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.

Long-term safety and efficacy of Oleogel-S10 (birch triterpenes) in epidermolysis bullosa wounds: 24-month open-label data from the EASE study

Objectives: The 90-day double-blind phase (DBP) of the Phase 3 EASE study demonstrated accelerated wound healing for Oleogel-S10 (birch triterpenes) versus control gel in epidermolysis bullosa (EB). Here, we report safety and total wound burden results from the 24-month open-label phase (OLP) in which all patients received treatment with Oleogel-S10. Method(s): Total wound burden was assessed using EB Disease Activity and Scarring Index (EBDASI) and Body Surface Area Percentage (BSAP). Data are reported without visit windows to reflect a realworld situation more accurately, particularly considering the COVID- 19 pandemic. Result(s): The patient population was made up of dystrophic EB (n = 178, 86.8%) and junctional EB (n = 25, 12.2%);71.7% (n = 147) of patients were aged <18 years. 141 patients (68.8%) completed the OLP. The mean (SD) treatment duration for all patients was 584.7 (246.1) days. Adverse events were reported in 77.1% of all patients in the OLP versus 81.7% of those receiving Oleogel-S10 in the DBP. Mean BSAP for patients treated with Oleogel-S10 in the DBP reduced from 12.1% at study entry to 6.1% with 27 months of treatment. Similarly, the mean EBDASI skin activity score in the Oleogel-S10 group improved from 19.6 to 15.1 after 27 months. In addition, reductions in both BSAP and EBDASI from OLP baseline were observed in patients who transitioned from control gel to Oleogel-S10 in the OLP. Discussion(s): These data support a reassuring long-term safety profile of Oleogel-S10. Furthermore, the reduction in wound burden previously reported with 15 months of Oleogel-S10 treatment is maintained to the end of OLP. This is encouraging given the nature of this chronic genetic disorder in which there is regular cycling of patients' fragile wounds.

Ndegree39 - Fulminant life-threatening myopathy of the genetic origin

Objectives: Acute myopathy are seen in critically ill patients, in severe SARS-CoV2 pneumonia requiring mechanical ventilation, and other infection illness, toxin and drug-induced complications, or systemic inflammation. Periodic paralysis or carnitine disorders are known genetic causes of acute muscular weakness, besides genetically determined muscle diseases rarely have an acute clinical course. Content: Case presentation: 61-years old, healthy woman, after a one-time vaccination against Covid-19 about 2 weeks earlier, was admitted to the Neurological Department due to symptoms lasting for 2 days. On the first day of the disease she complained of vertigo and double vision, on the following day dysarthia and dysphagia appeared, she stopped walking. On the second day of hospitalization, the patient required mechanical ventilation. The initial diagnosis of Guillaine-Barre syndrome was not confirmed in the electrophysiological and laboratory (CSF) studies. Myopathic pattern with polyphasic potentials of short duration and low amplitude was observed in EMG, without spontaneous activity. In the electron microscope numerous fat drops between bundles of myofibrils in most muscle fibers were seen. She received intravenous immunoglobulins, and steroid therapy, together with high doses of vitamin B2 with very good motor improvement. Multiple acyl-CoA dehydrogenase deficiency (MADD) was suspected, and the Whole Exome Sequencing (WES) was performed. Conclusion(s): The authors note the possibility of acute, life-threatening myopathy, which may be caused by a genetic defect. MADD is a very rare genetic entity which can manifest for the first time very suddenly, especially in the presence of triggers, including but not limited to after vaccinations. Keywords: Acute myopathy;Multiple acyl-CoA dehydrogenase deficiency;Vitamin B2.Copyright © 2023

Study on the risk signal mining related to lopinavir/ritonavir based on the US FDA Adverse Event Reporting System.

Objective: To explore the clinical safety of lopinavir/ritonavir (LPV/r) by mining the risk signals of adverse events (AEs) related to LPV/r for the safe application of the drug in the treatment of novel coronavirus pneumonia (COVID-19). Method(s): The risk signals related to LPV/r in AE reports of US FDA Adverse Event Reporting System (FAERS) from the first quarter of 2010 to the third quarter of 2019 were mined by reporting odds ratio (ROR). An AE with reports more than 3 and 95% confidence interval (CI) lower limit of ROR greater than 1 was defined as a positive signal. AEs were counted and classified using the preferred system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA). The PTs of top 50 adverse event reports and signal strength were selected and analyzed. Result(s): From the first quarter of 2010 to the third quarter of 2019, a total of 13 335 AE reports with LPV/r as the primary suspicious drug were reported in the FAERS database. Four hundred and fifty-five AE risk signals with reports more than 3 and the 95%CI lower limit of ROR greater than 1 were detected, involving 7 718 AE reports. The top 2 system organs involved in AE reports were "injury, poisoning and procedural complications" [13.6% (1 051/7 718)] and "pregnancy, puerperium and perinatal conditions" [11.7% (899/7 718)]. However, 998 (95.0%) of 1051 AE reports involved in "injury, poisoning and procedural complications" were related to drug exposure during pregnancy. The system organ with the highest signals was "congenital, familial and genetic disorders" [16.3% (74/455)]. In addition, 144 AEs caused by drug interactions were detected, which ranked the 7th in the AE reports. Conclusion(s): The risk signals of fetal, neonatal and infant abnormalities related to LPV/r during pregnancy were detected, suggesting that attention should be paid to the risk of using LPV/r in pregnant women and infants. The interaction between LPV/r and other drugs was also worthy of attention.Copyright © 2020 by the Chinese Medical Association.

