and novel IEIs.Copyright © 2023 Elsevier Inc.

Mastocytosis and COVID19 infection and vaccination: A pediatric series

Introduction: Mastocytosis encompasses a heterogeneous group of diseases characterized by an accumulation of clonal mast cells (MC) in the skin and/or internal organs, and symptoms of MC activation. This MC activation can be elucidated by several factors, including infections or vaccination. Objective(s): We present our experience with COVID infection and vaccination in a series of 133 patients with pediatric mastocytosis. Method(s): Between January 1998 and December 2022, 133 pediatric patients have been referred to our hospital owing to clinically suspected MC disorder, mainly with mastocytosis in the skin. The final diagnoses of mastocytosis were established by the presence of typical skin lesions together with an increase of MC numbers in a biopsy from lesional skin or activating KIT mutations in lesional skin tissue. Serum baseline tryptase and total immunoglobulin E levels were measured, and patients underwent a comprehensive allergy workup to confirm atopic status and history of anaphylaxis. Regarding vaccination, REMA's (Spanish Network on Mastocytosis) protocol was followed. Result(s): 13 patients with COVID infection were identified, of which 25 (56,8%) were female and 0% had symptoms of MC activation. All of them had an asymptomatic or mild course of COVID infection. None of the patients experimented MC activation symptoms during viral illness. Regarding COVID vaccination, all patients received premedication with antihistamine 60 minutes prior vaccination. No one experimented immediate reactions and only one patient (0,75%) referred worsening of MC activation symptoms (baseline pruritus, urtication and brain fog) only after the first doses, recovering without changes in his treatment (oral cromoglycate and antihistamine) in two months. Discussion(s): Although MC have been implicated in the pathogenesis of cytokine storm in COVID19, there is no clinical evidence of SARSCoV- 2-induced MC activation, perhaps related to the fact that bone marrow MC lack angiotensin-converting enzyme 2 receptors.

What's Next for C0VID-19 Vaccines and Variants?

Telma Lery Janssen EMEA therapeutic area lead for infectious diseases and vaccines at Johnson & Johnson, explains that the company's COVID-19 vaccine candidate (also known as Ad26.COV2.S, Ad26COVS1, VAC31518, JNJ-78436735, or Ad26-S.PP) is a monovalent, recombinant, inactivated/non-infective adenovirus vector (similar to a cold virus), which contains a transgene that codes for the coronavirus spike (S) protein. The vaccine technology, AdVac, is based on the development and production of adenovirus vectors (gene carriers). Adenovirus vectors (gene carriers) are genetically altered forms of an adenovirus and lack the DNA needed to replicate. Some of the main differences between a COVID-19 oral tablet vaccine from injectable COVID-19 vaccines, according to Tucker, include: * Immune responses are triggered in the mucosa and the serum with a COVID-19 oral tablet vaccine (based on preclinical and clinical testing), unlike the existing vaccines that are serum-only. * Ease of distribution and vaccination with a COVID-19 oral tablet vaccine, which eliminates the need for special accommodations to transport injectable vaccines that require cold chain infrastructure as well as the need for trained professionals to administer vaccines.

