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

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 the course COVID-19.^{1 , 2} This observation is biologically plausible, as gastric acid is a well-established line of defense against microbial pathogens, including SARS-CoV-1.³ In addition, PPI use may worsen outcomes in patients with COVID-19 through alterations of the gut microbiome and intestinal immune apparatus.⁴ Conversely, recent data suggest that histamine 2 receptor antagonists (H2RAs), which are less potent than PPIs in terms of acid suppression, may be beneficial in SARS-CoV-2^{5 , 6} through direct antiviral effects.⁷

Considering that acid suppressive medications are among the most commonly consumed drugs in the United States, an understanding of the impact of these agents on COVID-19 outcomes is of significant importance. In particular, data informing the public on whether there is an evidence-based rationale to modify the use of these chronic medications during the pandemic are necessary. We studied whether preadmission exposure to PPIs or H2RAs was associated with worse outcomes among patients hospitalized with COVID-19.

Methods

This was a secondary analysis of a retrospective cohort study aiming to better characterize digestive manifestations in patients hospitalized with COVID-19 across 36 medical centers in North America.⁸ The first 50 to 100 consecutive patients with a confirmed diagnosis of COVID-19 at each participating institution were included. Clinical data from the time of symptom onset until discharge, death, or the end of the study period were manually abstracted from electronic health records by study personnel under the oversight of a primary clinician-investigator. Conventional regression and propensity score matched analyses were performed to evaluate the association between preadmission acid suppressive medication exposure and mechanical ventilation or death. Sensitivity analyses were conducted to evaluate the validity of excluding patients with unknown PPI/H2RA status and of imputing missing data. More comprehensive methods are provided in the Supplementary Material.

Results

Between April 15 and June 5, 2020, data were collected from 1992 subjects. There were 146 patients excluded from the primary analysis because PPI or H2RA use within 1 month of admission was unknown. Characteristics of the final study cohort (1846 patients with COVID-19) are shown in the Supplementary Table 1. A total of 417 patients (22.6%) had recent PPI use, 167 (9.1%) had recent H2RA use, and 29 (1.6%) had both. The baseline variables included in the final regression models are listed in Supplementary Table 2.

After adjusting for measured baseline confounders, PPI use was not independently associated with the need for mechanical ventilation in the primary regression analysis (odds ratio [OR] 1.02; 95% confidence interval [CI] 0.73–1.43; P = .89) (Figure 1 ). In contrast, H2RA use was associated with 1.55 times the odds of requiring mechanical ventilation relative to patients not exposed to H2RA (OR 1.55; 95% CI 1.11–2.19; P = .01) (Figure 1). Propensity score matched analysis confirmed the lack of association between PPI use and mechanical ventilation and demonstrated a significant increase in the likelihood of mechanical ventilation among patients exposed to H2RA (risk difference 9.72%; 95% CI 1.26%–18.2%; P = .02). In sensitivity analyses, removal of patients with at least 1 missing covariate value (480 observations) or inclusion of patients with unknown PPI/H2RA use (139 additional observations) did not change the findings.

Figure 1.

ORs (95% CIs) for mechanical ventilation (blue) or death (red) based on final regression models.

PPI use was not independently associated with increased death (OR 0.87; 95% CI 0.66–1.14; P = .31) (Figure 1). Similarly, H2RA exposure was not associated with increased death (OR 1.37; 95% CI 0.96–1.95; P = .08) (Figure 1). Propensity score matched analysis showed similar findings. In the sensitivity analyses, removal of patients with at least 1 missing covariate value (375 observations) did not change the findings pertaining to PPI use. However, this analysis did demonstrate a statistically significant association between H2RA exposure and in-hospital mortality (OR 1.48; 95% CI 1.04–2.12; P = .03). The sensitivity analysis that included patients with unknown PPI/H2RA status (139 additional observations) did not change the results.

Discussion

In this large-scale study of patients hospitalized with COVID-19 across 36 medical centers in North America, preadmission exposure to PPI and/or H2RA did not appear to strongly affect the likelihood of mechanical ventilation or death. Our findings do not support the putative deleterious effects of PPIs and in fact contradict the hypothesized benefits of H2RAs in SARS-CoV-2 infection. These observations suggest that modified use of these medications for the purpose of improving COVID-19 outcomes is not justified. Instead, the results reinforce the preexisting guidance of taking acid suppressive medications only when indicated and at the lowest dose that achieves the clinical objective for which they were recommended.

The observation that preadmission H2RA use increased the risk of mechanical ventilation in this cohort is noteworthy, as it opposes growing evidence of the beneficial effect of famotidine. The reasons for this finding are unclear and may not apply to famotidine specifically, as the exact H2RA consumed by patients in the cohort was not determined. However, since the estimated effect size was relatively small, there was no association between H2RA use and death, and residual confounding is always a risk in observational studies of this nature, the finding largely serves to caution against overuse of this medication and highlights the importance of additional research prior to clinical care or policy changes. It is also important to emphasize that recent studies showing the favorable effect of famotidine have evaluated active treatment rather than preadmission exposure, as we assessed in this study.

This study has several important limitations. First, PPI and H2RA exposure was not verified against pharmacy records and their consistent use could not be confirmed. However, these medications are commonly acquired over the counter, limiting the ability of prescription claims to confirm use. Furthermore, medication use in this study was collected manually by comprehensive review of electronic health records by clinicians or study coordinators under the oversight of a clinician-investigator, with likely increased accuracy compared with administrative data. Second, as noted previously, we did not specifically query the use of famotidine relative to the other H2RAs, and thus a beneficial effect of this medication may have been diluted by other drugs in this class. Third, we did not collect data on in-hospital acid suppressive medication administration, which may have been associated with preadmission exposure and could have confounded the analysis. Last, observations from this cohort reflect the earliest phase of the pandemic and may not apply to the current time.

In conclusion, we did not observe a strong deleterious effect of preadmission PPI use or a beneficial effect of preadmission H2RA use among patients hospitalized with COVID-19. These findings caution against the modified use of these medications to improve COVID-19–related outcomes.

Supplementary Material

Methods

This was a secondary analysis of a large-scale retrospective cohort study aiming to better understand COVID-19 and the digestive system. The study was conducted through an alliance of 36 medical centers in the United States and Canada. Institutional review board approval was obtained at each site before patient identification and data collection.

Adult patients who were hospitalized with a confirmed diagnosis of COVID-19 were considered eligible. To limit sampling bias, we aimed to include the first 50 to 100 consecutive patients meeting eligibility criteria at each participating institution. Potentially eligible patients were identified by site investigators using multiple methods, including data warehouse queries, electronic research subject identification tools, and COVID-19 patient lists provided by relevant hospital entities.

Clinical data from the time of symptom onset until discharge, death, or the end of the study period, including the use of PPI or H2RA within 1 month of admission, were manually abstracted through review of electronic health records. Data abstraction was performed by clinical research coordinators, medical students, internal medicine and gastroenterology trainees, as well as faculty gastroenterologists, depending on site. Every site had a designated clinician investigator who oversaw and vouched for the integrity of data collection. Data quality was ensured to the greatest extent possible using a multifaceted strategy that has been described previously and included manual review of all incoming data by a dedicated data management specialist.¹ The data collection form is provided later in this Supplementary Material.

The association between acid suppressive medication use and mechanical ventilation or death was evaluated using 2 separate multivariable generalized linear regression models. PPI and H2RA use, the independent variables of interest, as well as age, race, and sex were included in both models. Lasso regression, an agnostic, data-driven approach to variable selection, was used to select the other covariates. Only laboratory values at admission were included as covariates in the models because in-hospital laboratory values (highest/lowest) could have occurred after mechanical ventilation (a primary outcome) and could have been confounded by in-hospital treatments. To account for clustering by center, generalized estimating equation models with a random center effect were used.

To assess the validity of findings from the primary regression analysis, we performed a propensity score matched analysis of the association between PPI or H2RA use with mechanical ventilation or death. Propensity scores were estimated for PPI or H2RA use based on the predicted probability of exposure, estimated from generalized linear mixed models with either PPI/H2RA use as the outcome and all other patient factors (excluding mechanical ventilation and death) as predictors. A random center effect was used in this model as well. Four-to-one control-to-treatment caliper matching with caliper = 0.2 was applied to the propensity scores to obtain matched patients by H2RA or PPI use.

