Dupilumab as a steroid-sparing treatment option in pediatric severe asthma and chronic rhinosinusitis with nasal polyps

Case report Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent comorbidity in severe asthma in adults. Both diseases share key pathophysiological mechanisms that can involve type-2 inflammatory pathways. However, this is an uncommon presentation in pediatric patients. Dupilumab, a fully human monoclonal antibody against IL-4Ralpha, inhibits IL-4/ IL-13 signaling, which are key drivers of type-2 inflammation and interfere with both eosinophilic and allergic pathways. It is approved for patients >= 12-year- old with moderate to severe uncontrolled asthma, but its approval in CRSwNP is limited to adults. We report a case of a 12-year- old boy with severe uncontrolled asthma and highly symptomatic CRSwNP referred to our center in May 2021. He was sensitized to house dust mite and pollens, and a specific immunotherapy had been tried previously. He was treated with high dose inhaled corticosteroid, long-acting beta agonist, long-acting muscarinic antagonist, montelukast and daily intra-nasal corticosteroids. Furthermore, a bilateral endoscopic sinus surgery with polypectomy was performed in April 2021. Despite adherence to medication and surgical treatment, both diseases were uncontrolled with frequent exacerbations requiring unscheduled visits and multiple systemic corticosteroid courses. This led to failure to thrive and several missed school days. Oral corticosteroid (OCS) tapering was unachieved due to symptoms rebound and so maintenance therapy with prednisolone 10mg daily was attempted, with only a slight improvement. High levels of eosinophils (1010 cells/muL), FeNO (122 ppb) and IgE (2255 kU/L) were present. Treatment with subcutaneous dupilumab was started in July 2021. A clinical and analytical improvement was evident at the 3-month evaluation (Table 1). He was able to stop prednisolone, and no clinically relevant exacerbations occurred. He also was fully vaccinated and had an asymptomatic COVID-19 infection in December 2021. Patients with CRSwNP and comorbid asthma have a higher disease burden than patients with each disease alone. In this adolescent, dupilumab was effective as an add-on treatment, for both severe asthma and CRSwNP. It led to disease control, OCS withdrawal, reduced eosinophilic inflammation, improved lung function, smell recovery and absence of exacerbations during follow-up. Dupilumab, targeting the type 2 inflammatory process, may allow a better management of pediatric patients >=12 years old with severe CRSwNP and comorbid asthma. (Table Presented).

Prevalence of asthmatic patients and clinical trend among hospitalized for Sars-Cov2 infection during the first pandemic wave in North-West Italy

Background: In first pandemic wave, SARS-CoV2 infection was hypothesized to be more frequent and severe in asthmatic patients with reduced anti-viral immune response and typical disease flares during viral respiratory infections. Despite this, the studies performed to date have not confirmed these data. The purpose of our research is to evaluate the prevalence and clinical trend in patients with bronchial asthma among hospitalized for COVID-19 in North-West Italy. Method(s): In our multicentre retrospective study, we enrolled all patients hospitalized for COVID-19 from February to July 2020 at four leading hospitals: City of Health and Science of Turin (Molinette-unit), Umberto I Hospital (Turin), Umberto Parini Hospital (Aosta) and Santa Croce and Carle Hospital (Cuneo). We inclueded all patients with SARS-CoV- 2 positive nasopharyngeal swab and/or serology and/or clinical features highly suggestive of SARS-CoV- 2 infection and a hospital stay for COVID-19 of more than 48 hours. We excluded patients with exacerbation of disease not related to SARS-CoV- 2 and fewer than 48 hours of hospital stay;for each patient were collected demographic and clinical data before and during admission. Result(s): We evalueted 1016 patients: 110 (10.8%) had obstructive airway disease [71 COPD (6.9%) and 39 bronchial asthma (6.9%)]. The majority of patients with asthma took an inhaled corticosteroids (ICS) with or without Short or Long Acting Beta-Agonists (SABA, LABA) at home (56.4%);only two cases had severe asthma, both in therapy with biologics. A comparison of clinical trend and outcomes in patients with asthma, COPD and no history of obstructive lung disease is in Table 1. Conclusion(s): The prevalence of asthma among hospitalized for COVID-19 was lower than the prevalence data reported in the general population (3.8 vs 6.6% reported by ISTAT), in Piedmont and Val d'Aosta1 (3.8 vs 5.7%) and in recent meta-analysis2 (3.8 vs 8.08%). There were no significant differences between asthmatics and non-asthmatics in gender, age, smoking habits, associated comorbidities, length of hospital stay, development of disease complications, invasive and/or non-invasive ventilation, treatment with hydroxychloroquine, antivirals or biologics or mortality.