Function and interaction of coronavirus ion channel proteins

Objective: COVID-19 has emerged as a significant global health crisis causing devastating effects on world population accounting for over 6 million deaths worldwide. Although acute RTI is the prevalent cause of morbidity, kidney outcomes centered on a spectrum of AKI have evolved over the course of the pandemic. Especially the emerging variants have posed a daunting challenge to the scientific communities, prompting an urging requirement for global contributions in understanding the viral dynamics. In addition to canonical genes, several subgroup- specific accessory genes are located between the S and E genes of coronaviruses regarding which little is known. Previous studies have shown that accessory proteins (aps) in viruses function as viroporins that regulate viral infection, propagation and egress [1]. In this study we attempted to characterize the function of aps of coronavirus variants as ion channels. Furthermore, we also probed the interaction of ap4 with the host system. Method(s): Serial passaging (selection pressure), growth kinetics, confocal imaging, genome sequence analysis and proteomics were performed in Huh-7, MRC5 cells and/or human monocyte derived macrophages. Potassium uptake assay was performed in a Saccharo myces cerevisiae strain, which lacks the potassium transporters trk1 and trk2. Ion conductivity experiments were performed in Xenopus laevis oocytes using Two Electrode Voltage Clamp (TEVC) method. Result(s): Serial passaging demonstrated the acquisition of several frameshift mutations in ORF4 resulting in C-terminally truncated protein versions (ap4 and ap4a) and indicate a strong selection pressure against retaining a complete ORF4 in vitro. Growth kinetics in primary cells illustrated a reduction of viral titers when the full-length ap4 was expressed compared to the C-terminally truncated protein ap4a. Confocal imaging showed that ap4 and ap4a are not exclusively located in a single cellular compartment. Potassium uptake assay in yeast and TEVC analyses in Xenopus oocytes showed that ap4 and ap4a act as a weak K+ selective ion channel. In addition, accessory proteins of other virus variants also elicited microampere range of currents. Conclusion(s): Our study provides the first evidence that ap4 and other accessory proteins of coronavirus variants act as viroporins. Future studies are aimed at demonstrating the role of ap4 during the viral life cycle by modulating ion homeostasis of host cell in vivo (interacting proteins obtained from proteomic studies) and thereby serve as a tool for potential drug target.

Feline Coronavirus Infections

• First Described: 1963 (Holzworth, 1963);a viral etiology was not identified until the 1970s. • Cause: Feline coronavirus (family Coronaviridae, genus Coronavirus). • Affected Hosts: Cats and wild felids, especially cheetahs. • Modes of Transmission: Fecal-oral (FECV), internal mutation (FIPV) • Geographic Distribution: Worldwide. • Major Clinical Signs: Fever, lethargy, inappetence, vomiting, diarrhea, dehydration, icterus, tachypnea, uveitis, neurologic signs, abdominal distention due to ascites. • Differential Diagnoses: Toxoplasmosis, congestive heart failure, carcinomatosis, lymphoma, pancreatitis, rabies, cryptococcosis, bacterial peritonitis, pyothorax, bacterial meningitis, chronic stomatitis, multiple myeloma, FeLV or FIV infection. • Human Health Significance: Feline coronaviruses do not infect humans. © 2021 Elsevier Inc. All rights reserved.

Upskilling haematological services for WGS and germline assessments through a regional skin biopsy training programme

NHS England Genomics introduced whole genome sequencing (WGS) with standard-of- care (SoC) genetic testing for haemato-oncology patients who meet eligibility criteria, including patients with acute leukaemia across all ages, and exhausted SoC testing. Alongside, the role of germline mutations in haematological cancers is becoming increasingly recognised. DNA samples are required from the malignant cells (somatic sample) via a bone marrow aspirate, and from non-malignant cells (germline sample) for comparator analysis. Skin biopsy is considered the gold-standard tissue to provide a source of fibroblast DNA for germline analysis. Performing skin punch biopsies is not within the traditional skillset for haematology teams and upskilling is necessary to deliver WGS/germline testing safely, independently and sustainably. A teaching programme was designed and piloted by the dermatology and haematology teams in Sheffield and delivered throughout the NHS trusts in North East & Yorkshire Genomic Laboratory Hub. The training programme consisted of a 90-min session, slides, video and practical biopsy on pork belly or synthetic skin, designed to teach up to six students at one time. To disseminate best practice, the standard operating procedure and patient information used routinely in Sheffield were shared, to be adapted for local service delivery. From January 2021 to December 2022, 136 haematology staff from 11 hospitals, including 34 consultants, 41 registrars, 34 nurses and 8 physician associates, across the NEY GLH region completed the skin biopsy training programme. Feedback from the course was outstanding, with consistently high scores in all categories. Practical components of the course were especially valued;98.6% (71/72) trainees scored the practical element of the programme a top score of 5 out of 5, highlighting that despite the challenges of delivering face-to- face teaching due to COVID-19, teaching of practical skills was highly valued;training in this way could not have been replicated virtually. Costs of the programme have been approximately 16 000, including consultant input and teaching/educational materials. Recent support has been provided by a separately funded Genomic Nurse Practitioner (GNP), with succession planning for the GNP to take over leadership from the consultant dermatologist. Plans are in place to use the remaining budget to disseminate the programme nationally. Our training programme has shown that skin biopsy can be formally embedded into training for haematology consultants, trainees, nursing team, and physician associates. Delivery of training can be effective and affordable across regional GLHs with appropriate leadership and inter-speciality coordination, and ultimately sustainable with specialist nursing staff, including GNPs.

