key: cord-0981849-8g5kbtz8 authors: Zein, Joe G.; Strauss, Ronald; Attaway, Amy H.; Hu, Bo; Milinovich, Alex; Jawhari, Nesreen; Chamat, Soulaima S.; Ortega, Victor E. title: Eosinophilia is associated with improved COVID-19 outcomes in inhaled corticosteroids-treated patients. date: 2022-01-13 journal: J Allergy Clin Immunol Pract DOI: 10.1016/j.jaip.2021.12.034 sha: 3f1fc250b0d325f641fcc65ae32e7a9528bac19f doc_id: 981849 cord_uid: 8g5kbtz8 Background In addition to their proinflammatory effect, eosinophils have anti-viral properties. Similarly, inhaled corticosteroids (iCS) were found to suppress coronavirus replication in-vitro and were associated with improved outcomes in coronavirus disease 2019 (COVID-19). However, the interplay between the two and its effect on COVID-19 needs further evaluation. Objective Determine the association between pre-existing blood absolute eosinophil counts (AEC), iCS and COVID-19-related outcomes. Methods We analyzed data from the Cleveland Clinic COVID-19 Research Registry (April 1, 2020 to March 31, 2021). Of the 82,096 individuals who tested positive, 46,397 had blood differential cell counts obtained before SARS-CoV-2 testing dates. Our endpoints included need for hospitalization, admission to the intensive care unit (ICU) and in-hospital mortality. The effect of eosinophilia on outcomes was estimated after propensity weighting and adjustment. Results Of the 46,397 patients included in the final analyses, 19,506 had pre-existing eosinophilia (>0.15 x103 cells/μL), 5,011 received iCS, 9,096 (19.6%) were hospitalized, 2,129 (4.6%) required ICU admission, and 1,402 (3.0%) died during index hospitalization. Adjusted analysis associated eosinophilia with lower odds for hospitalization (OR [95% CI]: 0.86 [0.79; 0.93]), ICU admission (OR [95% CI]: 0.79 [0.69; 0.90]), and mortality (OR [95% CI]: 0.80 [0.68; 0.95]) among iCS-treated, but not in untreated patients. The correlation between AEC and the estimated probability of hospitalization, ICU admission and death was non-linear (U-shaped) among patients not treated with iCS, and negative in treated patients. Conclusion The association between eosinophilia and improved COVID-19 outcomes depends on iCS. Future randomized controlled trials are needed to determine the role of iCS and its interaction with eosinophilia in COVID-19 therapy. in treated patients. 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 In March 2020, the coronavirus disease 2019 (COVID-19) outbreak caused by 181 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a 182 pandemic, and has since caused more than 4.5 million deaths worldwide. (11, 12) , neutrophil activation (13, 14) , and hematopoietic alterations resulting 203 in immature and dysfunctional neutrophils (12, 15 (pre-existing) and a peri-testing CBC with differential measurements available for 245 analysis. Unless specified as "peri-testing", all differential cell counts results in this article 246 refer to baseline (pre-existing) measurements. The primary outcome was COVID-19-related hospitalizations. We also studied two The effect of COVID-19 on immune cell profile reconfiguration was assessed by 268 evaluating the association between COVID-19 outcomes and peri-testing CBC differential 269 cell subtypes in 12,944 patients. We also examined the association between outcomes 270 and changes from baseline in these cell subtypes in 9,650 patients. variables were compared using a chi-square test. To account for observed covariate differences between patients with and without 280 eosinophilia (i.e. AEC >0.15 x10 3 /µL), we used inverse weighting on the propensity score. The propensity score for each patient is the predicted probability of eosinophilia from a 282 nonparsimonious logistic regression model using covariates knowna priorito be were female (Table I ). The clinical characteristics of patients with asthma and COPD are 331 detailed in the online repository of this article (see Table E1 and than those without pre-existing eosinophilia in unadjusted comparisons (Table I) . and outcome measures (see Table E3 in this article's Online Repository at www.jaci-355 inpractice.org). Using a likelihood ratio test, non-linear models were found to be different 356 from models assuming a linear association (p<0.001). (Table II) . Results from analyses using the original non-imputed data (i.e. complete cases) 394 were consistent with findings from the main analyses using imputed data (see Table E4 395 in this article's Online Repository at www.jaci-inpractice.org) In contrast to eosinophilia, eosinopenia (<0.1 x10 3 cells/µL) was associated with 398 worse COVID-19 outcomes irrespective of iCS use (see Table E5 .09] ICU stands for intensive care unit; SARS-CoV-2 stands for severe acute respiratory syndrome coronavirus 2 *Baseline