CLINICAL CASE OF COVID-19 IN A CHILD WITH A RARE SMITH-LEMLI-OPITZ SYNDROME.

Severe forms of COVID-19 are more likely to develop in children of the first year of life with genetic disorders and congenital malformations. Only a few lethal outcomes of the disease in children have been registered ongoing Worldwide over the entire period of the COVID-19 pandemic. This Article represents a clinical case of COVID-19 in a child with a rare Smith-Lemli-Opitz syndrome. On the 2nd day after the reported contact with a family member with COVID-19 the patient aged 3 years and 2 months old was hospitalized in the infectious diseases department with the diagnoses of <<Severe coronavirus infection (PCR-confirmed);cardiopulmonary insufficiency;and congenital heart disease>>. Since the age of 1.5 months old the patient repeatedly underwent inpatient examination and treatment with the Psycho-Neurological Department of the Belgorod Oblast Regional Children's Clinical Hospital (located in Belgorod, Russia). Furthermore, at the age of 1.5 y/o, according to the results of the medical genetic counseling, the diagnosis of Smith- Lemli-Opitz syndrome was established. Due to the COVID-19, the patient's condition deteriorated rapidly, and on the 5th day after the hospitalization the patient has died due to acute heart failure, cardiogenic pulmonary edema and pulmonary hemorrhage.Copyright © 2023 T.A. Kryuchkova.

The burden of a new coronavirus infection in a Children's multidisciplinary hospital in St. Petersburg 2020-2021.

Objective: To describe the burden of COVID-19 in a children's multidisciplinary hospital for two years of the pandemic, taking into account of age, severity of the disease, the spectrum of underlying conditions and the intensive care need. Method(s): An assessment of 6048 cases of COVID-19 in patients under 18 years of age hospitalized from March 26, 2020 to December 31, 2021 was carried out. The diagnosis was confirmed by PCR on an outpatient basis or after hospitalization with the help of diagnostic kits registered in the Russian Federation. The features of the work of a children's multidisciplinary hospital in new conditions, the dynamics of hospitalization, age characteristics and new coronavirus (CV) infection severity in the pandemic development process are presented. The analysis of the underlying condition's structure depending on the severity of the disease, as well as the need and volume of therapy in the intensive care unit. The frequency and main characteristics of children's multisystem inflammatory syndrome (MIS-C) in hospital conditions, long-term PCR positivity and its effect on the duration of inpatient treatment of children have been established. Result(s): The spread of SARS-COV-2 in St. Petersburg required a radical change in the work of the children's multidisciplinary hospital. During the two years of the pandemic, four waves of hospitalization of children with new CV were revealed, differing in duration, intensity, and frequency of lung damage, but having no significant differences in the proportion of severe forms of the disease (1.7-2.8% of cases). Intensive therapy was required in 3.6% of cases, of which only 1/3 was due to the severe course of COVID-19 with a lung lesion volume of up to 100%. In 1/3 of cases, patients had risks of developing severe forms and in 1/3 - other pathology. Severe course of new CV was significantly more often accompanied by the need for respiratory support, anticoagulants and anti-inflammatory therapy. Contributing factors of severe forms and unfavorable outcomes were: pathology of the central nervous system, genetic diseases and malformations, obesity, as well as chronic bronchopulmonary pathology. Mortality in the hospital was recorded only among children with severe underlying conditions (0.1% of cases). D-MVS was registered significantly more often in boys (7 out of every 10 patients), accounting for 1.2% of cases of hospitalization of children with new CV over the entire period. Convalescent PCR-positivity in the outcome of COVID-19 was detected in 1/3 of children, significantly more often during the autumn-winter waves of the pandemic and among patients of high school age. Conclusion(s): New CV is gradually strengthening its position in the structure of acute respiratory pathology in children. Some of SARS-COV-2 infection cases is accompanied by extensive lung damage, as well as severe systemic inflammation independently or in the other infectious diseases structure, induction of the debut of various somatic pathology is not excluded. The presented data confirm the need for increased attention at high risk of adverse respiratory diseases outcomes children. All severe cases of COVID-19 in children require a personalized approach, taking into account the existing background diseases and possible options for the progression of the process. MIS-C should be considered as a systemic inflammatory response syndrome within the framework of an infectious disease of various etiologies, differentiated with Kawasaki disease and the debut of systemic diseases. The long-term PCR-positivity in the outcome of COVID-19 requires further study to address the need and nature of therapy in order to prevent further spread of infection in the population.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.

The burden of a new coronavirus infection in a Children's multidisciplinary hospital in St. Petersburg 2020-2021.

