Association Between Preadmission Acid Suppressive Medication Exposure and Severity of Illness in Patients Hospitalized With COVID-19

• DOI: 10.1053/j.gastro.2020.11.007
• Publication Date: 2020-11-12T16:21:18Z
• Authors: B. Joseph Elmunzer; Bethany J. Wolf; James M. Scheiman; William M. Tierney; Jason R. Taylor; Ambreen A. Merchant; Vaishali A. Patel; Field F. Willingham; Eric F. Howard; Mary K. West; Casey L. Koza; Patrick S. Yachimski; Emad Qayed; Rosemary Nustas; Ali Zakaria; Marc S. Piper; Lujain Jaza; Nauzer Forbes; Millie Chau; Luis F. Lara; Georgios I. Papac...; Uchechi Okafor; Darwin L. Conwell; Michael L. Volk; Evan Mosier; Mohamed Azab; Anish Patel; Liam G. Hilson; Selena Zhou; James Buxbaum; Vladimir M. Kushnir; Alexandria M. Lenyo; Ian P. Sloan; Thomas Hollander; Caroline G. McLeod; Rebecca L. Spitzer; Lauren Wakefield; Haley Nitchie; Collins O. Ordiah; Don C. Rockey; Teldon B. Alford; Sunil Amin; Gabriela N. Kuftinec; Amar R. Deshpande; Dhiraj Yadav; Melissa Saul; Melanie Mays; Gulsum Anderson; Kelley Wood; Laura Mathews; Charlie Fox; Jennifer M. Kolb; Sachin Wani; Swati Pawa; Rishi Pawa; Andrew Canakis; Christopher Huang; Laith H. Jamil; Andrew M. Aneese; V. Mihajlo Gjeorg...; Zaid Imam; Fadi Odish; Ahmed I. Edhi; Molly Orosey; Abhinav Tiwari; Soumil Patwardhan; Benita K. Glamour; Zachary L. Smith; Amy E. Hosmer; Nancy Furey; Amitabh Chak; Katherine A. Hanley; Jordan Wood; Rajesh N. Keswani; Harsh K. Patel; Janak N. Shah; Emil Agarunov; Nicholas G. Brown; Anish A. Patel; Amrita Sethi; Evan L. Fogel; Gail McNulty; Abdul Haseeb; Judy A. Trieu; Rebekah E. Dixon; Jeong Yun Yang; Christopher J. Di...; Robin B. Mendelsohn; Delia Calo; Olga C. Aroniadis; Joseph F. LaComb; Lilian Cruz; Olga Reykhart; Bryan G. Sauer; Galina Diakova; Duyen T. Dang; Cyrus R. Piraka; Eric D. Shah; Molly Caisse; Natalia H. Zbib; John A. Damianos; Heiko Pohl; Stephanie Mitchell; Michael S. Bronze; Ashwinee Condon; Adrienne Lenhart; Raman Muthusamy; Kulwinder S. Dua; Vikram S. Kanagala; James Esteban; Ayesha Kamal; Marcia I. Canto; Vikesh K. Singh; Maria Ines Pinto-...; Joy M. Hutchinson; Richard S. Kwon; Sheryl J. Korsnes; Akbar K. Waljee; Weijing Tang; Yueyang Zhang; Ji Zhu; Harminder Singh; Zahra Solati; Nick Hajidiacos
• Keywords: 2019-20 coronavirus outbreak; Betacoronavirus; Illness severity; Association (psychology)

Recent studies have suggested that proton pump inhibitor (PPI) use may increase the risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and worsen course COVID-19.1Almario C.V. et al.Am J Gastroenterol. 2020; 115: 1707-1715Crossref PubMed Scopus (146) Google Scholar,2Lee S.W. al.Gut. 2021; 70: 76-84Crossref (145) Scholar This observation is biologically plausible, as gastric acid a well-established line defense against microbial pathogens, including SARS-CoV-1.3Darnell M.E. al.J Virol Methods. 2004; 121: 85-91Crossref (514) In addition, PPI outcomes in patients with COVID-19 through alterations gut microbiome intestinal immune apparatus.4Freedberg D.E. al.Gastroenterology. 2015; 149: 883-885Abstract Full Text PDF (245) Conversely, recent data suggest histamine receptor antagonists (H2RAs), which are less potent than PPIs terms suppression, be beneficial SARS-CoV-25Freedberg 159: 1129-1131Abstract (185) Scholar,6Mather J.F. 1617-1623Crossref (90) direct antiviral effects.7Wu C. al.Acta Pharm Sin B. 10: 766-788Crossref (1613) Considering suppressive medications among most commonly consumed drugs United States, an understanding impact these agents on significant importance. particular, informing public whether there evidence-based rationale to modify chronic during pandemic necessary. We studied preadmission exposure or H2RAs was associated worse hospitalized COVID-19. secondary analysis retrospective cohort study aiming better characterize digestive manifestations across 36 medical centers North America.8Elmunzer B.J. al.Clin Gastroenterol Hepatol. 