Safety of SGLT2 Inhibitors: A Pharmacovigilance Study from 2013 to 2021 Based on FAERS

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are widely used in clinical practice for their demonstrated cardiorenal benefits, but multiple adverse events (AEs) have been reported. We aimed to describe the distribution of SGLT2i-related AEs in different systems and identify important medical event (IME) signals for SGLT2i.Methods: Data from the first quarter (Q1) of 2013–2021 Q2 in FAERS were selected to conduct disproportionality analysis. The definition of AEs and IMEs relied on the system organ classes (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA-version 24.0). Two signal indicators, the reported odds ratio (ROR) and information component (IC), were used to estimate the association between SGLT2is and IMEs.Results: A total of 57,818 records related to SGLT2i, with 22,537 SGLT2i-IME pairs. Most SGLT2i-related IMEs occurred in monotherapy (N = 21,408, 94.99%). Significant signals emerged at the following SOCs: “metabolism and nutrition disorders” (N = 9,103; IC025 = 4.26), “renal and urinary disorders” (3886; 1.20), “infections and infestations” (3457; 0.85). The common strong signals were observed in diabetic ketoacidosis, ketoacidosis, euglycaemic diabetic ketoacidosis and Fournier’s gangrene. Unexpected safety signals such as cellulitis, osteomyelitis, cerebral infarction and nephrolithiasis were detected.Conclusion: Our pharmacovigilance analysis showed that a high frequency was reported for IMEs triggered by SGLT2i monotherapy. Different SGLT2is caused different types and the association strengths of IMEs, while they also shared some specific PTs. Most of the results are generally consistent with previous studies, and more pharmacoepidemiological studies are needed to validate for unexpected AEs. Based on risk-benefit considerations, clinicians should be well informed about important medical events that may be aggravated by SGLT2is.

A Semi-Automated Term Harmonization Pipeline Applied to Pulmonary Arterial Hypertension Clinical Trials

Objective Data harmonization is essential to integrate individual participant data from multiple sites, time periods, and trials for meta-analysis. The process of mapping terms and phrases to an ontology is complicated by typographic errors, abbreviations, truncation, and plurality. We sought to harmonize medical history (MH) and adverse events (AE) term records across 21 randomized clinical trials in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Methods We developed and applied a semi-automated harmonization pipeline for use with domain-expert annotators to resolve ambiguous term mappings using exact and fuzzy matching. We summarized MH and AE term mapping success, including map quality measures, and imputation of a generalizing term hierarchy as defined by the applied Medical Dictionary for Regulatory Activities (MedDRA) ontology standard. Results Over 99.6% of both MH (N = 37,105) and AE (N = 58,170) records were successfully mapped to MedDRA low-level terms. Automated exact matching accounted for 74.9% of MH and 85.5% of AE mappings. Term recommendations from fuzzy matching in the pipeline facilitated annotator mapping of the remaining 24.9% of MH and 13.8% of AE records. Imputation of the generalized MedDRA term hierarchy was unambiguous in 85.2% of high-level terms, 99.4% of high-level group terms, and 99.5% of system organ class in MH, and 75% of high-level terms, 98.3% of high-level group terms, and 98.4% of system organ class in AE. Conclusion This pipeline dramatically reduced the burden of manual annotation for MH and AE term harmonization and could be adapted to other data integration efforts.

Risk Factors and Outcomes of ICU Admission Following Allogeneic Hematopoietic Stem Cell Transplantation