Objective: To describe the burden of COVID-19 in a children's multidisciplinary hospital for two years of the pandemic, taking into account of age, severity of the disease, the spectrum of underlying conditions and the intensive care need. Method(s): An assessment of 6048 cases of COVID-19 in patients under 18 years of age hospitalized from March 26, 2020 to December 31, 2021 was carried out. The diagnosis was confirmed by PCR on an outpatient basis or after hospitalization with the help of diagnostic kits registered in the Russian Federation. The features of the work of a children's multidisciplinary hospital in new conditions, the dynamics of hospitalization, age characteristics and new coronavirus (CV) infection severity in the pandemic development process are presented. The analysis of the underlying condition's structure depending on the severity of the disease, as well as the need and volume of therapy in the intensive care unit. The frequency and main characteristics of children's multisystem inflammatory syndrome (MIS-C) in hospital conditions, long-term PCR positivity and its effect on the duration of inpatient treatment of children have been established. Result(s): The spread of SARS-COV-2 in St. Petersburg required a radical change in the work of the children's multidisciplinary hospital. During the two years of the pandemic, four waves of hospitalization of children with new CV were revealed, differing in duration, intensity, and frequency of lung damage, but having no significant differences in the proportion of severe forms of the disease (1.7-2.8% of cases). Intensive therapy was required in 3.6% of cases, of which only 1/3 was due to the severe course of COVID-19 with a lung lesion volume of up to 100%. In 1/3 of cases, patients had risks of developing severe forms and in 1/3 - other pathology. Severe course of new CV was significantly more often accompanied by the need for respiratory support, anticoagulants and anti-inflammatory therapy. Contributing factors of severe forms and unfavorable outcomes were: pathology of the central nervous system, genetic diseases and malformations, obesity, as well as chronic bronchopulmonary pathology. Mortality in the hospital was recorded only among children with severe underlying conditions (0.1% of cases). D-MVS was registered significantly more often in boys (7 out of every 10 patients), accounting for 1.2% of cases of hospitalization of children with new CV over the entire period. Convalescent PCR-positivity in the outcome of COVID-19 was detected in 1/3 of children, significantly more often during the autumn-winter waves of the pandemic and among patients of high school age. Conclusion(s): New CV is gradually strengthening its position in the structure of acute respiratory pathology in children. Some of SARS-COV-2 infection cases is accompanied by extensive lung damage, as well as severe systemic inflammation independently or in the other infectious diseases structure, induction of the debut of various somatic pathology is not excluded. The presented data confirm the need for increased attention at high risk of adverse respiratory diseases outcomes children. All severe cases of COVID-19 in children require a personalized approach, taking into account the existing background diseases and possible options for the progression of the process. MIS-C should be considered as a systemic inflammatory response syndrome within the framework of an infectious disease of various etiologies, differentiated with Kawasaki disease and the debut of systemic diseases. The long-term PCR-positivity in the outcome of COVID-19 requires further study to address the need and nature of therapy in order to prevent further spread of infection in the population.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.

Dental Implants And Orthodontics In Patients With Ectodermal Dysplasia: A Systemic Review

Ectodermal dysplasia is a hereditary disease that is associated with the involvement of organs with embryonic ectodermal structure such as teeth, nails, hair and sweat glands, lacrimal and salivary glands. The prevalence rate of this disease is 1 in every 100,000 people. The most common and severe form of ectodermal dysplasia is the X-linked hypo hidrotic type. The second common type of hidrotic ectodermal dysplasia is autosomal dominant, unlike the first type, sweat glands are not involved. Small and fragile nails, hyperkeratosis of the palms and feet, dry mouth, decreased tear production are some of the clinical symptoms of ectodermal dysplasia, which are the result of intolerance to heat. The facial features of the patient include a prominent forehead, sunken nose bridge, protruding ears, prominent lips, hypoplasia of the middle part of the face, and skin pigment around the eyes and mouth. Dental involvement is one of the most prominent features of ectodermal dysplasia, which can be seen in both primary and permanent tooth systems. Reduction in the number of teeth, delay in tooth growth, abnormal shape of anterior teeth in peg-shaped or conical form, smaller size of posterior teeth and enamel defects are observed. Alveolar ridge hypoplasia is also common due to the lack of teeth, followed by a decrease in the vertical height of the occlusion. A child with ectodermal dysplasia faces many problems in feeding, chewing, and speaking. Early treatment with dental prostheses can significantly reduce these problems.Copyright © 2023 Authors. All rights reserved.

Safety of and antibody response to the BNT162b2 COVID-19 vaccine in adolescents and young adults with underlying disease

Background: Data are limited regarding the safety of and antibody response to the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid vaccine in adolescents and young adults with underlying disease. Methods: This prospective observational study enrolled patients age 12–25 years with chronic underlying disease who received 2 doses of BNT162b2. A 18-item questionnaire was used to assess adverse events within 7 days post-vaccination, and data regarding severe adverse events were collected from electronic medical records. An antibody titer for the receptor-binding domain of the spike protein in SARS-CoV-2 was used to assess antibody response after the second vaccine dose. Results: Study participants were 429 patients (241 [56.2%] age 12–15 years;188 [43.8%] age 16–25 years). The most common underlying diseases were genetic or chromosomal abnormalities and/or congenital anomalies, followed by endocrine or metabolic diseases;32% of participants were immunocompromised. Severe adverse events were observed after the second dose in 1 (0.4%) patient age 12–15 years and in 2 (1.1%) patients age 16–25 years;all patients recovered. Seropositivity after the second vaccine dose was 99.0%. The geometric mean antibody titer was higher in patients age 12–15 years versus 16–25 years (1603.3 [1321.8–1944.7] U/mL vs. 949.4 [744.2–1211.0] U/mL). Compared with immunocompetent patients, immunocompromised patients had a lower antibody titer (2106.8 [1917.5–2314.7] U/mL vs. 467.9 [324.4–674.8] U/mL). Conclusions: Vaccination with BNT162b2 was acceptably safe and immunogenic for adolescents and young adults with underlying disease. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