2020 Sep 30; (PMID: 33010411)Google The first 50 100 consecutive confirmed diagnosis at each participating institution were included. Clinical from time symptom onset until discharge, death, end period manually abstracted electronic health records by personnel under oversight primary clinician-investigator. Conventional regression propensity score matched analyses performed evaluate association between medication mechanical ventilation death. Sensitivity conducted validity excluding unknown PPI/H2RA status imputing missing data. More comprehensive methods provided Supplementary Material. Between April 15 June 5, 2020, collected 1992 subjects. There 146 excluded because H2RA within 1 month admission unknown. Characteristics final (1846 COVID-19) shown Table 1. A total 417 (22.6%) had use, 167 (9.1%) 29 (1.6%) both. baseline variables included models listed 2. After adjusting for measured confounders, not independently need (odds ratio [OR] 1.02; 95% confidence interval [CI] 0.73–1.43; P = .89) (Figure 1). contrast, 1.55 times odds requiring relative exposed (OR 1.55; CI 1.11–2.19; .01) Propensity lack demonstrated likelihood (risk difference 9.72%; 1.26%–18.2%; .02). sensitivity analyses, removal least covariate value (480 observations) inclusion (139 additional did change findings. increased death 0.87; 0.66–1.14; .31) Similarly, 1.37; 0.96–1.95; .08) showed similar (375 findings pertaining use. However, this demonstrate statistically in-hospital mortality 1.48; 1.04–2.12; .03). results. large-scale America, and/or appear strongly affect Our do support putative deleterious effects fact contradict hypothesized benefits SARS-CoV-2 infection. These observations modified purpose improving justified. Instead, results reinforce preexisting guidance taking only when indicated lowest dose achieves clinical objective they recommended. noteworthy, it opposes growing evidence effect famotidine. reasons finding unclear apply famotidine specifically, exact determined. since estimated size relatively small, no residual confounding always observational nature, largely serves caution overuse highlights importance research prior care policy changes. It also important emphasize showing favorable evaluated active treatment rather exposure, we assessed study. has several limitations. First, verified pharmacy their consistent could confirmed. acquired over counter, limiting ability prescription claims confirm Furthermore, review clinicians coordinators clinician-investigator, likely accuracy compared administrative Second, noted previously, specifically query other H2RAs, thus been diluted class. Third, collect administration, confounded analysis. Last, reflect earliest phase current time. conclusion, observe strong improve COVID-19–related outcomes. Teldon Alford, author manager Alliance now employed Emmes, organization conducts space; see Material American Study Digestive Badih Joseph Elmunzer, MD (Conceptualization: Lead; Data curation: Formal analysis: Writing D L Bethany Wolf, PhD (Formal Methodology: ad; editing: Supporting) James Scheiman, (Writing alysis: Formalht Equal) William Tierney, lysis: Jason Taylor, n original draft: Supporting; – & understand system. alliance States Canada. Institutional board approval