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) can develop complications such as life-threatening infections, multi-system organ failure, ICU admission and ventilator support in the immediate post-transplant period. Whereas outcomes of these complications, particularly ICU admission and ventilator support, are known to be poor, little is known about the risk factors leading to them. Methods: We conducted a retrospective study to analyze the impact of pre-transplant risk factors on acute inpatient complications, focusing on ICU admission, ventilator support and multi-system organ failure, following allo-hsct at the University of Alabama at Birmingham (UAB) between 2008 and 2016. Mortality rates and survival outcomes of patients admitted to the ICU were also analyzed. Pre-transplant individual comorbidities were defined as per Sorror's HCT-CI. Results: There were 304 patients included with a median age of 52y (18-72y). There were 51% male and 82% Non-Hispanic white patients. The most common indication for transplant was AML (45%). Donor type was matched-unrelated, haploidentical and matched-related in 53%, 35% and 12% of cases, respectively. Majority of the patients received myeloablative conditioning (74%). The prevalence of health behaviors and comorbidities at the time of transplant is shown in Table 1. There were 39% patients with HCT-CI score of ≥3, 23% with moderate pulmonary compromise, 22% with a psychiatric disorder, 13% with severe pulmonary compromise, 13% with diabetes mellitus (DM), 10% with cardiac abnormalities and 6% with infection at the time of transplant. During the initial hospitalization, 33 (11%) patients required ICU admission, 29 (10%) required ventilator support, 33 (11%) developed multi-system organ failure, 79 (26%) developed bacterial infections and 15 (5%) developed fungal infections. The median time to neutrophil engraftment was 13 days (7-48 days). In multivariable analysis (Table 2), risk factors for ICU admission included pre-transplant infection (HR 6.50, 95% CI 1.82-23.26, p=0.004), pre-transplant DM (HR 4.14, 95% CI 1.56-10.97, p=0.004), time to neutrophil engraftment (HR 1.13, 95% CI 1.05-1.21, p=0.0007), donor type (ref: matched related donor; haplo: HR 0.24 95% CI 0.07-0.82, p=0.02) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.18 95% CI 0.04-0.88, p=0.03; 2014-2016: HR 0.12 95% CI 0.03-0.4, p=0.0006). Risk factors for ventilator support included pre-transplant infection (HR 10.09, 95% CI 2.44-41.64, p=0.001), pre-transplant DM (HR 3.61, 95% CI 1.31-9.91, p=0.01), time to neutrophil engraftment (HR 1.17, 95% CI 1.11-1.23, p<0.0001) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.21 95% CI 0.06-0.81, p=0.02; 2014-2016: HR 0.07 95% CI 0.02-0.31, p=0.0005). Risk factors for multi-system organ failure included pre-transplant DM (HR 4.38, 95% CI 1.64-11.74, p=0.003), time to neutrophil engraftment (HR 1.13, 95% CI 1.08-1.19, p<0.0001) and HSCT era (ref: 2008-2010; 2010-2013: HR 0.21 95% CI 0.05-0.80, p=0.003; 2014-2016: HR 0.16 95% CI 0.05-0.48, p=0.001).Risk factor for bacterial infection included HSCT era (ref: 2008-2010; 2010-2013: HR 0.30 95% CI 0.14-0.65, p=0.002; 2014-2016: HR 0.24 95% CI 0.12-0.49, p<0.0001) and for fungal infection included pre-transplant pulmonary compromise (ref: no compromise; severe pulmonary compromise HR 5.16, 95% CI 1.05-25.4, p=0.04). For patients admitted to the ICU, the 60-day and 6-month mortality was 58% and 67%, respectively. No deaths were attributed to relapse disease. The median overall survival for patients admitted to the ICU was 1.4 months (Figure 1). Conclusion: Patients with DM and infection at the time of HSCT and delayed neutrophil engraftment during transplant are at an increased risk for ICU admission, ventilator support and multi-system organ failure following allo-hsct. Patients admitted to the ICU are also at a high risk for early mortality leading to poor survival. Optimizing glycemic control and delaying transplant until resolution of infection, if the underlying disease would allow, may help improve both morbidity and mortality in transplant recipients. Figure 1 Figure 1. Disclosures Di Stasi: Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Alabama at Birmingham: Current Employment.

The Spectrum of Manifestations of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) Infection in Children: What We Can Learn From Multisystem Inflammatory Syndrome in Children (MIS-C)

Multisystem Inflammatory Syndrome in Children (MIS-C) is defined as a clinically serious condition requiring hospitalization with fever, multi-system organ disfunction, inflammatory biomarkers increase. The syndrome develops in the context of a probable or ascertained Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) infection, but other possible etiologies should be ruled out for definitive diagnosis. On the clinical side, along with the multi-system involvement, myocarditis with heart failure and shock is the most striking feature. Capillary leak is another fundamental feature of MIS-C. In fact, shock and hemodynamic compromise in MIS-C can occur also in the absence of laboratory evidence of myocardial inflammation, with preserved cardiac function and rapid reversibility. Since the first observations of MIS-C patients, it was evident that there is a delay between the peak of adult cases of Coronavirus disease 19 (COVID-19) and the MIS-C peak. Moreover, SARS-Cov2 isolation in children with MIS-C is not always possible, due to low viral load, while positive serology is far more commonly observed. These observations lead to the interpretation of MIS-C as a post-infectious disease. Although the exact pathogenesis of MIS-C is far from being elucidated, it is clear that it is a hyperinflammatory disease with a different inflammatory response as compared to what is seen in acute SARS-CoV-2 infection and that the disease shares some, but not all, immunological features with Macrophage Activation Syndrome (MAS), Kawasaki Disease (KD), Hemophagocytic Lymphohistiocytosis (HLH), and Toxic Shock Syndrome (TSS). Different mechanisms have been hypothesized as being responsible, from molecular mimicry to antibody dependent enhancement (ADE). Some evidence has also been collected on the immunological profile of patients with MIS-C and their difference from COVID-19. This review is focused on critical aspects of MIS-C clinical presentation and pathogenesis, and different immunological profiles. We propose a model where this hyperinflammatory disease represents one manifestation of the SARS-CoV2 spectrum in children, going from asymptomatic carriers to the post-infectious MIS-C, through symptomatic children, a low number of which may suffer from a severe infection with hyperinflammation (pediatric Hyper-COVID).

Erythrocytes Identify Complement Activation in Patients with COVID-19

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-system organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in COVID-19 patients using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.

Prebiotic Mannan Oligosaccharide Pretreatment Improves Mice Survival Against Lethal Effects of Gamma Radiation by Protecting GI Tract and Hematopoietic Systems

Total body irradiation (TBI) results in critical injuries in a dose dependent manner that primarily damages highly proliferating tissues including hematopoietic stem cells (HSCs) and intestinal crypt stem cells etc. This may result in hematopoietic syndrome leading to bone marrow failure and gastrointestinal syndrome leading to chronic intestinal functional alterations. Death results from the gastrointestinal syndrome due to sepsis, bleeding, dehydration, and multi-system organ failure. We demonstrate that the prebiotic mannan oligosaccharide (MOS) pretreatment substantially prolongs survival in both male and female mice when administered 2 h prior to radiation either through oral or intraperitoneal route. The radioprotective efficacy of MOS was found to be age dependent and improves survival even in aged mice (12–13 months old). MOS pretreatment effectively abrogates radiation-induced hematopoietic injury and accelerates recovery of lymphocytes and WBCs and alleviates depletion of circulatory blood cells. Results also illustrate that MOS pretreatment abolishes crypt cell death and denudation of villi in comparison to the respective irradiated animals and ameliorates the overall radiation-induced damage to the GI system. MOS pretreatment facilitates intestinal recovery leading to enhanced animal survival demonstrating its protection efficacy against TBI induced mortality. Moreover, MOS pretreated animals show signs of accelerated recovery in terms of severity of radiation sickness symptoms including weight loss and completely abolish TBI associated mortality.

Hydroxychloroquine as Therapeutic Option in COVID-19: Analysis of Suspected Cardiovascular Adverse Drug Events Reported in the VigiBase