An Overview About Pediatric Type 1 Diabetes Mellitus

Background: Diabetes mellitus (DM) represents one of the most common metabolic diseases in the world, with rising prevalence in recent decades. Most cases are generally classified into two major pathophysiological categories: type 1 diabetes mellitus (DM1), which progresses with absolute insulin deficiency and can be identified by genetic and pancreatic islet autoimmunity markers, and type 2 diabetes mellitus (DM2), which is the most prevalent form and involves a combination of resistance to the action of insulin with an insufficient compensatory response of insulin secretion. In the last two decades, in parallel with the increase in childhood obesity, there has also been an increase in the incidence of DM2 in young people in some populations. Other forms of diabetes may affect children and adolescents, such as monogenic diabetes (neonatal diabetes, MODY – maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes), diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs, and diabetes related to certain genetic syndromes, which may involve different treatments and prognoses. DM1 is considered an immuno-mediated disease that develops as a result of gradual destruction of insulin-producing pancreatic beta cells that eventually results in their total loss and complete dependence on exogenous insulin. Clinical presentation can occur at any age, but most patients will be diagnosed before the age of 30 years

Risk Factors for Severe Covid-19 in Hospitalized Children in Canada: A National Prospective Study from March 2020-May 2021

BACKGROUND: Children living with chronic comorbid conditions are at increased risk for severe COVID-19 disease, though there is limited evidence regarding the risks associated with specific conditions and which children may benefit from targeted COVID-19 therapies. Age-specific baseline indicators of COVID-19 severity are also needed to evaluate the effectiveness of SARS-CoV-2 vaccination strategies in the paediatric population. OBJECTIVE(S): In this study, we aimed to 1) identify factors associated with severe COVID-19 in children, and 2) describe rates of hospitalization, intensive care unit (ICU) admission, and severe COVID-19 within specific pediatric age groups. DESIGN/METHODS: We conducted a national prospective study on hospitalized children with microbiologically confirmed SARS-CoV-2 infection via the Canadian Paediatric Surveillance Program from March 2020-May 2021. Cases were reported voluntarily by a network of >2800 paediatricians and paediatric subspecialists. SARS-CoV-2 hospitalizations were classified as COVID-19-related, incidental infection, or infection control/social admissions. Severe disease was defined as intensive care, ventilatory or hemodynamic requirements, select organ system complications, or death. Outcomes were described among children aged <6 months, 6-23 months, 2-4 years, 5-11 years, and 12-17 years. Risk factors for severe disease were identified using multivariable Poisson regression, adjusting for child age and sex, coinfections, and timing of hospitalization. RESULT(S): We identified 541 children hospitalized with SARS-CoV-2 infection, including 329 (60.8%) with COVID-19-related disease. Median age at admission was 2.8 years (IQR 0.3-13.5) and 42.9% (n=232) had at least one comorbidity. Among COVID-19-related hospitalizations, severe disease occurred in 29.5% of children (n=97/329), including a higher proportion of children aged 2-4 years (48.7%) and 12-17 years (41.3%) (Table 1). Comorbidities associated with severe disease are described in Figure 1, and included technology dependence (adjusted risk ratio [aRR] 1.96, 95% confidence interval [CI] 1.31-2.95), neurologic conditions (e.g. epilepsy and chromosomal/genetic conditions) (aRR 1.87, 95% CI 1.34-2.61), and pulmonary conditions (e.g. bronchopulmonary dysplasia and uncontrolled asthma) (aRR 1.66, 95% CI 1.13-2.42). CONCLUSION(S): While severe outcomes were detected at all ages and among patients with and without comorbidities, neurologic and pulmonary conditions as well as technology dependence were associated with increased risk of severe COVID-19. Children aged 2-4 years more commonly experienced severe COVID-19 in this study, which was conducted at a time when no children were eligible for SARS-CoV-2 vaccines. Notably, this high-risk group remains without access to approved vaccines. These findings may help guide vaccination programs and prioritize targeted COVID-19 therapies for children.