US drug approvals rise in 2020 over previous year

Several medicines were approved as first treatments, including Gilead Sciences' Veklury (remdesivir) for patients with COVID-19 who require hospitalization (4);Amivas' artesunate for injection for severe malaria (5);Horizon Therapeutics Ireland DAC's Tepezza (teprotumumab-trbw), an antibody drug conjugate (ADC) for treating thyroid eye disease (6);and Ultragenyx Pharmaceutical's Dojolvi (triheptanoin) and Alnylam Pharmaceuticals' Oxlumo (lumasiran), both first treatments for metabolic disorders-Dojolvi for treating paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (7) and Oxlumo (lumasiran) for treating the rare genetic disorder, primary hyperoxaluria type 1 (8). Blueprint Medicines Corporation) for treating unresectable or metastatic gastrointestinal stromal tumours harboring a platelet-derived growth factor receptor alpha exon 18 mutation (9);Koselugo (selumetinib, AstraZeneca Pharmaceuticals), for neurofibromatosis type 1 (10);Pemazyre (pemigatinib, Incyte Corporation), for certain types of previously treated, advanced bile duct cancer (cholangiocarcinoma) (11);Tabrecta (capmatinib, Novartis) for non-small cell lung cancer that has spread to other parts of the body and whose tumours have mutations that lead to MET exon 14 skipping (12);and Retevmo (selpercatinib, Loxo Oncology, a subsidiary of Eli Lilly and Company) for treating three types of tumours with alterations of the "rearranged during transfection" gene (13). Gilead, "U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma," Press Release, 24 July 2020.

Genotype-phenotype correlations in five patients harboring SERPINA1 mutations and previously showing a severe COVID-19 infection

Background/Objectives: During COVID-19 pandemic, it is essential to detect patients potentially at risk of life-threatening complications, due to possible specific genetic mutations. The aim of our work is to show a practical application of genetic testing, allowing a diagnosis of alpha 1 antitrypsin deficiency in cases with a severe clinical course during COVID-19 infection. Method(s): During hospitalization for COVID-19, we identified 5 patients (3 female, 2 males from two different families, age range 18-47 years) with a severe course of COVID-19 infection, requiring high pressure ventilation with high volume oxygen supply. Two months after discharge, those patients were reevaluated with respiratory function tests, biochemical tests, genetic counselling and genetic testing. A peripheral blood sampling for SERPINA1 genetic testing has been performed, using Sanger sequencing. Result(s): Two months after discharge, in all 5 patients respiratory function tests were consistent with a dysventilatory obstructive syndrome, in contrast with usual findings related to COVID-19 infection. Blood test still showed increase plasmatic transaminase concentration in 3 out of 5 patients, one having increased serum bilirubin as well. We performed SERPINA1 genetic testing showing homozygosity for SERPINA1 pathogenic mutations (c.193del and c.875C>T, respectively) in all 5 patients. Conclusion(s): These cases showed the importance of genetic testing for patients with unexplained severe COVID-19 infection. Genetic testing allowed the diagnosis of cases affected by alpha 1 antitrypsin deficiency, associated with dysventilatory obstructive syndrome, that may worsen the short and long term prognosis of COVID-19.