obtained site before patient identification collection. Adult who considered eligible. To limit sampling bias, aimed include meeting eligibility criteria institution. Potentially eligible identified investigators using multiple methods, warehouse queries, subject tools, lists relevant hospital entities. period, admission, records. abstraction coordinators, students, internal medicine gastroenterology trainees, well faculty gastroenterologists, depending site. Every designated clinician investigator oversaw vouched integrity quality ensured greatest extent possible multifaceted strategy described previously manual all incoming dedicated management specialist.1Almario collection form later separate multivariable generalized linear models. independent interest, age, race, sex both Lasso regression, agnostic, data-driven approach variable selection, used select covariates. Only laboratory values covariates (highest/lowest) occurred after (a outcome) treatments. account clustering center, estimating equation random center used. assess analysis, scores based predicted probability mixed either outcome factors (excluding death) predictors. model well. Four-to-one control-to-treatment caliper matching 0.2 applied obtain Missing assumed imputed development. whose subsequently imputation.Supplementary 1Patient CharacteristicsPatient CharacteristicOverall (N 1846)Demographics Age, y, mean (SD)59.9 (16.4) Sex, male, (%)1044 (56.6) Race, (%)White680 (36.8)Black774 (41.9)Other/Unknown392 (21.2) Body mass index, (SD)31.5 (8.14) Yes, (%)417 (22.6) H2 blocker (%)167 (9.1)Patient characteristics Comorbidities, (%)Hypertension1146 (62.1)Coronary artery disease/myocardial infarction284 (15.4)Congestive heart failure194 (10.5)COPD171 (9.26)Asthma240 (13.0)Obstructive sleep apnea197 (10.7)Peripheral vascular disease91 (4.93)Cerebrovascular accident TIA170 (9.21)Dementia118 (6.39)Diabetes Mellitus658 (35.6)ESRD175 (9.48)Current malignancy117 (6.34)Prior malignancy171 (9.26)Digestive disease183 (9.91)Other comorbidities829 (44.9)No comorbidities203 (11.0) No. median (min-max; IQR)2 (0-10; 3) Chemotherapy Immunosuppression, (%)Yes219 (11.9)No1621 (87.8)Unknown6 (0.33) Current ACE ARB (%)556 (30.1) NSAID (%)Yes506 (27.4)No1100 (59.6)Unknown240 (13.0) antibiotic (%)Yes560 (30.3)No1251 (67.8)Unknown35 (1.90)Admission lab measures White blood cell count, (SD)7.18 (4.00) Hemoglobin, (SD)12.9 (2.20) Platelets. (SD)207.5 (90.3) Aspartate, (SD)50.7 (54.1) Alanine aminotransferase, (SD)37.5 (34.5) Alkaline phosphate, (SD)82.3 (48.8) Bilirubin, (SD)0.64 (0.63) Albumin, (SD)3.63 (0.52) Creatinine, (SD)1.65 (2.76)Outcomes Mechanical required, (%)584 (31.6) ICU (%)795 (43.1) In-hospital (%)327 (17.7) HLOS, days, (min-max, IQR)8 (0.4-113; 13)ACE, angiotensin-converting enzyme; ARB, angiotensin blocker; COPD, obstructive pulmonary disease; ESRD, end-stage renal length stay; ICU, intensive unit; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory drug; TIA, transient ischemic attack. Open table new tab 2Variables Included Final Regression Models Ventilation DeathMechanical ventilationDeathH2RA useH2RA usePPI useAgeAgeBody indexSexSexRaceRaceDementiaDementiaCongestive failureNumber comorbiditiesNumber comorbiditiesWhite count admissionWhite admissionPlatelets admissionAspartate aminotransferase admissionAlkaline phosphatase admissionAlbumin admissionCreatinine admissionAntibiotics admissionDMC19 Registry Instructions 4_17_201)Please complete below (DCF) REDCap discharge will DMC19 database once entry verification complete.2)We aim capture inpatients diagnosis, regardless