Aortic thrombosis presenting as myocardial infarction in a child

Background: Ascending aortic thrombus is rare in children without history of trauma, hypercoagulable condition or vascular disease and carries a high mortality risk necessitating rapid identification and management. Aim(s): We aim to present the clinical course for a rare pediatric case. Method(s): We reviewed the medical record for a child with recurrent life-threatening thrombi. Result(s): A 12-year old previously healthy male presented with chest pain. ECG revealed ST segment elevation. Echocardiography revealed an ejection fraction of 25% and a mobile mass (10 x 20 mm) in the ascending aorta. COVID testing was negative. Troponin-I was elevated. He was emergently placed on cardiopulmonary bypass where a large organized thrombus was removed. The left anterior descending coronary artery was occluded. He underwent intracoronary tPA, aspiration thrombectomy and balloon angioplasty. Hypercoagulable and autoimmune work-up revealed elevated factor 8 activity, von willebrand factor (vWF) activity and thrombocytosis with increased function by viscoelastic testing (ROTEM). Myocarditis, cardiogenetics and genetic testing for thrombophilia were negative. He was discharged on heart failure therapy, triple anti-platelet therapy (aspirin, clopidogrel, dipyridamole) and apixiban. He underwent a heart transplant 5 months later. Three weeks post-transplantion, he was incidentally found to have a large left atrial thrombus. At this time, he was only on aspirin. Factor 8 activity at time of transplant and second thrombus discovery was >400%. vWF activity and platelet count were also elevated. ROTEM revealed elevated platelet and fibrinogen activity. He underwent left atrial thrombectomy and was restarted on triple antiplatelet therapy and apixiban. He has not had recurrence on this regimen for 8 months. Conclusion(s): Thrombocytosis and elevated pro-inflammatory coagulation factors may predispose to development of potentially fatal thrombi. Besides inflammation, etiology may be unknown, particularly in apparently healthy children, prompting additional research into potentially genetic conditions in these complex pathways to further elucidate patients at risk.

Risk Factors for Covid-19 Mortality in Paediatric Populations: A Scoping Review

Aims Paediatric populations are generally considered to be at a lower risk of mortality from COVID-19 infection compared with adult populations. Regardless, a notable number of deaths from COVID-19 have been reported in paediatric populations. Therefore, the purpose of our work was to conduct a scoping review of the literature to assess the risk factors for COVID-19 mortality among paediatric populations. Methods Our review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). Searches were performed in PubMed, Scopus, medRxiv, and WHO Coronavirus Database. There were no restrictions placed for searches based on date. Papers that were written in English, included at least one paediatric death from COVID-19, and described at least one risk factor for the death and/or clinical presentation of the child(ren) were eligible for inclusion. The paediatric population was defined as children aged 18 years and younger. Results Searches generated a total of 5828 papers and, of those, 75 were eligible for inclusion. There was a pooled total of 876 paediatric deaths. Significant risk factors for paediatric mortality included having co-infection of other pathogens, and at least one comorbidity;the comorbidities most frequently associated with mortality were malignancies, heart conditions, kidney disease, and genetic disorders such as Down Syndrome. The development of Paediatric Multisystem Inflammatory Syndrome (PMIS) was also consistently demonstrated to be a risk factor. Common clinical complications associated with paediatric COVID-19 infection resulting in mortality were sepsis, acute respiratory distress syndrome (ARDS), and acute kidney injury (AKI). Conclusion Our review has highlighted prominent risk factors for mortality from COVID-19 amongst paediatric populations. It is vital to consider the risk factors in order to assist prognostication and clinical decisions for severe paediatric infections of COVID-19. Our findings also highlight the importance of COVID-19 vaccination in paediatric populations.

RARE CASE OF G6PD DEFICIENCY DIAGNOSED IN AN ADULT AFTER COVID-19 INFECTION

SESSION TITLE: Genetic and Developmental Disorders Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is one of the more common hematologic disorders. Many individuals are asymptomatic until a triggering event. Events that lead to hemolysis in the setting of G6PD include certain medications, infections, and specific foods. We discuss a case of G6PD deficiency diagnosed in a hospitalized adult with COVID infection. CASE PRESENTATION: A 41 year old male presented to the hospital with altered mental status. On admission he was found to be in diabetic ketoacidosis and was COVID positive. He was admitted to the ICU and his acidosis was corrected with insulin. He did not require intubation but was treated with steroids, remdesivir, and supplemental oxygen for his COVID pneumonia. His hospitalization was complicated by hemolytic anemia. Testing for autoimmune hemolytic anemia and HIT (heparin induced thrombocytopenia) were negative. Genetic testing for G6PD deficiency came back positive. The patient was discharged and referred to hematology for follow up. DISCUSSION: Interestingly, our patient was asymptomatic prior to his COVID infection. It is likely that the stress from his COVID infection triggered worsening hemolysis. G6PD can be worsened with specific medications or foods but we cannot exclude infection. The inflammatory response secondary to COVID is the probable cause for the patient's hemolytic anemia presentation and subsequent G6PD deficiency diagnosis. CONCLUSIONS: G6PD deficiency should be included in the differential diagnosis for patients presenting with COVID infection and labs consistent with hemolytic anemia. Reference #1: Buinitskaya Y, Gurinovich R, Wlodaver CG, Kastsiuchenka S. Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications. Front Med (Lausanne). 2020;7:584112. Published 2020 Oct 22. doi:10.3389/fmed.2020.584112 DISCLOSURES: No relevant relationships by Sarin Atam No relevant relationships by Kathleen Coppola No relevant relationships by Malik Muhammad Uzair Khan No relevant relationships by Mackenzie Kramer No relevant relationships by Rameesha Mehreen No relevant relationships by Stephanie Tzarnas No relevant relationships by Laura Walters