Primary immunodeficiency associated with a SAMD9L mutation

Background: SAMD9L is a tumor suppressor involved in regulating the proliferation and maturation of cells, particularly those derived from the bone marrow, and appears to play an important role in cerebellar function. It can be activated in hematopoietic stem cells by type I and type II interferons. It has been hypothesized to act as a critical antiviral gatekeeper regulating interferon dependent demand driven hematopoiesis. Gain of function mutations can present with an immunodeficiency due to transient severe cytopenias during viral infection. Case presentation: We report a 3-year-old boy born full term with a history of severe thrombocytopenia requiring transfusions, developmental delay, ataxia, seizure disorder, and recurrent severe respiratory viral infections. His infectious history was significant for respiratory syncytial virus with shock requiring extracorporeal membrane oxygenation complicated by cerebral infarction and a group A streptococcus empyema, osteomyelitis requiring a left below the knee amputation, and infections with rhinovirus, COVID-19, and parainfluenza requiring hospitalizations for respiratory support. Initial immunologic evaluation was done during his hospitalization for parainfluenza. His full T cell subsets was significant for lymphopenia across all cell lines with CD3 934/microL, CD4 653/microL, CD8 227/microL, CD19 76/microL, and CD1656 61/microL. His mitogen stimulation assay to phytohemagglutinin and pokeweed was normal. Immunoglobulin panel showed a mildly decreased IgM of 25 mg/dL, but normal IgA and IgG. Vaccine titers demonstrated protective titers to 12/22 pneumococcus serotypes, varicella, diphtheria, mumps, rubella, and rubeola. Repeat full T cell subsets 6 weeks later revealed marked improvement in lymphocyte counts with CD3 3083/microL, CD4 2101/microL, CD8 839/microL, CD19 225/microL, and CD1656/microL. A primary immunodeficiency genetic panel was ordered and positive for a heterozygous SAMD9L c.1549T>C (p.Trp517Arg) mutation classified as a variant of unknown significance. Discussion(s): This patient's history of severe viral infections, ataxia, thrombocytopenia, and severe transient lymphopenia during infection is suggestive of a SAM9DL gain of function mutation. Protein modeling done by the laboratory suggests this missense mutation would affect protein structure. The mutation found has been observed in individuals with thrombocytopenia. This case highlights the importance of immunophenotyping both during acute illness and once recovered.Copyright © 2023 Elsevier Inc.

RHEUMATOLOGISTS BEWARE OF LOW ALP: A CASE OF HYPOPHOSPHATASIA MISDIAGNOSED AS FIBROMYALGIA, CAUSING LONG DIAGNOSTIC DELAY

BackgroundHypophosphatasia(HPP), a rare, inherited metabolic disease featuring low serum alkaline phosphatase (ALP) activity due to ALPL (encoding tissue non-specific alkaline phosphatase) gene mutation[1,2]. A wide-ranging clinical spectrum is often seen due to defective mineralisation affecting teeth, bones, joints and muscles[1]. This disease has a prevalence of 1/6370 in Europe and is often misdiagnosed and underdiagnosed with a diagnostic delay of more than ten years[1] The treatment is often supportive for milder cases and enzyme replacement therapy in severe cases.ObjectivesTo share this case to raise awareness among Rheumatologists.MethodsThis 58-year-old Caucasian female had her first HPP symptom as early eruption of deciduous teeth, along with recurrent dental infections and gum problems. She was diagnosed with flat feet at age five, had a big toe fracture at sixteen, followed by a metatarsal fracture. She experienced leg muscle cramps and aches, affecting her performance in sport during school life.At the age of thirty she began noticing weakness in arms and legs, which progressed over the years. She faced significant early morning stiffness along with painful ribs, hips, knees, shoulders, and small joints of feet when walking.She was diagnosed with Fibromyalgia at the age of forty-four. The following ten years she met numerous specialists including rheumatologist, pain specialist and physiotherapists. She was also diagnosed with early osteoarthritis, pernicious anaemia, hyperlipidemia, functional neurological syndrome, and central sensitization syndrome. She had multiple trials of steroids and opioids, all of which were stopped either due to side effects or inefficiency.A major flare of symptoms five years ago rendered her bedbound for three months, following which a chemical pathologist noticed a persistent low ALP levels and decided to investigate for HPP. It took another four years to complete these investigations due to the coronavirus pandemic.Currently, she is unable to weight bear or climb stairs and must stay indoors or in bed during flareup. She moved into a ground floor flat at the age of 54 and use a walking stick occasionally. By 58, she is unable to work and had given up her own business due to pain, weakness, and disability.ResultsOn clinical assessment, her height is 160 cm, faced difficulty getting up from chair, has an antalgic waddling gait, with a 6-minute walking distance of 60 metre, stopped after three minutes, and had a Brief Pain Inventory pain severity score of 7/10. Her ALP level is 24 U/L and PLP/PA ratio is 18.8 (ref < 5), and genetic testing showed heterozygous missense variant of ALPL gene mutation.ConclusionIt took more than forty years to reach a conclusive diagnosis of childhood onset HPP. Low ALP level is a signature of HPP and warrants investigations. Diagnosis can be challenging due to the rareness and variable presentation, however recognition of HPP features is crucial for timely referral, optimal disease management and potential improvement in quality of life.References[1]Högler W, Langman C, Gomes da Silva H, Fang S, Linglart A, Ozono K, Petryk A, Rockman-Greenberg C, Seefried L, Kishnani PS. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord. 2019 Feb 14;20(1):80. doi:10.1186/s12891-019- 2420-8. PMID: 30764793;PMCID: PMC6376686.[2]Injean P, Lee S, Downey C. Hypophosphatasia May Be Misdiagnosed as Fibromyalgia: A Single Center Experience []. Arthritis Rheumatol. 2020;72 (suppl 10). https://acrs.org//hypophosphatasia-may-be-misdiagnosed-as- ibromyalgia-a-single-center-experience/. Accessed January 14, 2023.[3]Lefever E, Witters P, Gielen E, Vanclooster A, Meersseman W, Morava E, Cassiman D, Laurent MR. Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates. J Clin Densitom. 2020 Jul-Sep;23(3):340- 48. doi: 10.1016/j.jocd.2018.12.006. Epub 2018 Dec 21. PMID: 30655187.Acknowledgements:N L.Disclosure of InterestsNone Declared.

A comprehensive knowledgebase of known and predicted human genetic variants associated with COVID-19 susceptibility and severity

Host genetic susceptibility is a key risk factor for severe illness associated with COVID-19. Despite numerous studies of COVID-19 host genetics, our knowledge of COVID-19-associated variants is still limited, and there is no resource comprising all the published variants and categorizing them based on their confidence level. Also, there are currently no computational tools available to predict novel COVID-19 severity variants. Therefore, we collated 820 host genetic variants reported to affect COVID-19 susceptibility by means of a systematic literature search and confidence evaluation, and obtained 196 high-confidence variants. We then developed the first machine learning classifier of severe COVID-19 variants to perform a genome-wide prediction of COVID-19 severity for 82,468,698 missense variants in the human genome. We further evaluated the classifier's predictions using feature importance analyses to investigate the biological properties of COVID-19 susceptibility variants, which identified conservation scores as the most impactful predictive features. The results of enrichment analyses revealed that genes carrying high-confidence COVID-19 susceptibility variants shared pathways, networks, diseases and biological functions, with the immune system and infectious disease being the most significant categories. Additionally, we investigated the pleiotropic effects of COVID-19-associated variants using phenome-wide association studies (PheWAS) in ~40,000 BioMe BioBank genotyped individuals, revealing pre-existing conditions that could serve to increase the risk of severe COVID-19 such as chronic liver disease and thromboembolism. Lastly, we generated a web-based interface for exploring, downloading and submitting genetic variants associated with COVID-19 susceptibility for use in both research and clinical settings (https://itanlab.shinyapps.io/COVID19webpage/). Taken together, our work provides the most comprehensive COVID-19 host genetics knowledgebase to date for the known and predicted genetic determinants of severe COVID-19, a resource that should further contribute to our understanding of the biology underlying COVID-19 susceptibility and facilitate the identification of individuals at high risk for severe COVID-19.Copyright © 2023 Elsevier Inc.

Medical Perspective on COVID-19

In December 2019, a series of acute respiratory illnesses were first reported in central China. Investigations have led to the identification of a novel coronavirus (2019-nCoV), subsequently designated as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as the causative agent of the so-called coronavirus disease 2019 (COVID-19). Since its emergence, SARS-CoV-2 has spread rapidly across the globe, resulting in the current ongoing COVID-19 pandemic, which has claimed the lives of millions of people throughout the world and continues to do so. Beginning with a brief overview of different historical and contemporary theories of infectious diseases, this chapter moves on to review the most recent literature on the origin, structure, pathogenesis, host immune responses, viral evasion of the host immunity, and mutated variants of SARS-CoV-2. In addition, patients' clinical characteristics and risk factors, clinical trials, preventative measures, and the COVID-19 death toll among different countries are discussed. We also overview the utilization of various technologies in the battle against the pandemic, the impact of the pandemic on clinical research and trials, medical insurance, biomedical waste (BMW) generation and management, and the clinical lessons learned. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.