manifestations. prevalence defined patients, numbers grow, focus known GI outpatients.3)Please make efforts your system.4)Eligible can should any means necessary, include, but limited to, institutional records, record tools/dashboards, discussions infectious disease critical services, etc. You elect emergency ICD-10 code U07.1 2019-nCov help identify patients.5)Please triple-check submission. Although performing central monitoring, cannot verify source documents, nor on-site monitoring visits. Therefore, overall assured primarily level.6)Along lines #5, confer ensure context accounted much interpretation questions involve element subjectivity.7)All fields affirmative, negative, options. inadvertent generate query.8)Please maintain secure key allows basis ID#. future long-term ACE, Primary authors: MD, J. PhD. committee: PhD, R. MD. Steering Committee: (Chair), Rebecca L. Spitzer, MPH, Rebekah E. Dixon, BS, Collins O. Ordiah, MBBS, Jennifer M. Kolb, MS, Sachin Wani, Olga Aroniadis, Robin Mendelsohn, Christopher DiMaio, Don Rockey, Amit G. Singal, Amar Deshpande, Swati Pawa, Darwin Conwell, MSc, Raman Muthusamy, MAS, Dhiraj Yadav, MPH. Statisticians: Weijing Tang, MA, Yueyang Zhang, Ji Zhu, Coordinating Center: BA, Lauren Wakefield, MHA, Haley Nitchie, Emory University: Ambreen A. Merchant Vaishali Patel Field F. Willingham Vanderbilt Eric Howard RN, BSN, Mary K. West Casey Koza Patrick S. Yachimski Grady Memorial Hospital: Emad Qayed Rosemary Nustas Ascension Providence Hospital/Michigan State Ali Zakaria Marc Piper MSc. Saint Louis Taylor Lujain Jaza University Calgary: Nauzer Forbes Millie Chau BSc. Ohio Wexner Medical Luis Lara Georgios I. Papachristou Uchechi Okafor BSc, Conwell Loma Linda Michael Volk Evan Mosier Mohamed Azab Anish Southern California: Liam Hilson Selena Zhou Buxbaum Washington School Medicine: Vladimir Kushnir Alexandria Lenyo Ian P. Sloan Thomas Hollander BSN. South Carolina: Caroline McLeod Spitzer Wakefield Nitchie Ordiah Rockey Wolf Elmunzer Miami Miller Sunil Amin Gabriela N. Kuftinec Deshpande Pittsburgh: Yadav Melissa Saul Melanie Mays Gulsum Anderson Kelley Wood Laura Mathews BS. Colorado: Charlie Fox Kolb Wani Wake Forest Pawa Rishi Boston Andrew Canakis DO, Huang Beaumont Health: Laith H. Jamil Aneese V. Mihajlo Gjeorgjievski, Zaid Imam Fadi Odish Ahmed Edhi Molly Orosey Abhinav Tiwari Soumil Patwardhan MBBS. Hospitals Cleveland Benita Glamour Zachary Smith Amy Hosmer Nancy Furey MBA, Amitabh Chak Northwestern Feinberg Katherine Hanley MMS, PAC, Jordan Rajesh Keswani MS. Ochsner Harsh Janak Shah Columbia Emil Agarunov Nicholas Brown Amrita Sethi Indiana Fogel Gail McNulty Loyola Abdul Haseeb Judy Trieu Icahn Medicine Mount Sinai: Dixon Jeong Yun Yang DiMaio Kettering Cancer Mendelsohn Delia Calo Renaissance Stony Brook Aroniadis LaComb Lilian Cruz Reykhart Virginia School: Scheiman Bryan Sauer Galina Diakova Henry Ford Health System: Duyen T. Dang Cyrus Piraka Dartmouth-Hitchcock VA River Junction: D. Caisse Natalia Zbib John Damianos Heiko Pohl Oklahoma Sciences Tierney Stephanie Mitchell Bronze David Geffen UCLA: Ashwinee Condon Adrienne Lenhart Muthusamy MAS. College Wisconsin: Kulwinder Dua Vikram Kanagala Esteban Johns Hopkins Institutions: Ayesha Kamal Marcia Canto Vikesh Singh McMaster Hamilton Sciences: Maria Ines Pinto-Sanchez MSc (37), Joy Hutchinson RD, Michigan Richard Kwon Sheryl Korsnes Akbar Waljee, Tang Zhang Zhu Manitoba: Harminder Zahra Solati Nick Hajidiacos MD.Tabled 1Subject ID #InstitutionEmail address (of individual entering data)Patient characteristicsAge (years)Sex□Male□Female-Pregnant-Not pregnant-UnknownRace (check apply)□American Indian Alaska Native□Asian□Black African American□Native Hawaiian Pacific Islander□White□UnknownEthnicity□Hispanic Latino□Not Hispanic Latino□UnknownBody index presentation (kg/m2): available?□Yes□Cannot calculate, obesity documented□Cannot calculateBody (kg/m2)Is worker?□Yes□No□UnknownCigarette smoking status□Current smoker□Ex-smoker□Non-smoker□UnknownVaping vaping□Prior vaping□Does vape□UnknownAlcoholism□Yes, current□Prior□No□UnknownCannabis use□Current user□Prior user□No□UnknownIllicit drug user□No□UnknownComorbidities (select apply)□Hypertension□Coronary disease/prior myocardial infarction (MI)□Congestive failure (CHF)□Chronic (COPD)□Asthma□Obstructive apnea (OSA)□Interstitial lung (ILD)/pulmonary fibrosis□Peripheral (PVD)□Prior cerebrovascular (CVA) attack (TIA)□Dementia□Collagen vascular/rheumatologic disease□Chronic liver disease-Alcoholic disease-Nonalcoholic fatty (NAFLD)-Hepatitis C virus-Hepatitis B virus-Other, specify□CirrhosisIf yes, Model End-Stage Liver Disease illness□Diabetes mellitus, uncomplicated□Diabetes mellitus end-organ damage□Moderate kidney (creatinine >3 mg/dL [ESRD], dialysis)□Active/Current malignancy, non-melanoma skin cancerIf specify□Prior malignancy□Human immunodeficiency virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS)□Solid organ transplant recipient□Bone marrow recipient□Irritable bowel syndrome□Chronic diarrhea□Chronic constipation□Celiac disease□Prior biliary disease, cholelithiasis, cholecystitis, choledocholithiasis cholangitis□Prior pancreatitisIf yes:□Acute pancreatitis□Recurrent pancreatitis□Chronic pancreatitis□Unknown□Inflammatory disease□None□Other, fitting into above categoryIf other, specifyRecent (within 6 months) (at admission) immunosuppression chemotherapy□Yes□No□UnknownIf specify(medication, dose, route, duration)Recent enzyme use□Yes□No□UnknownRecent (ARB) use□Yes□No□UnknownCOVID-19 parametersHistory contact positive individual(s)□Yes□No□UnknownHighest level care□Inpatient ward□Intensive unit (ICU)Duration symptoms seeking attention (days)Duration hospitalization (days)If admitted duration stay (days)Required ventilation□Yes□NoRequired extracorporeal membrane oxygenation (ECMO)□Yes□NoRequired vasopressor support□Yes□NoFinal disposition□Recovered (or almost recovered)□Discharged rehab nursing facility□DeceasedCOVID-specific treatments apply)□Remdesivir□Hydroxychloroquine□Chloroquine□Azithromycin□Glucocorticoids□Interferon alpha□Intravenous immunoglobulin (IVIG)□Lopinavir/ritonavir□Oseltamivir□Tocilizumab□Convalescent plasma□None□OtherIf duration)SymptomatologyRespiratory systemic apply)□Fever (subjective objective)□Chills/rigors□Fatigue subjective weakness□Myalgia□Sore throat□Rhinorrhea (runny nose)□Cough□Sneezing□Sputum production□Shortness breath-At rest-On exertion-Not specified□Chest tightness pain□Headache□Confusion altered mental status□Loss smell□Loss taste□None□OtherIf specifyGastrointestinal signs apply)□Anorexia□Nausea□Vomiting□Abdominal pain (including cramps)-Diffuse-Periumbilical-Epigastric-Right upper quadrant (RUQ)-Left (LUQ)-Right lower (RLQ)-Left (LLQ)-Not specified□Diarrhea-Maximum number movements 24 hour period□Not documented□Bloody diarrhea-Maximum documented□Hematemesis□Melena□Hematochezia (inc. bright red per rectum)□Dysphagia□Odynophagia□Constipation□Hiccups□Jaundice□None□OtherIf specifyTiming gastrointestinal (if any) respiratory/systemic any)□GI symptom(s) preceded symptoms□GI followed came concurrently manifestation□Can't tell reviewDuration present short portion (<25% duration) entire illness□GI (25-75% entire/almost illness□Can't reviewDid remain resolution symptoms?