IDENTIFYING A NOVEL SURFACTANT PROTEIN MUTATION IN A FAMILY WITH PULMONARY FIBROSIS

SESSION TITLE: Rare Genetic Mutations and Anatomical Variants SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal disease affecting older adults that results in progressive scarring of the lung parenchyma. Familial IPF (FPF), defined by disease in two or more first-degree relatives, is estimated to occur in 2–20% of all IPF cases and can present with varying phenotypes which may be difficult to diagnose. Inherited gene variation as well as environmental factors predispose a patient to disease development. Additionally, rare genetic variants in the genes encoding surfactant A (SFTPA1, and SFTPA2) that affect alveolar stability and endoplasmic reticulum stress have been reported in less than 1% of FPF cases. Understanding these genetic variants is essential in the diagnosis and management of patients with FPF. CASE PRESENTATION: A 47-year-old Hispanic male with a history of COVID-19 one year ago (not requiring hospitalization) presented to the hospital for a two-day history of subjective fever and shortness of breath. He was hypoxic requiring oxygen via high flow nasal cannula. He was admitted four months ago for shortness of breath and treated for pneumonia. Since then, he has had chronic dyspnea with exertion. Computed tomography of the chest showed extensive ground glass opacities, worse in the right lung, with basilar and upper lobe honeycombing, and air bronchograms in the bilateral lower lobes. Family history was significant for a mother, maternal aunt, maternal grandfather, and maternal cousin who all died from pulmonary fibrosis. His maternal cousin was treated at our facility, in which genetic sequencing revealed a mutation in SFTPA2, c.697T>C. Our patient was found to have the same genetic mutation. DISCUSSION: The genetic basis of IPF remains poorly understood. Prior studies suggest only 20-30% of FPF cases harbor an identifiable causative genetic variant. Rare variants in two biologic pathways contribute to the known heritability of FPF including pathologic variants in surfactant related genes which cause improper protein trafficking leading to endoplasmic reticulum stress, defects in autophagy, and type II alveolar cell toxicity. SFTPA1 and SFTPA2 variants have been associated with FPF and lung adenocarcinoma in a small number of families and there are few reported cases. While currently the SFTPA2, c.697T>C mutation, previously reported by our group in 2016, is considered a variant of unknown significance, its occurrence in two relatives with serious progressive interstitial lung diseases suggests that it is indeed pathogenic. CONCLUSIONS: Gene sequencing should be considered for all patients with a family history of pulmonary fibrosis as identification of a rare genetic variant may offer guidance to diagnosis, prognostication, and risk stratification when considering lung transplantation as well as identify additional relatives who may be affected by IPF. Reference #1: Kropski JA, Young LR, Cogan JD, et al. Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017;195(11):1423-1428. doi:10.1164/rccm.201609-1820PP Reference #2: Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009 Jan;84(1):52-9. doi: 10.1016/j.ajhg.2008.11.010. Epub 2008 Dec 18. PMID: 19100526;PMCID: PMC2668050. Reference #3: Pulmonary Fibrosis Due to a Novel Surfactant Protein Mutation R.A. Arciniegas Flores, I.A. Vital, K. Medepalli, D. DeMarzo, M.K. Glassberg Csete, R.A. Alvarez. https://doi.org/10.1164/ajrccm-conference.2019.199.1_Meetings.A5437 DISCLOSURES: No relevant relationships by Roger Alvarez No relevant relationships by Eduardo Lopez Gonzalez No relevant relationships by Anita Singh

Genomics and the Future of Medicine

The world population is getting older, but a great challenge is how to increase health span and not only lifespan. What is the role of genetics versus environment? Several recent breakthroughs such as the human genome project, the IPS stem-cells and the CRISPR technology for gene editing will allow a revolution in gene therapy, precision and regenerative medicine and xenotransplantation. Aiming to contribute to a healthier longevity, our group is developing several projects including the characterization of the genome of our elderly highly admixed population. We have performed whole genome sequencing of about 1500 healthy Brazilians older than 60, which represents the largest genome databank in Latin America. Our aims were a) to have a database from our population in order to improve the interpretation of pathogenicity of rare unknown variants in patients with undiagnosed genetic disorders and precision medicine b) identify “protective” variants underlying healthy longevity. We found 2 million genetic variants which were not present in the international databanks (Naslavsky et al., 2022). Since the advent of COVID-19 pandemic, we are investigating genetic variants in individuals, who were exposed to SARS-Cov-2 and remained asymptomatic. To address this question, we investigated discordant couples where one was infected and develop COVID-19 while the partner remained asymptomatic and serum negative. We collected samples from nonagenarians and centenarians who survived COVID-19 or remained asymptomatic. We will infect different IPS derived cell lines from “resistant” centenarians with SARS-Cov2 in an attempt to increase our understanding on “resistant genetic variants and mechanisms”.