A descriptive evaluation of COVID-19 disease in adult asthma patients at La Paz University Hospital

Background: COVID-19 is an infectious entity caused by the SARS-CoV-2 virus. There have been reported risk factors like chronic airway entities such as chronic obstructive pulmonary disease. Since asthma is a respiratory disease, it could be found as a risk factor to develop severe COVID-19 disease. However, most of the evidence reveals that asthma isn't associated with higher severity or worse prognosis. Madrid has been one of the most affected regions in the world during the pandemic. La Paz University Hospital has developed one of the largest cohorts in Europe. We used this data and described several characteristics around COVID-19 disease in asthma patients. Method(s): We collected data by individual review of the patients' electronic clinical records (DXC-HCIS, Healthcare Information System). Then we describe the general characteristics of the patients, their asthma, and COVID-19 evolution. The analyzed data includes general demographics, asthma classification (T2 or no T2), basal treatment, and pre-COVID-19 asthma control (by ACT and exacerbations). We studied acute COVID-19 disease symptoms and treatment, the presence of pneumonia, thromboembolism, the need for hospitalization, admission to the intensive care unit (ICU), and mortality. Result(s): The total number of patients studied was 173, the majority were women (67%) with an average age of 55 and type 2 asthma (67%) which was controlled before COVID-19 disease (ACT median was 25, the median of exacerbations was 0). The majority used the combination of long-acting beta 2 agonists and inhaled corticosteroids (ICS+LABA) for asthma treatment (67%). Only 2 patients were treated with omalizumab, which was discontinued during COVID-19 disease. The most frequent symptoms were cough and dyspnea (80% and 75% respectively). 4% of patients presented thromboembolism. 60% had pneumonia. 60% required hospitalization, 11% of whom died due to COVID-19 complications. The most common treatment was hydroxychloroquine and azithromycin (75% and 45% respectively), followed by oral corticosteroids (15%), lopinavir/ritonavir (8%), tocilizumab (5%), and remdesivir (2%). Conclusion(s): This cohort represents asthmatic patients in La Paz University Hospital. We observed that the proportion of hospitalizations, ICU admissions, and mortality due to COVID-19 was similar as described in previous studies and therefore no different from non-asthmatic patients. The characteristics presented in this study help us better understand the complications of asthmatic patients thanks to one of the largest COVID-19 cohorts in Europe.

Risk stratified physician associate asthma review

Background: COVID-19 placed unprecedented care on the NHS. Patients with asthma had limited chronic disease management. We adopted a Proactive Asthma Care framework1 to help prioritise those that were at highest risk of attacks. Aim(s): To target asthma reviews such that patients at highest risk were reviewed first. Result(s): Patients were categorised as red (Long-acting beta agonist (LABA) no Inhaled Corticosteroid (ICS), >/=2 Oral corticosteroid (OCS) courses, No ICS and >3 Short-acting beta agonist (SABA) in the past year) or amber (ICS & >6 SABA) or Green (<6 ICS & >3 SABA). Two Physician Associates attempted to contact 1,289 patients and successfully reviewed 785 patients. 600 patients fell into the red/amber categories with 428 of them being successfully contacted. Of those contacted 396 were amber, and the remaining 32 were red. In the green group (689 patients), 357 were successfully contacted and reviewed. Asthma management was optimised in 361 patients (46%) and 134 patients (17%) were referred to secondary care services. Of the 361 patients optimised, 20 (6%) were started on an ICS, 119 (33%) originally on an ICS alone were changed to ICS/LABA and 55 (15%) had a Long-acting Muscarinic Antagonist (LAMA) added to their regime. Conclusion(s): Adopting a risk-based review algorithm led to an improved asthma management in 63% of patients (those with changes in management and referral to secondary care).

PATHOPHYSIOLOGY OF LACTIC ACIDOSIS IN PATIENTS WITH ASTHMA

SESSION TITLE: Challenges in Asthma SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Asthma is a chronic illness affecting 334 million people worldwide[1]. Asthma affects the respiratory gas exchange, which plays a significant role in acid-base balance. Acid-base disorders in asthma involve respiratory alkalosis, respiratory acidosis, and AG acidosis[2]. CASE PRESENTATION: A 37 years old Hispanic male with a PMH of intermittent asthma presents with progressive dyspnea for three days, worse with activity and decreases with rest. He reported no [cough, fever, rhinorrhea, chest pain]. No orthopnea. He is vaccinated for COVID ( 2 Pfizer doses), has no sickness exposure, and works as a driver. The patient is not a smoker. Physical Exam: Blood pressure 124/72 mmHg. Heart Rate 100 PPM. Temperature 97.1 F.Respiratory Rate 21BPM.SPO2 90% General appearance: acute distress with nasal flaring. Heart: Normal S1, S2. RRR. Lung: Poor air entry with diffuse wheeze bilaterally. He was placed on a 6 LPM NC. CBC and differential were unremarkable. He was started on methylprednisone, Ceftriaxone, and azithromycin. The patient was started on inhaled Salbutamol and Budesonide. Chest X-ray was unremarkable, Chemistry was unremarkable except for elevated Lactic acid 4.7, There was no concern for reduced tissue perfusion or hypoxia, with no evidence of an infectious process because both viral and bacterial causes for pneumonia were excluded, and antibiotics were stopped. A serial lactic acid level trend was 4.5/4.3/ 4.1/ 4 on the first day, while on the next day, it was 3.1/ 2.9/ 2.7/ 2.5/ 3.5, we stopped trending his lactic acid level. He improved and was discharged on an oral taper steroid and inhaled steroids with a B2 agonist. DISCUSSION: There are two types of Lactic acidosis in patients with asthma: 1- Type-A results from impaired oxygen delivery to tissues and reduced tissue perfusion in severe acute asthma may be accompanied by reduced cardiac output. 2- Type B where oxygen delivery is normal, but the cellular function is impaired due to increased norepinephrine in plasma, increasing metabolic rate and lactate production, drugs like beta-agonists increase glycogenolysis leading to an increased pyruvate concentration;pyruvate is converted to lactic acid. B2 agonist increases lipolysis and increases Acetyl CoA, this increase in Acetyl CoA inhibits the conversion of pyruvate to Acetyl CoA, increasing pyruvate which will be converted to lactic acid[2], Theophylline is a non-selective 5'-phosphodiesterase inhibitor and potentiates the activity of ß-adrenergic agents by increasing the intracellular concentration of cAMP, Glucocorticoids are also known to increase the ß-receptor's sensitivity to ß-adrenergic agonists. CONCLUSIONS: Providers are increasingly challenged by hyperlactatemia,it is not harmful but elevated Lactic acid levels and clearance rate is used for prognostication,hyperlactatemia might be misleading,and all possible causes of elevated lactic acid levels must be explored. Reference #1: 10.5334/aogh.2412 Reference #2: https://doi.org/10.3390/jcm8040563 Reference #3: Edwin B. Liem, Stephen C. Mnookin, Michael E. Mahla;Albuterol-induced Lactic Acidosis. Anesthesiology 2003;99:505–506 doi: https://doi.org/10.1097/00000542-200308000-00036 DISCLOSURES: No relevant relationships by Vasudev Malik Daliparty No relevant relationships by Abdallah Khashan No relevant relationships by Samer Talib No relevant relationships by MATTHEW YOTSUYA

EFFECTS OF BENRALIZUMAB ON AIRWAY DYNAMICS IN SEVERE EOSINOPHILIC ASTHMA USING FUNCTIONAL RESPIRATORY IMAGING PARAMETERS: THE BURAN STUDY DESIGN