□Yes□No□UnknownIf how long (days)Prominence prominent related COVID-19□GI equally more COVID-19□Can't reviewWere (gastrointestinal hepatic) addressed Assessment/Plan section progress notes 3 days hospitalization?□Yes, symptoms□Yes, LFT abnormalities□Yes, both□NoDid hepatology service consult hospitalization, notes?□Yes, pancreaticobiliary)□Yes, hepatology/liver□Yes, both□NoWere stool FOBT (fecal occult test) hospitalization?□Yes□NoGastrointestinal diagnoses established shortly before, during, illness apply)□Esophagitis/esophageal ulcers□Gastritis□Peptic ulcer (stomach duodenum)□New enteritis□New colitis□Biliary cholangitis□Hepatitis□Pancreatitis□None□OtherIf specifyWas COVID-specific prescribed manifestations?□Yes□No□UnknownImaging endoscopyWas abdominal computed tomography (CT) abnormal illness?□Yes□No□UnknownIf list impression concerning CT reportWas magnetic resonance imaging (MRI) MRI ultrasound (US) US endoscopy illness? apply)□Yes (EGD)□Yes colonoscopy flexible sigmoidoscopy□Yes enteroscopy (balloon push)□Yes capsule endoscopy□Yes ERCP□Yes endoscopic (EUS)□No□UnknownIf performed, many sessions undergo? (EGD+colonoscopy EUS+ERCP same session)If require BEFORE procedure? nasal cannula□Yes high-flow oxygen□Yes non-invasive pressure ventilation□Yes ventilation, proned□Yes (ECMO)□No□UnknownIf what kind anesthesia receive DURING apply)□Conscious sedation□Deep sedation/monitored (MAC)□General endotracheal anesthesia□No sedation□UnknownIf experience adverse cardiopulmonary event procedures? Mild moderate compromise□Yes Severe Congestive failure/cardiomyopathy□Yes Myocardial infarction□No□UnknownEndoscopic (please report(s))Histologic pathology report(s))Laboratory hepatologic considerationsPrior COVID-19, ideally healthy:White cells (WBC)HemoglobinPlateletsAspartate (AST)Alanine (ALT)Alkaline (ALK-phos)Total bilirubinInternational normalized (INR)AlbuminFactor V levelLipaseCreatinineAt admission:White (ALK-phos)Gamma-Glutamyl Transferase (highest) U/LTotal bilirubinDirect levelLipase-What normalAmylase-What normalCreatinineHighest illness:WBC (highest lowest)Hemoglobin (lowest)Platelets (lowest)AST (highest)ALT (highest)ALK-phos (highest)Gamma-Glutamyl Bilirubin (highest)Direct (highest)INR (highest)Albumin (lowest)Factor 5 (lowest)Lipase (highest)-What normalAmylase normalCreatinine (highest)Absolute lymphocyte (lowest)C-Reactive Protein (CRP) (highest)Procalcitonin (highest)Troponin (highest)Ferritin ng/mL ug/LInterleukin-6 pg/mLDuration highest AST ALT bilirubin day (days)Abnormal LFTs were□Still close max discharge/death□Improved resolved discharge/death□Resolved discharge/death□Not applicableWere suspected due reaction (based progress/consult notes)?□Yes□No□Unclear recordsIf medication(s) suspected(medication, duration)If believed recordsAnti-HAV IgM□Positive□Negative□Not checkedAnti-HCV□Positive□Negative□Not checkedHCV RNA□Positive-Level (in IU/L)□Negative□Not checkedHBsAg□Positive□Negative□Not checkedAnti-HBc□Positive□Negative□Not checkedAnti-HBc checkedAnti-HBs□Positive□Negative□Not checkedEpstein-Barr Virus antibody IgM (Anti-EBV IgM)□Positive□Negative□Not checkedCytomegalovirus (Anti-CMV checkedAnti-nuclear (ANA)□Positive-Level (titer)□Negative□Not checkedAnti-smooth muscle (ASMA)□Positive□Negative□Not checkedAnti-mitochondrial (AMA)□Positive□Negative□Not checkedDid develop decompensated hepatic encephalopathy□Yes ascites□Yes variceal hemorrhage□Yes hepatorenal syndrome□NoWas biopsy hospitalization?□Yes□NoIf histologic report(s)).