Voretigene Neparvovec Exploratory Analysis (VNEAN): R-shiny app for the comprehensive and dynamic visualization of voretigene neparvovec clinical trial data

Purpose : R-shiny apps can be useful in maintaining and analyzing data collected in clinical trials of rare diseases, where a suite of measures is used to characterize retinal and visual function, functional vision, and safety courses over time following the treatment. In a phase 3 trial, participants with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD), an ultra-rare genetic disorder, received bilateral, subretinal injections of gene augmentation therapy, voretigene neparvovec and followed-up annually. We explored the development of a novel data visualization tool, VNEAN (R-shiny application), to help in maintenance and analyses of complex trial data into a visual storytelling form that is easier to understand for healthcare audience. Methods : We developed an interactive and dynamic application using Shiny package for R programming language. This app improves the ability to explore the longitudinal trajectory of main efficacy outcomes (mobility testing and full-field light sensitivity) in concert with other data, including visual function and safety that can be visualized overall and in subsets. Results : This app has 11 modules of data analyses (Figure 1), including longitudinal visualization, analyses of correlation between changes, and timeline of adverse events. It presents the durability in improvement of functional vision, retinal and visual function, and the safety data at the group, subset and participant levels. The dynamic interface allows the user to define a subset based on the measures at baseline and/or their changes and select measures and/or timepoints. Conclusions : COVID-19 demonstrated digital engagement at its peak. The R shiny app has the potential to provide alternative data visualization and interpretations of analyses that offer a comprehensive representation of the data generated in rare diseases, not easily achievable via traditional didactic lectures and static data methods. This patient-centric and enduring visualization approach enables health care professionals to learn and retain information for the management and engagement of IRD patients in their clinical practice. Additionally, this application can progress the knowledge and understanding of treatment effects of rare diseases and help inform the design of future small- or largescale trials.

Regulatory Science Challenges - Encouraging Innovation Through an Adaptive Regulatory System

ATMPs - a new era A boy from Hungary, Zente, was one and a half years old when the crowd-funding campaign to finance his life-saving medicine Zolgensma concluded with a happy end. He was the third European patient that received the new gene therapy, which replaces the function of the missing or nonworking survival motor neuron 1 (SMN1) gene with a new, working copy of a human SMN gene that helps motor neuron cells work properly and survive. From a European perspective, it has been almost 15 years by now since regulatory framework for advanced therapy medicinal products (ATMPs) had been established to ensure the free movement of these medicines within the European Union, to facilitate their access to the EU market, and to foster the competitiveness of European pharmaceutical companies in the field. Zolgensma has been approved in the EU in May 2020. The FDA expects it will be reviewing and approving up to 20 cell and gene therapies each year until 2025. Rapid development of technology and better understanding of the manufacturing challenges are not the only prerequisites of the growth. Assessment of products like Zolgensma requires very specific knowledge and often an adaptive approach from regulators. They have to gain enough experience and need to be able to summarize knowledge in guidelines that would help developers of products that are substantially different from traditional medicines. FDA issued seven new guidelines in January 2020, in which, for example, they highlight the importance of long-term follow-up for gene therapies that offer one-time fix for inherited diseases and where pre-market studies may have limited value. 2. Regulatory tools These examples may already show that rapid change in technology leads to new kinds of medicines that require a properly adapted regulatory system. Patients would expect state-of-the-art medicines within the shortest possible time frame, however, authorities are traditionally more cautious. Still, there are several various initiatives from the EMA and the FDA to foster early access to medicines. Some of these have been available for a longer time. EMA's accelerated assessment reduces the timeframe for review of innovative applications of medicines with major public health interest. Conditional marketing authorisation grants authorization before a complete dataset is available, and compassionate use allows the use of an unauthorized medicine for patients with an unmet medical need. A more recent regulatory tool of EMA is the priority medicines scheme (PRIME) that aims to enhance support for the development of medicines that are expected to make a real difference to patients. Early dialogue between EMA and the developers is a crucial part of the tool, together with accelerated assessment and continuous scientific advice and protocol assistance. Up to now, 282 applications for PRIME eligibility have been assessed by the CHMP of which 95 have received a green light. Most of the applicants are small and medium size enterprises, and the major therapeutic area is oncology. FDA has similar programs, such as the Fast Track, Breakthrough Therapy and Priority Review designations, and is also aiming to facilitate and accelerate development and marketing authorization of key medicines. By 2018, about 70% of new drug approvals by the FDA were expedited, compared to about 50% in 2010. The result is a growing pro-portion of medicines authorized with less premarket evidence, a trade-off, that most patients with fatal or debilitating disease would likely accept. Nevertheless, conditional approval requires a strong post-marketing attention from regulators, and lack of enough evidence sometimes leads to difficult decisions. In April 2019 a fast-tracked cancer drug, Lartruvo was withdrawn because a large study was not able to prove a favourable benefit-risk profile, which was established previously on a smaller patient population. The regulators approach is not expected to be changed, but experience from such cases would gradually be built into the decision-making process. In addition to this real world evidence (RWE) and patient recorded outcomes may also help in decision making. 3. Digital revolution The rapid development of biotechnology is not the only area where an adaptive regulatory approach is needed. Digital medicine is a new field, as smartphones and sensors open up new ways of generating data. For example, collecting and analysing RWE seems to be a good solution for single arm studies where randomized trials are not feasible. FDA has approved easy-to-use devices that are able to track several physiological systems of our body, which in turn can give a boost to developments in this field. In addition to these simpler devices, digital revolution in terms of artificial intelligence (AI) and cognitive machine learning is another challenge that our regulatory systems should tackle. It has been recently announced that a new drug candidate, a long-acting and potent serotonin 5-HT1A receptor agonist, which was created using an artificial intelligence platform, will enter into clinical study. There are also numerous radiological applications based on AI, including computer aideddetection and diagnosis software, where images are analysed, and clinically relevant findings suggested to aid diagnostic decisions. Many of these new developments require a tailored approach from regulators to find a way for authorization within the existing regulatory framework. The fact, that many of these new developments are carried out by academic research groups or small companies without extensive regulatory experience, adds an extra layer of difficulty. To meet this challenge, EMA and the Heads of Medicines Agencies have established the EU-Innovation Network, to support medicine innovation and early development. As a milestone of its function, beginning in 1 February 2020 a pilot for simultaneous scientific advice is starting, where the applicants will receive a consolidated advice from the participating agencies. Innovative products often require specific expertise;therefore this new form of advice is also extremely beneficial for regulators as they are able to learn from each other and broaden their knowledge. 4. Conclusions The rapid development of pharmaceutical and digital technology requires a concerted action from all stakeholders. Or, as we all experience, a global pandemic can be an important driving force of the evolution of regulatory policies. Appropriate usage of currently available regulatory tools and a continuous discussion between academia, industry and regulators would be the only way to ensure quick access to state-of-the-art, safe and efficacious medicines, and medical devices. It is clearly shown currently by the concerted action of various stakeholders and series of rolling reviews which led to the expedited authorization of COVID-19 vaccines.