Background: Hydroxychloroquine(HCQ), one of the repurposed drugs in COVID-19, has several known cardiovascular(CVS) toxicities. Methods: VigiBase data were used to analyze the reported ADEs linked to HCQ. The data were analyzed based on age, gender, and seriousness of ADEs at the System Organ Classification level and the individual Preferred Term level. Results: The majority were above 18 years(91.6%) and from Europe(41.6%). A total of 5,315 ADEs were associated with HCQ use in COVID-19. Of these, 918 ADEs were attributed to CVS and reported from 773 patients. Grossly, CVS ADEs were associated with concomitant use of HCQ and azithromycin(AZM), and only 40 ADEs were solely due to HCQ. The majority were serious (69.3%) and resolved afterward (51%). In CVS ADEs, there were 366 cardiac disorders, 38 vascular disorders, and 514 ADEs under investigation. Among the cardiac disorders, palpitation was the most typical (N=65), followed by bradycardia(N=44) and tachycardia(N=33). Among arrhythmias, QT prolongation (N=469), atrial fibrillation (N=25), and ventricular tachycardia(N=16) were common. The odds of developing serious CVS ADEs increased with age, patients aged 45-64 years(OR=1.75; p= 0.015) and >65 years(OR=1.93, p=0.003) as compared to younger ones. Conclusion: Hydroxychloroquine with known CVS toxicities and increased risk with co-administering AZM makes physicians cautious while prescribing in COVID-19 patients. Bangladesh Journal of Medical Science Vol.20(4) 2021 p.897-910

Serious adverse events reported from the COVID-19 vaccines: A descriptive study based on WHO database

Background: In the light of the current pandemic, the emergency approval of few COVID-19 vaccines seems to provide a ray of hope. However, their approval is solely based on limited data available from the clinical trials in a short period of time; thereby imposing a necessity to study the adverse events (AEs) associated with their use. This study therefore aims to assess the Serious Adverse Events (SAEs) associated with various COVID 19 vaccines reported in the WHO database (VigiBase). Methods: The data from VigiBase was analyzed to assess the reported SAEs linked to various COVID 19 vaccines. The duplicates in the data were removed and were analyzed on the basis of age, gender, and seriousness of adverse events at the System Organ Classification (SOC) level and the individual Preferred Term (PT) level. Results: A total 103954 adverse events reported from 32044 subjects were taken for analysis. Of 32044 subjects, majority were females (80%). Also, a total of 28799 (27.7%) SAEs were reported from the 8007 individuals. Most of the SAEs were reported from Europe (83%), amongst females (79.4%) and between 18 to 64 years (80.74%) of age. Majority of SAEs (74%) were reported for BNT162b2 (Pfizer) vaccine. On system wise classification, general disorders (30%) were the commonest followed by nervous system (19.1%) and musculoskeletal (11.2%) disorders. In individual category, headache (8.1%) was the commonest, followed by pyrexia (7%) and fatigue (5.1%). The number of SAEs were reported with various vaccines were comparatively lesser as compared to the non-serious ones and incidence of death was low with all the vaccines candidates. Elderly (> 65 years) people reported more serious SAEs as compared to other age groups. Conclusion: The reported SAEs from the COVID 19 vaccines were in line with the data published in clinical trials. To link these SAEs to vaccines will need causality analysis and review of individual reports.

Prebiotic Mannan oligosaccharide pretreatment Improves Mice Survival Against Lethal Effects of Gamma Radiation by protecting GI Tract and Hematopoietic systems

Total body irradiation (TBI) results in critical injuries in a dose dependent manner that primarily damages highly proliferating tissues including hematopoietic stem cells (HSCs) and intestinal crypts stem cells etc. This may result in hematopoietic syndrome leading to bone marrow failure and gastrointestinal syndrome leading to chronic intestinal functional alterations. Death results from the gastrointestinal syndrome due to sepsis, bleeding, dehydration and multi-system organ failure. We demonstrate that the prebiotic mannan oligosaccharide (MOS) pretreatment substantially prolongs survival in both male and female mice when administered 2 hours prior to radiation either through oral or intraperitoneal route. The radioprotective efficacy of MOS was found to be age dependent and improves survival even in aged mice (12–13 month old). MOS pretreatment effectively abrogates radiation-induced hematopoietic injury, and accelerates recovery of lymphocytes and WBCs and alleviates depletion of circulatory blood cells. Results also illustrate that MOS pretreatment abolish crypt cell death and denudation of villi in comparison to the respective irradiated animals and ameliorates the overall radiation-induced damage to the GI system. MOS pretreatment facilitates intestinal recovery leading to enhanced animal survival demonstrating its protection efficacy against TBI induced mortality. Moreover, MOS pretreated animals show signs of accelerated recovery in terms of severity of radiation sickness symptoms including weight loss and completely abolish TBI associated mortality.