pre-existing eosinophilia defined by a blood absolute eosinophil count >0.15 x10 3 cells/µL, obtained at least 2 weeks prior to SARS-CoV-2 test date. † The effect of high blood absolute eosinophil count >0.15 x10 3 cells/µL on hospital outcomes is estimated by weighting each patient with the inverse propensity score and controlling for the propensity score as a covariate in the model. Medications = Nonsteroidal Anti-inflammatory drugs, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, inhaled corticosteroids, intranasal corticosteroids, immunosuppressive therapy (that includes systemic corticosteroids). Comorbidities = asthma, COPD/emphysema, diabetes, hypertension, coronary artery disease, heart failure and cancer (historical of or current), immunosuppressive diseases, and connective tissue diseases. J o u r n a l P r e -p r o o f An interactive web-based dashboard to track COVID-19 in real time Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells Expression of SARS-CoV-2 receptor ACE2 and coincident host response signature varies by asthma inflammatory phenotype Clinical Outcome of Eosinophilia in Patients with COVID-19: A Controlled Study Do Blood Eosinophils Predict in-Hospital Mortality or Severity of Disease in SARS-CoV-2 Infection? Eosinophilia in Asthma Patients Is Protective Against Severe COVID-19 Illness. The journal of allergy and clinical immunology In practice Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19 Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19) A single-cell atlas of the peripheral immune response in patients with severe COVID-19 SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans Longitudinal analyses reveal immunological misfiring in severe COVID-19 Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids. American journal of respiratory and critical care medicine Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells Dexamethasone inhibits SARS-CoV-2 spike pseudotyped virus viropexis by binding to ACE2 Intranasal Corticosteroids are Associated with Better Outcomes in Coronavirus Disease 2019 (COVID-19) Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19 The impact of COVID-19 on patients with asthma. The European respiratory journal Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective. The European respiratory journal Inhaled corticosteroids and COVID-19-related mortality: confounding or clarifying? Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform SARS-CoV-2 infection in the COPD population is associated with increased healthcare utilization: An analysis of Cleveland clinic's COVID-19 registry Association of Smoking and Cumulative Pack-Year Exposure With COVID-19 Outcomes in the Cleveland Clinic COVID-19 Registry Safety of Influenza Vaccine during COVID-19 Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19) Extracting and utilizing electronic health data from Epic for research Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial Mepolizumab treatment in patients with severe eosinophilic asthma. The New England journal of medicine Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma Oral glucocorticoidsparing effect of mepolizumab in eosinophilic asthma Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies Eosinopenia <100/muL as a marker of active COVID-19: An observational prospective study Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine Trends in COVID-19 Risk-Adjusted Mortality Rates Improving Survival of Critical Care Patients With Coronavirus Disease 2019 in England: A National Cohort Study mice: Multivariate Imputation by Chained Equations in R Eosinophils and their interactions with respiratory virus pathogens Human and Mouse Eosinophils Have Antiviral Activity against Parainfluenza Virus. American journal of respiratory cell and molecular biology Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. American journal of respiratory cell and molecular biology Eosinophils and Respiratory Viruses Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, m(2) muscarinic receptor dysfunction, and antiviral effects Genetic and nongenetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium Inhaled glucocorticoids, lymphocytes, and dendritic cells in asthma and obstructive lung diseases The trinity of COVID-19: immunity, inflammation and intervention Eosinophil responses during COVID-19 infections and coronavirus vaccination COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City The relationship of asthma severity to COVID-19 outcomes. The journal of allergy and clinical immunology In practice Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses Inhibition of SARScoronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. American journal of respiratory and critical care medicine Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids