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Factors Associated With Poor Outcomes Among Patients With SARS-CoV-2 Coronavirus Infection and Gastrointestinal Symptoms

Open AccessPublished:August 26, 2022DOI:https://doi.org/10.1016/j.gastha.2022.08.004

      Background and Aims

      Gastrointestinal (GI) symptoms are present in 20% of patients with SARS-CoV-2 coronavirus infection (COVID-19). We studied the association of GI symptoms (in patients with COVID-19) with adverse outcomes and factors associated with poor outcomes in these patients.

      Methods

      The study cohort included 100,902 patients from the Cerner Real-World Data COVID-19 Database of hospital encounters and emergency department visits with COVID-19 infection from December 1, 2019, to November 30, 2020. Multivariate analysis was used to study the effect of GI symptoms on adverse outcomes and the factors associated with mortality, acute respiratory distress syndrome (ARDS), sepsis, and ventilator requirement or oxygen dependence in patients with COVID-19 and GI symptoms.

      Results

      Patients with COVID-19 and GI symptoms were significantly more likely to have ARDS (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.11, 1.29), sepsis (OR 1.19, 95% CI 1.14, 1.24), acute kidney injury (OR 1.30, 95% CI 1.24, 1.36), venous thromboembolism (OR 1.36, 95% CI 1.22, 1.52), or GI bleed (OR 1.62, 95% CI 1.47, 1.79) and less likely to experience cardiomyopathy (OR 0.87, 95% CI 0.77, 0.99) or death (OR 0.71, 95% CI 0.67, 0.75). Among those with GI symptoms, older age, higher Charlson comorbidity index scores, and use of proton pump inhibitors/H2 receptor antagonists were associated with higher mortality, ARDS, sepsis, and ventilator or oxygen requirement.

      Conclusion

      Patients with COVID-19 who have GI symptoms have overall worse in-hospital complications but less cardiomyopathy and mortality. Older age, higher comorbidity scores, and the use of proton pump inhibitors and H2 receptor antagonists are associated with poor outcomes in these patients.

      Keywords

      Abbreviations used in this paper:

      AKI (Acute kidney injury), ARDS (acute respiratory distress syndrome), CCI (Charlson comorbidity index), CI (confidence interval), COVID-19 (SARS-CoV-2 coronavirus infection), CRWD (Cerner Real-World Data), ER (emergency department), GERD (gastroesophageal reflux disease), GI (gastrointestinal), H2RA (H2 receptor antagonist), PPI (proton pump inhibitors), OR (odds ratio), VTE (venous thromboembolism)

      Introduction

      The SARS-CoV-2 coronavirus (COVID-19) pandemic continues to afflict the global community, with 570,159,393 cases and 6,384,239 deaths reported globally as of July 24, 2022.
      John Hopkins University [database on the Internet].
      Initially recognized as a primary respiratory disorder, subsequent expansive research has identified COVID-19 as a multisystemic condition.
      • Singh A.
      • Zaheer S.
      • Kumar N.
      • et al.
      Covid19, beyond just the lungs: a review of multisystemic involvement by Covid19.
      Although our understanding of the disease has grown exponentially since its identification, the relationships between specific systemic involvement and outcomes remain elusive.
      Gastrointestinal (GI) symptoms, including diarrhea, nausea, vomiting, anorexia, and abdominal pain, affect approximately 20%–60% of patients with COVID-19.
      • Tariq R.
      • Saha S.
      • Furqan F.
      • et al.
      Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis.
      ,
      • Marasco G.
      • Cremon C.
      • Barbaro M.R.
      • et al.
      Prevalence of gastrointestinal symptoms in severe acute respiratory syndrome coronavirus 2 infection: results of the prospective controlled multinational GI-COVID-19 study.
      There is also a growing interest in the role of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) in COVID-19–related outcomes with studies reporting divergent results regarding the impact of PPI/H2RA use on adverse outcomes.
      • Lee S.W.
      • Ha E.K.
      • Yeniova A.
      • et al.
      Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching.
      • Almario C.V.
      • Chey W.D.
      • Spiegel B.M.R.
      Increased risk of COVID-19 among users of proton pump inhibitors.
      • Israelsen S.B.
      • Ernst M.T.
      • Lundh A.
      • et al.
      Proton pump inhibitor use is not strongly associated with SARS-CoV-2 related outcomes: a nationwide study and meta-analysis.
      The association of GI symptoms with adverse outcomes, however, has been controversial in previous studies.
      • Bishehsari F.
      • Adnan D.
      • Deshmukh A.
      • et al.
      Gastrointestinal symptoms predict the outcomes from COVID-19 infection.
      • Ramachandran P.
      • Onukogu I.
      • Ghanta S.
      • et al.
      Gastrointestinal symptoms and outcomes in hospitalized coronavirus disease 2019 patients.
      • Ghimire S.
      • Sharma S.
      • Patel A.
      • et al.
      Diarrhea is associated with increased severity of disease in COVID-19: systemic review and metaanalysis.
      Knowledge of specific factors driving outcomes in this subset of patients with COVID-19 would be beneficial in triage, monitoring, risk stratification, and treatment decisions. We investigated the effect of demographics, comorbidities including GI diseases, and specific medication use (PPI/H2RA) on adverse outcomes in patients with COVID-19 with GI symptoms.

      Methods

      Study Design and Population

      Data from Cerner Real-World Data (CRWD) COVID-19 database was used for our study. CRWD is extracted from the electronic medical records (EMRs) of hospitals in which Cerner has a data use agreement. Encounters may include pharmacy, clinical and microbiology laboratory, admission, and billing information from affiliated patient care locations. All admissions, medication orders and dispensing, laboratory orders, and specimens are date and time stamped, providing a temporal relationship between treatment patterns and clinical information. Cerner Corporation has established Health Insurance Portability and Accountability Act–compliant operating policies to establish deidentification for CRWD. Access is granted under a data use agreement to organizations and individuals after approval of a submitted research proposal. Patients with at least one encounter (emergency department [ER] or inpatient) with a diagnosis code associated with COVID-19 exposure or infection or an emergency department or inpatient encounter with a positive result for a COVID-19 laboratory test were eligible for inclusion in CRWD COVID-19 database. Only diagnoses and laboratory results from encounters with a service date of December 1, 2019, forward were considered. Longitudinal data were included from all encounters for each patient (labeled by a unique identification number) from January 2015 (to account for variables of interest in medical history) until November 2020.
      The data set included demographics, including patient age, race, gender, ethnicity, and hospital characteristics. Mortality was defined using the “deceased” indicator provided by the database. In addition to capturing in-hospital mortality, this indicator allowed administrative updates based on available knowledge of any patient’s death outside the hospital. The International Classification of Diseases, Ninth Revision, Clinical Modification and the International Classification of Diseases, Tenth Revision, Clinical Modification, diagnosis codes recorded during each visit were also separately available. First, laboratory test results for COVID-19 of all patients were examined to filter out those patient records without a confirmed COVID-19 test or only exposure. The included patient data sets were then merged with visits categorized as COVID-19 by Cerner. Cerner identifies each patient with a unique identification number, which allowed us to track multiple visits of a patient. Patients were then categorized as those with and without GI symptoms. GI symptoms were defined as stated in Table A1. Charlson comorbidity index (CCI) was calculated using the Quan et al. coding algorithm.
      • Quan H.
      • Sundararajan V.
      • Halfon P.
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      Binary variables were created for the presence or absence of disease and complications in each patient (Table A1). The study was exempt from review under the minimal risk protocol from Providence St Joseph Hospital Institution Review Board, Seattle, WA, USA.

      Statistical Analysis

      Bivariate analysis was used to compare patient demographics, hospital characteristics, comorbidities, concomitant GI conditions, and medication use (Table 1). In each case, proportions in the 2 groups (GI symptoms vs without GI symptoms) were compared using Z-scores. Bivariate and multivariate analyses were used to compute the associations between GI symptoms and complications. These multivariate models were adjusted for race, gender, age (stratified), CCI (stratified), gastroesophageal reflux disease (GERD), other GI conditions (composite of GI malignancy, inflammatory bowel disease, celiac disease), and PPI and H2RA use (Table 2). Statistical significance was defined as a P value of <.05. The outcomes of interest were acute respiratory distress syndrome (ARDS), sepsis, acute kidney injury (AKI), venous thromboembolism (VTE), cardiomyopathy, mortality, and use of invasive mechanical ventilation or oxygen dependence. In addition, the GI-specific complications studied were GI bleed, intestinal ischemia, pancreatitis, acute liver injury, and intestinal pseudoobstruction. Subsequently, multivariate logistic regression models were used to estimate factors associated with ARDS, sepsis, ventilator requirement/oxygen dependence, and mortality in the subset of patients with GI symptoms (Table 3). Statistical analysis was performed using Python and SAS programming languages.
      Table 1Baseline Characteristics of Patients With COVID-19 With and Without Gastrointestinal Symptoms Presenting to the Hospital
      VariableInpatients/emergency roomGI symptomsNo GI symptomsP value
      N = 100,902N = 19,915 (19.7%)N = 80,987 (80.3%)
      n (%)n (%)n (%)
      Age (y)
      To protect patient identity in smaller populations based on age groups, Cerner Real-World Data codes individuals aged <18 years as age 17 years and more than 90 years of age as age 90. The mean age was thus calculated by removing all patients of age <18 and >89 years, with an age range of 18–89 years.
       Mean (SD)52.39 (19.32)
       Median (IQR)52 (67–36)
       ≤17 y8238 (8.2%)1366 (6.9%)6872 (8.5%)<.0001
       18–3420,822 (20.6%)3455 (17.3%)17,367 (21.4%)<.0001
       35–4920,661 (20.5%)3946 (19.8%)16,715 (20.6%).0099
       50–6423,821 (23.6%)5010 (25.2%)18,811 (23.2%)<.0001
       65–7918,316 (18.2%)4155 (20.9%)14,161 (17.5%)<.0001
       ≥809044 (9%)1983 (10%)7061 (8.7%)<.0001
      Gender
       Men49,331 (48.9%)8978 (45.1%)40,353 (49.8%)<.0001
       Women51,172 (50.7%)10,845 (54.5%)40,327 (49.8%)<.0001
       Unknown/other399 (0.4%)92 (0.5%)307 (0.4%).095
      Race
       White58,655 (58.1%)11,999 (60.3%)46,656 (57.6%)<.0001
       Black18,538 (18.4%)3855 (19.4%)14,683 (18.1%)<.0001
       Other23,709 (23.5%)4061 (20.4%)19,648 (24.3%)<.0001
      Ethnicity
       Hispanic43,266 (42.9%)8321 (41.8%)34,945 (43.1%).0005
       Non-Hispanic53,343 (52.9%)10,774 (54.1%)42,569 (52.6%).0001
       Other or unknown4293 (4.3%)820 (4.1%)3473 (4.3%).28
      Hospital region
       Midwest8309 (8.2%)1504 (7.6%)6805 (8.4%).0001
       Northeast20,827 (20.6%)3764 (18.9%)17,063 (21.1%)<.0001
       South40,448 (40.1%)9305 (46.7%)31,143 (38.5%)<.0001
       West31,318 (31%)5342 (26.8%)25,976 (32.1%)<.0001
      Hospital beds, no
       <3004600 (4.6%)993 (5%)3607 (4.5%).0012
       300–4997983 (7.9%)1594 (8%)6389 (7.9%).6
       500–99920,972 (20.8%)3622 (18.2%)17,350 (21.4%)<.0001
       >100067,347 (66.7%)13,706 (68.8%)53,641 (66.2%)<.0001
      Charlson comorbidity index
       CCI, mean (SD)1.217 (2.02)1.58 (2.3)1.13 (1.94)<.0001
       055,848 (55.3%)9479 (47.6%)46,369 (57.3%)<.0001
       1–436,072 (35.7%)7929 (39.8%)28,143 (34.8%)<.0001
       ≥58982 (8.9%)2507 (12.6%)6475 (8%)<.0001
      Charlson comorbidities (components of CCI)
       Myocardial infarction4060 (4%)908 (4.6%)3152 (3.9%)
       Congestive heart failure8269 (8.2%)1863 (9.4%)6406 (7.9%)
       Peripheral vascular disease2995 (3%)796 (4%)2199 (2.7%)
       Cerebrovascular disease3240 (3.2%)1028 (5.2%)2212 (2.7%)
       Dementia5597 (5.5%)1392 (7%)4205 (5.2%)
       Chronic pulmonary disease13,865 (13.7%)2953 (14.8%)10,912 (13.5%)
       Rheumatological disease1458 (1.4%)425 (2.1%)1033 (1.3%)
       Peptic ulcer disease475 (0.5%)185 (0.9%)290 (0.4%)
       Mild liver disease3517 (3.5%)1191 (6%)2326 (2.9%)
       Diabetes25,522 (25.3%)5955 (29.9%)19,567 (24.2%)
       DM with no complications23,411 (23.2%)5483 (27.5%)17,928 (22.1%)
       DM with chronic complications7842 (7.8%)2131 (10.7%)5711 (7.1%)
       Hemiplegia/paraplegia787 (0.8%)273 (1.4%)514 (0.6%)
       Kidney disease10,345 (10.3%)2645 (13.3%)7700 (9.5%)
       Any malignancy, including leukemia or lymphoma2389 (2.4%)694 (3.5%)1695 (2.1%)
       Moderate/severe liver disease711 (0.7%)225 (1.1%)486 (0.6%)
       Metastatic solid tumor605 (0.6%)205 (1%)400 (0.5%)
       AIDS/HIV428 (0.4%)109 (0.5%)319 (0.4%)
       Hypertension31,258 (31%)7592 (38.1%)23,666 (29.2%)
       Hyperlipidemia17,549 (17.4%)4335 (21.8%)13,214 (16.3%)
      Concomitant GI conditions
       Acute liver failure444 (0.4%)144 (0.7%)300 (0.4%)<.0001
       GERD7541 (7.5%)2296 (11.5%)5245 (6.5%)<.0001
       GI malignancy, ALL376 (0.4%)132 (0.7%)244 (0.3%)<.0001
       GI malignancy, esophagus/stomach/colon/liver265 (0.3%)87 (0.4%)178 (0.2%)<.0001
       IBD (UC + Crohn's)316 (0.3%)137 (0.7%)179 (0.2%)<.0001
       Celiac disease36 (0.04%)11 (0.1%)25 (0.03%).1
      Medications
       PPI (1 mo history)15,741 (15.6%)4566 (22.9%)11,175 (13.8%)<.0001
       H2RA (1 mo history)11,335 (11.2%)3281 (16.5%)8054 (9.9%)<.0001
      CCI, Charlson comorbidity index; DM, diabetes mellitus; GERD, gastroesophageal reflux disease; GI, gastrointestinal; H2RA, H2 receptor antagonists; IBD, inflammatory bowel disease; IQR, interquartile range; PPI, proton pump inhibitors; SD, standard deviation; UC, ulcerative colitis.
      a To protect patient identity in smaller populations based on age groups, Cerner Real-World Data codes individuals aged <18 years as age 17 years and more than 90 years of age as age 90. The mean age was thus calculated by removing all patients of age <18 and >89 years, with an age range of 18–89 years.
      Table 2Adjusted Associations of GI Symptoms With Outcomes and Complications in Patients With COVID-19 Presenting to the Hospital
      Outcomes and complicationsTotalGI symptomsNo GI symptomsP valueAdjusted OR (95% confidence intervals)
      Adjusted for race, gender, age (stratified), Charlson comorbidity index (stratified), gastroesophageal reflux disease, other GI conditions (composite of GI malignancy, Inflammatory bowel disease, celiac disease), and proton pump inhibitor and H2 receptor antagonist use.
      P value for adjusted OR
      n (%)n (%)n (%)
      Total100,90219,91580,987
      Outcomes
       ARDS4135 (4.1%)1137 (5.7%)2998 (3.7%)<.00011.20 (1.11, 1.29)<.0001
       Sepsis16,145 (16%)4127 (20.7%)12,018 (14.8%)<.00011.19 (1.14, 1.24)<.0001
       Acute kidney injury14,782 (14.6%)3999 (20.1%)10,783 (13.3%)<.00011.30 (1.24, 1.36)<.0001
       Venous thromboembolism1559 (1.5%)467 (2.3%)1092 (1.3%)<.00011.36 (1.22, 1.52)<.0001
       Cardiomyopathy8475 (8.4%)1993 (10%)6482 (8%)<.00010.87 (0.77, 0.99).027
       Mortality8574 (8.5%)1666 (8.4%)6908 (8.5%).460.71 (0.67, 0.75)<.0001
       Mechanical ventilation/oxygen dependence3177 (3.1%)817 (4.1%)2360 (2.9%)<.00011.05 (0.96, 1.14).2729
      GI complications
       GI bleed2000 (2%)706 (3.5%)1294 (1.6%)<.00011.62 (1.47, 1.79)<.0001
       Intestinal ischemia37 (0.037%)16 (0.1%)21 (0%).00031.75 (0.88, 3.50).1122
       Pancreatitis554 (0.55%)294 (1.5%)260 (0.3%)<.00010.84 (0.67, 1.05).1266
       Acute liver injury444 (0.44%)144 (0.7%)300 (0.4%)<.00011.13 (0.90, 1.42).2777
       Pseudoobstruction13 (0.01%)7 (0.035%)6 (0.007%).0020.32 (0.04, 2.47)
      Given only 13 patients, not adjusted for other GI conditions and gender to get reliable estimates.
      .2745
      ARDS, Acute respiratory distress syndrome; GI, gastrointestinal; OR, odds ratio.
      a Adjusted for race, gender, age (stratified), Charlson comorbidity index (stratified), gastroesophageal reflux disease, other GI conditions (composite of GI malignancy, Inflammatory bowel disease, celiac disease), and proton pump inhibitor and H2 receptor antagonist use.
      b Given only 13 patients, not adjusted for other GI conditions and gender to get reliable estimates.
      Table 3Factors Associated With Adverse Outcomes in Patients With COVID-19 and Gastrointestinal Symptoms Presenting to the Hospital
      VariableMortalityARDSSepsisVentilator/oxygen dependence
      OR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P value
      Black race vs White1.02 (0.88, 1.18).80321.10 (0.92, 1.32).28381.03 (0.96, 1.14).60630.87 (0.71, 1.07).1913
      Other race vs White0.98 (0.84, 1.15).82831.90 (1.63, 2.21)<.00011.15 (1.04, 1.27).00560.97 (0.80, 1.17).7388
      Men vs women1.47 (1.32, 1.64)<.00011.47 (1.30, 1.68)<.00011.44 (1.33, 1.55)<.00011.14 (0.99, 1.32).0727
      Unknown gender vs men1.27 (0.58, 2.80).54651.02 (0.36, 2.89).96741.43 (0.85, 2.41).17490.63 (0.15, 2.61).5202
      Bed size 300–499 vs <3001.33 (0.9, 1.96).15330.84 (0.56, 1.26).39731.50 (1.14, 1.96).00371.05 (0.70, 1.55).8265
      Bed size 500–999 vs <3001.73 (1.22, 2.47).00241.50 (1.06, 2.13).02232.33 (1.82, 2.97)<.00010.69 (0.48, 0.998).049
      Bed size >1000 vs <3001.24 (0.88, 1.74).21571.07 (0.77, 1.47).70082.26 (1.80, 2.84)<.00010.59 (0.42, 0.82).0015
      Region Northeast vs South1.25 (1.08, 1.46).00361.05 (0.87, 1.27).61711.46 (1.31, 1.62)<.00011.81 (1.47, 2.21)<.0001
      Region Midwest vs South0.72 (0.57, 0.90).00441.12 (0.87, 1.45).37060.45 (0.38, 0.55)<.00010.92 (0.68, 1.25).578
      Region West vs South1.20 (1.04, 1.38).01452.13 (1.81, 2.50)<.00011.78 (1.62, 1.95)<.00011.62 (1.34, 1.96)<.0001
      Age group 18–34 vs ≤172.46 (0.86, 7.02).09245.27 (1.90, 14.64).00140.86 (0.68, 1.09).21960.75 (0.37, 1.52).4239
      Age group 35–49 vs ≤173.82 (1.39, 10.49).00949.42 (3.46, 25.65)<.00011.14 (0.91, 1.43).26771.74 (0.94, 3.24).0779
      Age group 50–64 vs ≤179.53 (3.52, 25.74)<.000115.18 (5.61, 41.09)<.00011.51 (1.21, 1.88).00032.33 (1.27, 4.25).0062
      Age group 65–79 vs ≤1719.46 (7.21, 52.52)<.000115.39 (5.67, 41.74)<.00011.81 (1.45, 2.27)<.00013.22 (1.76, 5.89).0001
      Age group ≥80 vs ≤1737.21 (13.76, 100.63)<.00016.32 (2.28, 17.48).00041.67 (1.32, 2.12)<.00011.96 (1.05, 3.66).0351
      CCI score 1–4 vs 03.88 (3.20, 4.71)<.00012.32 (1.95, 2.76)<.00012.63 (2.39, 2.89)<.00013.84 (3.00, 4.90)<.0001
      CCI score ≥5 vs 08.23 (6.70, 10.12)<.00012.79 (2.27, 3.43)<.00015.02 (4.44, 5.67)<.00017.07 (5.41, 9.25)<.0001
      GI malignancy, all1.45 (0.73, 2.86).29061.65 (0.80, 3.39).17171.02 (0.60, 1.73).94950.76 (0.27, 2.14).6055
      Acute liver failure1.68 (0.83, 3.41).15050.83 (0.32, 2.17).70020.72 (0.40, 1.30).26921.30 (0.51, 3.32).5901
      IBD (UC and Crohn's)1.01 (0.52, 1.93).99771.00 (0.47, 2.15).99721.96 (1.29, 2.97).00151.43 (0.70, 2.94).3251
      GERD0.85 (0.73, 0.98).02640.71 (0.59, 0.85).00030.91 (0.82, 1.02).09831.19 (0.99, 1.43).0639
      Celiac disease
      Celiac disease removed from multivariate analysis for mortality as it was generating unreliable estimates.
      7.44 (1.44, 38.46).01661.05 (0.21, 5.32).95262.47 (0.28, 21.55).4128
      PPI1.48 (1.32, 1.66)<.00012.19 (1.91, 2.50)<.00011.88 (1.73, 2.05)<.00011.73 (1.48, 2.02)<.0001
      H2RA1.78 (1.57, 2.02)<.00013.75 (3.29, 4.28)<.00012.50 (2.28, 2.73)<.00011.97 (1.68, 2.30)<.0001
      Percent concordant84.78177.579.3
      P values <.05 are designated in bold.
      ARDS, acute respiratory distress syndrome; CCI, Charlson comorbidity index; CI, confidence interval; GERD, gastroesophageal reflux disease; GI, gastrointestinal; H2RA, H2 receptor antagonists; IBD, inflammatory bowel disease; OR, odds ratio; PPI, proton pump inhibitors; UC, ulcerative colitis.
      a Celiac disease removed from multivariate analysis for mortality as it was generating unreliable estimates.