Missing data were assumed to be missing at random and were imputed before model development. In the primary analysis, we excluded patients whose PPI and/or H2RA use within 1 month of admission was unknown. Sensitivity analyses were subsequently conducted to evaluate the validity of excluding patients with unknown PPI/H2RA status and of imputation.

Supplementary Table 1.

Patient Characteristics

Patient Characteristic	Overall (N = 1846)
Demographics
Age, y, mean (SD)	59.9 (16.4)
Sex, male, n (%)	1044 (56.6)
Race, n (%)
White	680 (36.8)
Black	774 (41.9)
Other/Unknown	392 (21.2)
Body mass index, mean (SD)	31.5 (8.14)
PPI use, Yes, n (%)	417 (22.6)
H2 blocker use, Yes, n (%)	167 (9.1)
Patient health characteristics
Comorbidities, Yes, n (%)
Hypertension	1146 (62.1)
Coronary artery disease/myocardial infarction	284 (15.4)
Congestive heart failure	194 (10.5)
COPD	171 (9.26)
Asthma	240 (13.0)
Obstructive sleep apnea	197 (10.7)
Peripheral vascular disease	91 (4.93)
Cerebrovascular accident or TIA	170 (9.21)
Dementia	118 (6.39)
Diabetes Mellitus	658 (35.6)
ESRD	175 (9.48)
Current malignancy	117 (6.34)
Prior malignancy	171 (9.26)
Digestive disease	183 (9.91)
Other comorbidities	829 (44.9)
No comorbidities	203 (11.0)
No. Comorbidities, median (min-max; IQR)	2 (0-10; 3)
Chemotherapy or Immunosuppression, n (%)
Yes	219 (11.9)
No	1621 (87.8)
Unknown	6 (0.33)
Current or recent ACE or ARB use, Yes, n (%)	556 (30.1)
Current or recent NSAID use, n (%)
Yes	506 (27.4)
No	1100 (59.6)
Unknown	240 (13.0)
Current or recent antibiotic use, n (%)
Yes	560 (30.3)
No	1251 (67.8)
Unknown	35 (1.90)
Admission clinical lab measures
White blood cell count, mean (SD)	7.18 (4.00)
Hemoglobin, mean (SD)	12.9 (2.20)
Platelets. mean (SD)	207.5 (90.3)
Aspartate, mean (SD)	50.7 (54.1)
Alanine aminotransferase, mean (SD)	37.5 (34.5)
Alkaline phosphate, mean (SD)	82.3 (48.8)
Bilirubin, mean (SD)	0.64 (0.63)
Albumin, mean (SD)	3.63 (0.52)
Creatinine, mean (SD)	1.65 (2.76)
Outcomes
Mechanical ventilation required, Yes, n (%)	584 (31.6)
ICU admission, Yes, n (%)	795 (43.1)
In-hospital death, Yes, n (%)	327 (17.7)
HLOS, days, median (min-max, IQR)	8 (0.4-113; 13)

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; HLOS, hospital length of stay; ICU, intensive care unit; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory drug; TIA, transient ischemic attack.

Supplementary Table 2.

Variables Included in the Final Regression Models for Mechanical Ventilation or Death

Mechanical ventilation	Death
H2RA use	H2RA use
PPI use	PPI use
Age	Age
Body mass index
Sex	Sex
Race	Race
Dementia	Dementia
	Congestive heart failure
Number of comorbidities	Number of comorbidities
White blood cell count at admission	White blood cell count at admission
Platelets at admission	Platelets at admission
Aspartate aminotransferase at admission	Aspartate aminotransferase at admission
Alkaline phosphatase at admission
Albumin at admission	Albumin at admission
Creatinine at admission
Antibiotics before admission