SESSION TITLE: Imaging Across the Care Spectrum SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Eosinophilic airway inflammation and mucus plugs are common in asthma patients. Eosinophil depletion may reduce mucus plugging and improve airway patency and airflow distribution. This study will investigate the short-term benefits of sustained depletion of airway eosinophils by benralizumab, an anti-IL-5Rα monoclonal antibody, on airway structure and dynamics using functional respiratory imaging (FRI) in adults with severe eosinophilic asthma (SEA). METHODS: A multicenter, single-arm, open-label, phase 4 study enrolling approximately 138 patients. Screening will be followed by a run-in period of up to 21 days, before administration of subcutaneous benralizumab 30 mg at Weeks 0, 4 and 8, final assessment at Week 13, and a 2-week follow-up period. RESULTS: Key inclusion criteria: age 18-70 years with diagnosed SEA inadequately controlled by high-dose inhaled corticosteroid and long-acting β2-agonist (ICS-LABA) treatment +- oral corticosteroids (OCS) or other asthma controllers;documented post-bronchodilator (BD) reversibility;≥2 exacerbations in prior 12 months;baseline peripheral blood eosinophil count ≥300/μL (≥150 cells/μL if OCS-dependent);pre-BD forced vital capacity (FVC) <65% predicted, pre-BD FEV1 <80% predicted and Asthma Control Questionnaire (ACQ-6) ≥1.5. Key exclusion criteria: exacerbation/pulmonary infection 6 weeks pre-screening;smokers or ex-smokers who stopped smoking ≤12 months pre-screening and/or history of >10 pack-years;positive for COVID-19 at or ≤6 weeks before screening, or severe COVID-19 at any time.The primary endpoint is mean change from baseline in specific airway volume measured at total lung capacity. Secondary objectives include change from baseline in airway dynamics (lung, airway and blood vessel volumes, airflow distribution, airway resistance, air trapping, ventilation/perfusion mapping) and mucus plug scores, and correlations with conventional lung function measurements (FVC, FEV1) at baseline and Week 13. FRI will be via computed tomography scans assessed using computer modelling. Exploratory objectives include: relationships between airway dynamics and patient-reported outcomes (PROs) such as the Asthma Impairment and Risk Questionnaire (AIRQ), ACQ-6, and St George's Respiratory Questionnaire (SGRQ) at baseline, from baseline to Week 13, and change from baseline in Central/Peripheral (C/P) lung deposition ratio of inhaled drugs. Safety and tolerability will also be assessed. CONCLUSIONS: This study will advance understanding of the eosinophil-depletion effects of benralizumab on airway structure, dynamics, and mucus plugs and could provide additional useful insights into the relationship of PROs with changes in airway dynamics and structure. CLINICAL IMPLICATIONS: Our results may help further characterize physiologic changes resulting from eosinophil depletion with benralizumab and better delineate the impact of changes in lung function and structure on PROs. DISCLOSURES: stockholder relationship with AstraZeneca Please note: 2 years Added 03/31/2022 by Donna Carstens, value=Salary No relevant relationships by Wilfried De Backer Employee relationship with AstraZeneca LP Please note: Since 2014 by Eduardo Genofre, value=Salary Shareholder relationship with AstraZeneca LP Please note: Since 2014 by Eduardo Genofre, value=LTIs Employee relationship with FLUIDDA Inc Please note: Aug 2021 - Present Added 04/12/2022 by Patrick Muchmore, value=Salary Advisory Committee Member relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Consultant relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with AstraZeneca Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/20 2 by Reynold Panettieri Advisory Committee Member relationship with RIFM Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Consultant relationship with RIFM Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Equillium Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Equillium Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Genetech Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with Genetech Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with Sanofi/Regeneron Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Consultant relationship with Bayer Please note: 24 months by Reynold Panettieri, value=Honoraria Advisory Committee Member relationship with Theravance Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Advisory Committee Member relationship with Novartis Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Contracted Research relationship with Optikira Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Medimmune Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Contracted Research relationship with Maven Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Contracted Research relationship with Evelobio Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Contracted Research relationship with Johnson & Johnson Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Advisory Committee Member relationship with AstraZeneca;RIFM;Equillium;Genentech;Thervance Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Consultant relationship with AstraZeneca;RIFM;Equillium;Bayer Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with AstraZeneca;Sanofi/Regeneron;Genentech Please note: 24 months by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Research grant recipient relationship with Novartis;Optikira;Medimmune;Maven;Evelobio Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Research grant recipient relationship with Johnson & Johnson;AstraZeneca;RIFM;Equillium;Genentech Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Research grant recipient relationship with Theravance Please note: 24 months by Reynold Panettieri, value=Grant/Research Support Advisory Committee Member relationship with AstraZeneca Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Removed 03/29/2022 by Reynold Panettieri Principal Investigator relationship with AstraZeneca Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with AstraZeneca Please note: $1001 - $5000 by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with MedImmune Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Removed 0 /29/2022 by Reynold Panettieri Principal Investigator relationship with MedImmune Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Reseaerch Institute for Fragrance Materials Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Removed 03/29/2022 by Reynold Panettieri Principal Investigator relationship with Reseaerch Institute for Fragrance Materials Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Equillium Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Removed 03/29/2022 by Reynold Panettieri Principal Investigator relationship with Equillium Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Theravance Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Removed 03/29/2022 by Reynold Panettieri Advisory Committee Member relationship with Avillion Please note: $1001 - $5000 by Reynold Panettieri, value=Consulting fee Speaker/Speaker's Bureau relationship with Sanofi/Regeneron Please note: $1001 - $5000 by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Speaker/Speaker's Bureau relationship with Genentech Please note: $1001 - $5000 by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Principal Investigator relationship with Genentech Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Principal Investigator relationshipwith OncoArendi Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Metera Please note: $20001 - $100000 by Reynold Panettieri, value=Grant/Research Support Removed 03/29/2022 by Reynold Panettieri Consultant relationship with TEVA Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Removed 03/29/2022 by Reynold Panettieri Consultant relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Advisory Committee Member relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Speaker/Speaker's Bureau relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Principal Investigator relationship with AstraZeneca Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Consultant relationship with RIFM Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Advisory Committee Member relationship with RIFM Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Principal Investigator relationship with RIFM Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Advisory Committee Member relationship with Genentech Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Principal Investigator relationship with Genentech Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Consultant relationship with TEVA Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Principal Investigator relationship with TEVA Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Equillium Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Novartis Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Medimmune Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator r lationship with Origo Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with ACTIV-1 Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Janssen Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Principal Investigator relationship with Vault Health Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Grant/Research Support Speaker/Speaker's Bureau relationship with Sanofi Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Speaker/Speaker's Bureau relationship with Merck & Co Please note: 24 months Added 03/29/2022 by Reynold Panettieri, value=Honoraria Employee No relevant relationships by Vivian Shih Shareholder relationship with AstraZeneca Please note: >5 years by Frank Trudo, value=Shares