Cardiac Injury and Severe Outcome in Children and Adolescents with COVID-19

Background: Cardiac injury associated with multi-system inflammatory syndrome in children (MIS-C) has been extensively reported but the impact of cardiac injury in children with SARSCoV-2 infection in the absence of MIS-C has not been well described. In this study we describe the cardiac involvement found in children with positive SARS-CoV-2 PCR tests and evaluate the association of cardiac injury with severe outcome in this population. Methods: A retrospective chart review of all patients ages 0-21 presenting to the emergency department or admitted at our institution during and just beyond the peak of the COVID-19 pandemic at our institution was performed. We excluded patients with MIS-C, cardiomyopathy, or complex congenital heart disease. Cardiac injury was defined as elevated high sensitivity troponin and/or N-terminal pro-brain type natriuretic peptide above 99th percentile. Severe illness was defined as need for advanced respiratory support (positive pressure or mechanical ventilation above baseline), inotropic or vasopressor support, and/or death from any cause during admission. Results: During the study period there were 103 patients with positive SARS-CoV-2 PCR, 17 of whom were excluded for MIS-C, 4 of whom were excluded for cardiomyopathy, 2 for complex congenital heart disease including one with repaired Taussig-Bing anomaly and one with double outlet right ventricle who underwent Fontan surgery. Of the 80/103 (78%) patients remaining in the analysis, 31/80 (39%) were female and the median age was 12.5 years (IWR 1.9-17.5). High-sensitivity troponin T and/or NT-proBNP were measured in 27/80 (34%) patients and abnormalities were present in 5/27 (19%), all of whom had underlying comorbidities such as lung disease, diabetes, or genetic syndromes. Severe outcome occurred in 14/27 (52%) patients and 5/5 (100%) of those with cardiac injury as compared to 9/22 (41%) patients without cardiac injury (p<0.05). Advanced respiratory support was more common in those with cardiac injury as compared to those without, occurring in 5/5 (100%) patients with cardiac injury and in 8/22 (36%) patients without cardiac injury (p<0.05). Electrocardiographic abnormalities were identified in 14/38 (37%) studies and no left ventricular dysfunction was identified on echocardiography. Conclusion: During the initial peak of the pandemic at our institution, cardiac injury was present in 19% of those for whom high-sensitivity troponin and/or NT-proBNP were measured. Presence of cardiac injury was associated with greater risk of severe outcomes including advanced respiratory support. Larger studies to determine the true incidence of cardiac injury in children with COVID-19 would be useful to guide recommendations for standard workup and management.

Gender differences in functional somatic disorders of indigenous adolescents in Khakassia

Rationale - The goal of the study was to investigate gender characteristics of functional somatic disorders in adolescents of the indigenous population of Khakassia (using the case study of the Abakan city). Material and methods - The object of the study was 215 (46.8%) boys and 244 (53.2%) girls of four secondary schools in Abakan. Their average age was 14.5±1.3 years. Data collection was conducted by means of an original screening questionnaire developed by Professor S.Yu. Tereshchenko. Results - The incidence of recurrent pain in the total sample of the surveyed youths was 184 (40.1%) for cephalalgia, 225 (49.0%) for abdominal pain, and 269 (58.7%) for back pain. The prevalence and structure of functional somatic disorders in Khakas adolescents depended on their gender. Asthenic syndrome was more common among girls - 42 (17.2%) vs. 14 (6.5%) in boys. In girls, the percentage of frequent headaches was higher than in boys: 22 (9.0%) vs. 8 (3.7%), respectively. Similar trend was observed in case of rare headaches: 100 (41.0%) vs. 54 (25.1%). Also, girls, compared with boys, were characterized by a higher incidence of both frequent and rare abdominal pains: 38 (15.6%) vs. 9 (4.2%) and 106 (43.4%) vs. 72 (33.5%), correspondingly. Conclusion - The case study of surveyed ethnic sample of Abakan school students revealed a high prevalence of recurrent pain syndromes in the indigenous youths of Khakassia. We have also established that incidence, structure and severity of recurrent pain, as well as its negative impact on well-being and daily activities, were associated with gender.