DMC19 Registry Instructions 4_17_20

• 1)
  Please complete the below data collection form (DCF) in REDCap at the time of discharge or death. Data will appear in the DMC19 database once entry and verification are complete.
• 2)
  We aim to capture inpatients with a confirmed COVID-19 diagnosis, regardless of whether they have digestive manifestations. After prevalence is defined in hospitalized patients, and as the numbers grow, we may focus on patients who are known to have GI manifestations and/or include outpatients.
• 3)
  Please make all efforts to collect data on the first 50 to 100 consecutive patients at your hospital or health system.
• 4)
  Eligible patients can and should be identified by any means necessary, which may include, but is not limited to, institutional laboratory records, data warehouse queries, electronic health record research subject identification tools/dashboards, and discussions with the infectious disease or critical care services, etc. You may elect to use the emergency ICD-10 code of U07.1 – 2019-nCov acute respiratory disease – to help identify eligible patients.
• 5)
  Please triple-check data for accuracy before submission. Although we are performing central data monitoring, we cannot verify incoming data against source documents, nor are we performing on-site monitoring visits. Therefore, the overall quality of the data is assured primarily at the site level.
• 6)
  Along the lines of #5, coordinators should confer with a clinician during data collection to ensure that clinical context is accounted for as much as possible in the interpretation of questions that involve an element of subjectivity.
• 7)
  All data fields should have affirmative, negative, and unknown options. Therefore, missing data will be assumed to be inadvertent and this will generate a query.
• 8)
  Please maintain a secure key at your site that allows patient identification on the basis of subject ID#. This may be used in the future for to collect data pertaining to long-term outcomes.

Authors for this North American Alliance for the Study of Digestive Manifestations of COVID-19 study

Primary authors: B. Joseph Elmunzer, MD, and Bethany J. Wolf, PhD.

Writing committee: B. Joseph Elmunzer, MD, Bethany J. Wolf, PhD, Jason R. Taylor, MD, William Tierney, MD, James Scheiman, MD.

Steering Committee: B. Joseph Elmunzer, MD (Chair), Rebecca L. Spitzer, MPH, Rebekah E. Dixon, BS, Collins O. Ordiah, MBBS, Jennifer M. Kolb, MD, MS, Sachin Wani, MD, Olga C. Aroniadis, MD, Robin B. Mendelsohn, MD, Christopher J. DiMaio, MD, Don C. Rockey, MD, Amit G. Singal, MD, MS, Amar R. Deshpande, MD, Swati Pawa, MD, Darwin L. Conwell, MD, MSc, Raman Muthusamy, MD, MAS, William M. Tierney, MD, Dhiraj Yadav, MD, MPH.

Statisticians: Bethany J. Wolf, PhD, Weijing Tang, MA, Yueyang Zhang, BS, Ji Zhu, PhD.

Data Coordinating Center: Teldon B. Alford, BA, Lauren Wakefield, MHA, Haley Nitchie, MHA, Collins O. Ordiah, MBBS, Rebecca L. Spitzer, MPH.

Clinical sites in order of number of patients contributed

Emory University: Ambreen A. Merchant MBBS, Vaishali A. Patel MD, Field F. Willingham MD, MPH.

Vanderbilt University: Eric F. Howard RN, BSN, Mary K. West RN, BSN, Casey L Koza BS, Patrick S. Yachimski MD.

Grady Memorial Hospital: Emad Qayed MD, MPH, Rosemary Nustas MD.

Ascension Providence Hospital/Michigan State University: Ali Zakaria MD, Marc S. Piper MD, MSc.

Saint Louis University: Jason R. Taylor MD, Lujain Jaza MD.

University of Calgary: Nauzer Forbes MD, MSc, Millie Chau BSc.

The Ohio State University Wexner Medical Center: Luis F. Lara MD, Georgios I. Papachristou MD, PhD, Uchechi Okafor BSc, Darwin L. Conwell MD, MSc.

Loma Linda University: Michael L. Volk MD, MSc, Evan Mosier MD, Mohamed Azab MD, Anish Patel MD.

University of Southern California: Liam G. Hilson MD, Selena Zhou MD, James Buxbaum MD.

Washington University School of Medicine: Vladimir M. Kushnir MD, Alexandria M. Lenyo BS, Ian P. Sloan BS, Thomas Hollander RN, BSN.

Medical University of South Carolina: Caroline G. McLeod BS, Rebecca L. Spitzer MPH, Lauren Wakefield MHA, Haley Nitchie MHA, Collins O. Ordiah MBBS, MPH, Don C. Rockey MD, Bethany J. Wolf PhD, B. Joseph Elmunzer MD.

University of Miami Miller School of Medicine: Sunil Amin MD, MPH, Gabriela N. Kuftinec MD, MPH, Amar R. Deshpande MD.

University of Pittsburgh: Dhiraj Yadav MD, MPH, Melissa Saul MS, Melanie Mays BS, Gulsum Anderson PhD, Kelley Wood BS, Laura Mathews BS.

University of Colorado: Charlie Fox MD, Jennifer M. Kolb MD, MS, Sachin Wani MD.

Wake Forest University School of Medicine: Swati Pawa MD, Rishi Pawa MD.

Boston University: Andrew Canakis DO, Christopher Huang MD.

Beaumont Health: Laith H. Jamil MD, Andrew M. Aneese MD, V. Mihajlo Gjeorgjievski, MD, Zaid Imam MD, Fadi Odish MD, Ahmed I. Edhi MD, Molly Orosey DO, Abhinav Tiwari MD, Soumil Patwardhan MBBS.

University Hospitals of Cleveland Medical Center: Benita K. Glamour BA, Zachary L Smith DO, Amy E. Hosmer MD, Nancy Furey RN, BSN, MBA, Amitabh Chak MD.

Northwestern University: Feinberg School of Medicine: Katherine A. Hanley MMS, PAC, Jordan Wood BS, Rajesh N. Keswani MD, MS.

Ochsner Health: Harsh K. Patel MBBS, Janak N. Shah MD.

Columbia University Medical Center: Emil Agarunov BS, Nicholas G. Brown MD, Anish A. Patel MD, Amrita Sethi MD.

Indiana University School of Medicine: Evan L. Fogel MD, MSc, Gail McNulty RN, BSN.

Loyola University Medical Center: Abdul Haseeb MD, Judy A. Trieu MD.

Icahn School of Medicine at Mount Sinai: Rebekah E. Dixon BS, Jeong Yun Yang MD, Christopher J. DiMaio MD.

Memorial Sloan Kettering Cancer Center: Robin B. Mendelsohn MD, Delia Calo MD.

Renaissance School of Medicine at Stony Brook University: Olga C. Aroniadis MD, MSc, Joseph F. LaComb BS, Lilian Cruz BS, Olga Reykhart BS.

University of Virginia Medical School: James M. Scheiman MD, Bryan G. Sauer MD, Galina Diakova MS.

Henry Ford Health System: Duyen T. Dang MD, Cyrus R. Piraka MD.

Dartmouth-Hitchcock Health and VA White River Junction: Eric D. Shah MD, MBA, Molly Caisse BS, Natalia H. Zbib MD, John A. Damianos MD, Heiko Pohl MD.

University of Oklahoma Health Sciences Center: William M. Tierney MD, Stephanie Mitchell RN, Michael S. Bronze MD.

David Geffen School of Medicine at UCLA: Ashwinee Condon MD, Adrienne Lenhart MD, Raman Muthusamy MD, MAS.

Medical College of Wisconsin: Kulwinder S. Dua MD, Vikram S. Kanagala MD, James Esteban MD.

Johns Hopkins Medical Institutions: Ayesha Kamal MD, Marcia I. Canto MD, Vikesh K. Singh MD, MS.

McMaster University Hamilton Health Sciences: Maria Ines Pinto-Sanchez MD, MSc (37), Joy M. Hutchinson RD, MSc.

Michigan Medicine: Richard S. Kwon MD, Sheryl J. Korsnes MA, Akbar K. Waljee, MD, MS, Weijing Tang MA, Yueyang Zhang BS, Ji Zhu PhD.

University of Manitoba: Harminder Singh MD, MPH, Zahra Solati MSc, Nick Hajidiacos MD.

Subject ID #
Institution
Email address (of individual entering data)

Patient characteristics
Age (years)
Sex	□Male □ Female - Pregnant - Not pregnant - Unknown
Race (check all that apply)	□American Indian or Alaska Native □Asian □Black or African American □Native Hawaiian or other Pacific Islander □White □Unknown
Ethnicity	□Hispanic or Latino □Not Hispanic or Latino □Unknown
Body mass index at presentation (kg/m2): available?	□Yes □Cannot calculate, but obesity documented □Cannot calculate
Body mass index at presentation (kg/m2)
Is the patient a health care worker?	□Yes □No □Unknown
Cigarette smoking status	□Current smoker □Ex-smoker □Non-smoker □Unknown
Vaping status	□Current vaping □Prior vaping □Does not vape □Unknown
Alcoholism	□Yes, current □Prior □No □Unknown
Cannabis use	□Current user □Prior user □No □Unknown
Illicit drug use	□Current user □Prior user □No □Unknown
Comorbidities (select all that apply)	□Hypertension □Coronary artery disease/prior or current myocardial infarction (MI) □Congestive heart failure (CHF) □Chronic pulmonary obstructive disease (COPD) □Asthma □Obstructive sleep apnea (OSA) □Interstitial lung disease (ILD)/pulmonary fibrosis □Peripheral vascular disease (PVD) □Prior or current cerebrovascular accident (CVA) or transient ischemic attack (TIA) □Dementia □Collagen vascular/rheumatologic disease □ Chronic liver disease - Alcoholic liver disease - Nonalcoholic fatty liver disease (NAFLD) - Hepatitis C virus - Hepatitis B virus - Other, specify □ Cirrhosis If yes, Model for End-Stage Liver Disease score before COVID-19 illness □Diabetes mellitus, uncomplicated □Diabetes mellitus with end-organ damage □Moderate to severe kidney disease (creatinine >3 mg/dL prior to admission, end-stage renal disease [ESRD], dialysis) □ Active/Current malignancy, excluding non-melanoma skin cancer If yes, specify □Prior malignancy □Human immunodeficiency virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) □Solid organ transplant recipient □Bone marrow transplant recipient □Irritable bowel syndrome □Chronic diarrhea □Chronic constipation □Celiac disease □Prior biliary disease, including cholelithiasis, cholecystitis, choledocholithiasis or cholangitis □ Prior pancreatitis If yes: □Acute pancreatitis □Recurrent acute pancreatitis □Chronic pancreatitis □Unknown □Inflammatory bowel disease □None □Other, not fitting into an above category
If other, specify
Recent (within 6 months) or current (at admission) immunosuppression or chemotherapy	□Yes □No □Unknown
If yes, specify	(medication, dose, route, duration)
Recent (within 1 month of admission) or current (at admission) angiotensin-converting enzyme inhibitor use	□Yes □No □Unknown
Recent (within 1 month of admission) or current (at admission) angiotensin receptor blocker (ARB) use	□Yes □No □Unknown
Recent (within 1 month of admission) or current (at admission) nonsteroidal anti-inflammatory drug use	□Yes □No □Unknown
Recent (within 1 month of admission) or current (at admission) antibiotic use	□Yes □No □Unknown
Recent (within 1 month of admission) or current (at admission) PPI use	□Yes □No □Unknown
Recent (within 1 month of admission) or current (at admission) H2 blocker use	□Yes □No □Unknown

COVID-19 parameters
History of known contact with COVID-19 positive individual(s)	□Yes □No □Unknown
Highest level of care	□Inpatient ward □Intensive care unit (ICU)
Duration of symptoms prior to first seeking medical attention (days)
Duration of symptoms prior to hospitalization (days)
Duration of hospitalization (days)
If admitted to ICU, duration of ICU stay (days)
Required mechanical ventilation	□Yes □No
Required extracorporeal membrane oxygenation (ECMO)	□Yes □No
Required vasopressor support	□Yes □No
Final discharge disposition	□Recovered (or almost recovered) □Discharged to rehab or nursing facility □Deceased
COVID-specific treatments (select all that apply)	□Remdesivir □Hydroxychloroquine □Chloroquine □Azithromycin □Glucocorticoids □Interferon alpha □Intravenous immunoglobulin (IVIG) □Lopinavir/ritonavir □Oseltamivir □Tocilizumab □Convalescent plasma □None □Other
If other, specify	(medication, dose, route, duration)

Symptomatology
Respiratory or systemic symptoms (select all that apply)	□Fever (subjective or objective) □Chills/rigors □Fatigue or subjective weakness □Myalgia □Sore throat □Rhinorrhea (runny nose) □Cough □Sneezing □Sputum production □ Shortness of breath - At rest - On exertion - Not specified □Chest tightness or pain □Headache □Confusion or altered mental status □Loss of smell □Loss of taste □None □Other
If other, specify
Gastrointestinal symptoms or signs (select all that apply)	□Anorexia □Nausea □Vomiting □ Abdominal pain (including cramps) - Diffuse - Periumbilical - Epigastric - Right upper quadrant (RUQ) - Left upper quadrant (LUQ) - Right lower quadrant (RLQ) - Left lower quadrant (LLQ) - Not specified □ Diarrhea - Maximum number of bowel movements in a 24 hour period □Not documented □ Bloody diarrhea - Maximum number of bowel movements in a 24 hour period □Not documented □Hematemesis □Melena □Hematochezia (inc. bright red blood per rectum) □Dysphagia □Odynophagia □Constipation □Hiccups □Jaundice □None □Other
If other, specify
Timing of gastrointestinal symptoms (if any) relative to respiratory/systemic symptoms (if any)	□GI symptom(s) preceded other symptoms □GI symptom(s) followed other symptoms □GI symptom(s) came on concurrently with other symptoms □GI symptoms were the only manifestation □Can’t tell from medical records review
Duration of gastrointestinal symptoms	□GI symptom(s) were present for a short portion (<25% of the duration) of the entire COVID-19 illness □GI symptom(s) were present for significant portion (25-75% of the duration) of the entire COVID-19 illness □GI symptom(s) were present for the entire/almost entire COVID-19 illness □Can’t tell from medical records review
Did gastrointestinal symptoms remain after resolution of other COVID-19 symptoms?	□Yes □No □Unknown
If yes, how long (days)
Prominence of gastrointestinal symptoms	□GI symptoms were less prominent than other symptoms related to COVID-19 □GI symptoms were equally prominent to other symptoms related to COVID-19 □GI symptoms were more prominent than other symptoms related to COVID-19 □Can’t tell from medical records review
Were digestive manifestations (gastrointestinal or hepatic) specifically addressed in the Assessment/Plan section of any progress notes for 3 or more days during the hospitalization?	□Yes, GI symptoms □Yes, LFT abnormalities □Yes, both □No
Did the gastroenterology or hepatology service consult on the patient during the hospitalization, as evidence by consult notes?	□Yes, GI (including pancreaticobiliary) □Yes, hepatology/liver □Yes, both □No
Were stool studies other than FOBT (fecal occult blood test) obtained during the hospitalization?	□Yes □No
Gastrointestinal diagnoses established shortly before, during, or shortly after COVID-19 illness (select all that apply)	□Esophagitis/esophageal ulcers □Gastritis □Peptic ulcer disease (stomach or duodenum) □New enteritis □New colitis □Biliary disease, including cholelithiasis, cholecystitis, choledocholithiasis or cholangitis □Hepatitis □Pancreatitis □None □Other
If other, specify
Was COVID-specific treatment prescribed specifically for digestive manifestations?	□Yes □No □Unknown

Imaging and endoscopy
Was abdominal computed tomography (CT) performed and abnormal shortly before, during, or shortly after COVID-19 illness?	□Yes □No □Unknown
If yes, list abnormal findings in the impression section of the most concerning CT report
Was abdominal magnetic resonance imaging (MRI) performed and abnormal shortly before, during, or shortly after COVID-19 illness?	□Yes □No □Unknown
If yes, list abnormal findings in the impression section of the most concerning MRI report
Was abdominal ultrasound (US) performed and abnormal shortly before, during, or shortly after COVID-19 illness?	□Yes □No □Unknown
If yes, list abnormal findings in the impression section of the most concerning US report
Was endoscopy performed during COVID-19 illness? (select all that apply)	□Yes – upper endoscopy (EGD) □Yes – colonoscopy or flexible sigmoidoscopy □Yes – enteroscopy (balloon or push) □Yes – capsule endoscopy □Yes – ERCP □Yes – endoscopic ultrasound (EUS) □No □Unknown
If performed, how many total endoscopic sessions did the patient undergo? (EGD+colonoscopy or EUS+ERCP at the same time is considered 1 session)
If performed, did the patient require respiratory support BEFORE their first procedure? (select all the apply)	□Yes – nasal cannula □Yes – high-flow oxygen □Yes – non-invasive positive pressure ventilation □Yes – mechanical ventilation □Yes – mechanical ventilation, proned □Yes – extracorporeal membrane oxygenation (ECMO) □No □Unknown
If performed, what kind of anesthesia did the patient receive DURING their first procedure? (select all that apply)	□Conscious sedation □Deep sedation/monitored anesthesia care (MAC) □General endotracheal anesthesia □No sedation □Unknown
If performed, did the patient experience an adverse cardiopulmonary event related to any of the endoscopic procedures? (select all that apply)	□Yes – Mild to moderate respiratory compromise □Yes – Severe respiratory compromise □Yes – Congestive heart failure/cardiomyopathy □Yes – Myocardial infarction □No □Unknown
Endoscopic findings (please list abnormal findings in impression section of endoscopy report(s))
Histologic findings (please list abnormal findings in impression section of pathology report(s))