IMPAIRED BETA-2ADRENERGIC ENDOTHELIUM-DEPENDENT VASODILATION IS REVERSED BY PHOSPHODIESTERASE INHIBITION IN PATIENTS PREVIOUSLY HOSPITALIZED WITH COVID-19

Objective: Endothelial dysfunction is thought to underlie many of the complications of COVID-19 but to what degree this persists after recovery is unknown. Here we examine endothelial function in subjects previously hospitalized with COVID- 19, those with mild symptoms who were not hospitalized and negative controls (absence of SARS-CoV-2-antibodies). Endothelial function was measured as pulse wave response to the β2 adrenergic agonist salbutamol (PWRS) which is mediated through the nitric oxide - cyclic guanosine monophosphate pathway (NO-cGMP). Design and method: Echocardiography was used to exclude subjects with cardiac abnormalities. Tonometry of the radial artery (SphygmoCor, AtCor Medical, Sydney, Australia) was performed in duplicate by a single operator before and after inhalation of 200 mcg of salbutamol using a spacer device. The PWRS was taken as the change from baseline in augmentation index (Aix) as calculated by the SphygmoCor system. In a sub-sample, PWRS was assessed in the presence and absence of the phosphodiesterase type 5 inhibitor sildenafil which inhibits the breakdown of cGMP. Results: We recruited 88 subjects (49 men) aged 47.9 ± 14.3 (mean ± SD) years of whom 32 were previously hospitalized with COVID-19 (~6 months). Subjects previously hospitalized with COVID-19 were all previously assessed in a dedicated pulmonary clinic. Age, gender, BMI, smoking status, diabetes and estimated 10-year cardiovascular risk (Q-RISKâ3) were similar between the groups. Administration of salbutamol reduced AIx in controls and those with mild COVID-19 but produced an increase in AIx in previously hospitalized COVID-19 cases (mean [95% CI]): -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % respectively, P = 0.017 between the groups. In a sub-sample (11 hospitalized and 11 non-hospitalized) the PWRS was measured again 30 minutes after oral administration of sildenafil 25 mg. This produced a greater reduction in AIx: -5.28 [-9.00, -1.54] % in non-hospitalized and a reduction: -3.90 [-7.60, -0.21] % in hospitalized patients, and an overall improvement in the PWRS (P = 0.006). Conclusions: In subjects previously hospitalized with severe COVID-19, endothelial function is impaired for many months after hospital discharge and the impaired NO-cGMP mediated vasodilation may be reversed by sildenafil.

Undifferentiated Shock: A Case of Idiopathic Capillary Leak Syndrome

Systemic capillary leak syndrome (SCLS or Clarkson's disease) is a rare condition characterized by episodes of vascular hyperpermeability. The extravasation of plasma to the interstitial space results in hemoconcentration, hypoalbuminemia, hypovolemia and compartment syndrome of the extremities. The disease can be idiopathic or secondary to causes including viral infections or chemotherapeutic toxicity. We present a fatal case of idiopathic SCLS which rapidly deteriorated to multiple organ failure despite initial improvement with methylene blue. A 57-year-old male presented for worsening back pain over one month. He described a flulike illness 2 weeks prior. Testing for respiratory viruses including SARS-CoV-2 was negative. He received intravenous crystalloid fluids acutely developed respiratory distress and hypotension requiring emergent intubation and initiation of norepinephrine infusion. CT angiography of the chest demonstrated pulmonary edema. Early during his hospitalization urine output ceased and body weight increased by 10 kg, developing tense anasarca. Hematocrit concentrated from 42.7 to 54.4%. Serum albumin dropped from 4.6 to 2.5 g/dL. C1 esterase inhibitor level and IgM were normal. Ferritin was elevated at 2515 ng/ml. He received cefepime and vancomycin, though infectious workup returned unremarkable. Continuous renal replacement therapy and stress dose steroids were initiated. Vasopressor requirement worsened until he was on three vasopressors at one point. Given the constellation of hemoconcentration, hypoalbuminemia, and shock a diagnosis was made of idiopathic SCLS. Treatment was started with methylene blue, montelukast, and the β-adrenergic agonist terbutaline. Blood pressure improved and patient came off pressors and lactate improved from 13 to 4. However, he later developed rising creatine kinase continued to climb to >40,000 U/L. He developed rhabdomyolysis with concern for compartment syndrome of the extremities due to third spacing of fluids. Orthopedic surgery was consulted;but did not believe a fasciotomy was indicated due to rapid decline. Lactic acidosis rose to 18 mmol/L. His family decided to transition to comfort measures. He passed with family at bedside on Day 4 of hospitalization. There are fewer than 500 cases of SCLS reported since initial discovery in 1960. Given the overlap in presentation with common causes of plasma leakage such as sepsis, it is likely that many cases are unrecognized. Patients are often mismanaged;development of severe hypovolemia despite fluids and compartment syndrome is overlooked. This case builds on our evolving recognition of this disease, and the potential for the use of methylene blue to help acute exacerbations of the disease.

Emergent temporary transvenous pacemakers were infrequently needed for patients presenting with complete heart block at a regional hospital

Introduction: Patients presenting with Complete heart block (CHB) are emergently referred for placement of a temporary transvenous pacemaker (TTVP) for hemodynamic stability. Data on the immediate management and outcomes of such patients are lacking. Methods: Data collected;through retrospective chart review of patients presenting to the Emergency Department (ED) at a regional hospital from October 2017 to January 2021 with a diagnosis of new CHB;included age, sex, clinical, laboratory and ECG data, medications, interventions and length of stay. Results: There were 71 patients (31 women) of whom 19 were on beta blocker or Calcium channel blockers. Data (see Table 1) for all variables was available in 68 patients. Syncope, lightheadedness and dyspnea were common symptoms. The median age was 77 years. The median heart rate was 41bpm. Atropine was used in 13 patients. Five patients with initial Systolic Blood Pressure (SBP) < 100mmHg received sympathomimetics. Syncope with pause occurred in 3 patients. A TTVP was placed in 12 patients. Among 22 patients with initial SBP > 160mmHg one patient with a recent TAVR had a TTVP placed. All but five were managed in the ICU setting. On Univariate logistic regression (R statistical software 3.6.1) initial SBP, SBP < 100mmHg and Initial Serum K level were clinically significant. In multivariate analysis, SBP was significant with a lower SBP predicting need for a TTVP [OR 0.96 (CI 0.91-0.99, p = 0.019)]. A permanent pacemaker (PPM) prior to discharge was placed in 64 patients on average in 1.6 days from presentation. 3 patients with STEMI and TTVP did not need a PPM. 1 transitioned to hospice and 1 patient died of sepsis. In 1 it was attributed to COVID-19 infection. Conclusions: TTVP was infrequently needed (16.66%) among patients presenting to the ED with CHB. Initial SBP and Serum K were clinically relevant factors. Prospective data related to the acute management of CHB is needed to identify predictors that can improve the care for such patients.

Characteristics and Outcomes of Adult Asthmatic Patients Presenting with Coronavirus Disease 2019 (COVID-19) in Qatar

Introduction: Around one in every five people in Qatar has bronchial asthma. Asthma may be associated with worse Coronavirus disease 2019 (COVID-19) outcomes. Research Question or Hypothesis: What are the characteristics and outcomes of adult asthmatic patients presenting with COVID-19 and what factors, including asthma medications, are associated with worse disease outcomes? Study Design: Retrospective observational cohort study Methods: Adult patients with documented history of asthma and laboratory-confirmed diagnosis of COVID-19 were included. Relevant data was retrieved through electronic chart review. Descriptive statistics were used to summarize the characteristics and the outcomes of the study cohort. Factors independently associated with COVID-19 related hospitalization were determined by multivariable logistic regression models. Results: Between March and August 2020, 616 patients met the inclusion criteria, of whom 52% were females. Median age was 44 years (interquartile range [IQR], 34-57 years). Forty-four percent of patients received inhaled corticosteroids (ICS) and 41.7% received long-acting beta agonists (LABA). Montelukast and tiotropium were used by 17.9% and 2.9% of patients, respectively. One patient was receiving long term oral corticosteroid and two patients were on biological agents. The most common comorbidities were hypertension (31%) and diabetes (27.1%). Two-hundred thirty-six patients (38.3%) required hospitalization for COVID-19, with a median hospital stay of 10 days (IQR, 5-15). Invasive mechanical ventilation was required in 26 patients (4.2%) and 16 patients (2.6%) died. The need for hospitalization was independently associated with older age (odds ratio [OR] for 10-years, 1.32;95% confidence interval [CI], 1.13-1.54) and hypertension (OR, 2.4;95% CI, 1.43-3.93) but not with the use of ICS, LABA, montelukast or tiotropium. Conclusion: In Qatar, adult patients with asthma appear to be at higher risk of COVID-19 related hospitalization compared to the general adult COVID-19 infected population. Older age and hypertension were associated with worse outcomes while asthma medications were not.

Diagnostic algorithm in CoViD-19 pulmonary outcomes

Background and Aim: Pulmonary involvement from CoViD-19 is frequent, after acute phase dyspnoea, cough, desaturation, respiratory insufficiency, can persist, pneumonia leads to interstitial disease (ground- glass) and to pulmonary fibrosis (honeycomb lung). A diagnostic algorithm can be a simple way for differential diagnoses (pulmonary embolism, PE) and to set up therapies in a systematic way. Our objective was to propose a simple and easy diagnostic algorithm, to identify with chest CT scan, excluding PE in high dimer- D patients, suggestive gait test and compatible objectivity. Methods: Prescription of: blood tests, radiological (CT chest CMC or High Resolution), respiratory physiopathology (Walking test, Global spirometry, Plethysmography, DLCO). Set drug therapies in case of PE, oral steroid (OCS) in case of extensive interstitial disease, long-acting beta 2 agonist bronchodilators (LABA), antimuscarinics (LAMA), inhaled steroids (ICS). For fibrosis and a honeycomb pattern, treatment with dipalmitoylethanolamide (PEA). Results: 258 outpatients, average 60.68 years, 115 women, 143 men, with an urgent request for pneumological visit and treated on an outpatient basis. 1 pt died during treatment, 4 pts were diagnosed with pulmonary embolism. 4 pts required a prescription for oxygen therapy. 228 pts presented ground-glass, 30 pts showed normal chest CT. Conclusions: DLCO shows progressive improvement in values after ICS treatment. Small pathway deficiency evidenced by spirometry can be treated with LABA-LAMA especially in patients with a previous history of cigarette smoking or COPD.