Laboratory data and other hepatologic considerations
Prior to COVID-19, ideally when patient was healthy: White blood cells (WBC) Hemoglobin Platelets Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Alkaline phosphatase (ALK-phos) Total bilirubin International normalized ratio (INR) Albumin Factor V level Lipase Creatinine
At time of hospital admission: White blood cells (WBC) Hemoglobin Platelets Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Alkaline phosphatase (ALK-phos) Gamma-Glutamyl Transferase (highest) U/L Total bilirubin Direct bilirubin International normalized ratio (INR) Albumin Factor V level Lipase -What is the upper limit of normal Amylase -What is the upper limit of normal Creatinine
Highest or lowest level during illness: WBC (highest and lowest) Hemoglobin (lowest) Platelets (lowest) AST (highest) ALT (highest) ALK-phos (highest) Gamma-Glutamyl Transferase (highest) U/L Total Bilirubin (highest) Direct Bilirubin (highest) INR (highest) Albumin (lowest) Factor 5 (lowest) Lipase (highest) -What is the upper limit of normal Amylase (highest) -What is the upper limit of normal Creatinine (highest) Absolute lymphocyte count (lowest) C-Reactive Protein (CRP) (highest) Procalcitonin (highest) Troponin (highest) Ferritin (highest) ng/mL or ug/L Interleukin-6 (highest) pg/mL
Duration between first onset of symptoms and highest AST (days)
Duration between first onset of symptoms and highest ALT (days)
Duration between first onset of symptoms and highest total bilirubin (days)
Duration between first hospital day and highest AST (days)
Duration between first hospital day and highest ALT (days)
Duration between first hospital day and highest total bilirubin (days)
Abnormal LFTs were	□Still close to max at discharge/death □Improved but not resolved at discharge/death □Resolved or close to resolved at discharge/death □Not applicable
Were the increased LFTs suspected to be due to a drug reaction (based on review of progress/consult notes)?	□Yes □No □Unclear based on records
If yes, which medication(s) were suspected	(medication, dose, route, duration)
If yes, was this a COVID-specific treatment that was believed to increase LFTs (based on review of progress/consult notes)?	□Yes □No □Unclear based on records
Anti-HAV IgM	□Positive □Negative □Not checked
Anti-HCV	□Positive □Negative □Not checked
HCV RNA	□ Positive - Level (in IU/L) □Negative □Not checked
HBsAg	□Positive □Negative □Not checked
Anti-HBc	□Positive □Negative □Not checked
Anti-HBc IgM	□Positive □Negative □Not checked
Anti-HBs	□Positive □Negative □Not checked
Epstein-Barr Virus antibody IgM (Anti-EBV IgM)	□Positive □Negative □Not checked
Cytomegalovirus antibody IgM (Anti-CMV IgM)	□Positive □Negative □Not checked
Anti-nuclear antibody (ANA)	□ Positive - Level (titer) □Negative □Not checked
Anti-smooth muscle antibody (ASMA)	□Positive □Negative □Not checked
Anti-mitochondrial antibody (AMA)	□Positive □Negative □Not checked
Did the patient develop evidence of decompensated liver disease during or shortly after COVID-19 illness? (select all that apply)	□Yes – hepatic encephalopathy □Yes – ascites □Yes – variceal hemorrhage □Yes – hepatorenal syndrome □No
Was a liver biopsy performed during the COVID-19 hospitalization?	□Yes □No
If yes, histologic findings (please list abnormal findings in impression section of pathology report(s)).