      Results

      Baseline Characteristics

      Of 100,902 patients who presented with a confirmed diagnosis of COVID-19 to the hospital or ER, 20% had GI symptoms. The mean age was 52 years (range: 18–89 years). A higher proportion of patients with GI symptoms were aged ≥50 years (vs without GI symptoms; Table 1). Of those who had GI symptoms, 54.5% were women. Overall, 58.1% of the study population identified as White. Patients with GI symptoms were more commonly of the White race or Black race. Among patients with GI symptoms, a higher 46.7% (vs 38.5% without GI symptoms) came from the Southern region. Overall, 66.7% of all patients studied were evaluated at large hospitals with more than 1000 bed size. Patients with GI symptoms were more likely to be evaluated at large hospitals at 68.8% compared with 66.2% without GI symptoms. The mean CCI was higher in patients with GI symptoms, 1.58 compared with 1.13. The CCI score was 1–4 in 39.8% (vs 34.8%) and ≥5 in 12.6% (vs 8%) of patients with GI symptoms (compared with those without GI symptoms). All component comorbidities of the CCI as well as acute liver failure, GERD, GI malignancy, and inflammatory bowel diseases were more common in patients with GI symptoms (Table 1). The use of PPI (22.9% vs 13.8%, P < .0001) and H2RA (16.5% vs 9.9%, P < .0001) was also more common in patients with GI symptoms.

      Outcomes

      Impact of the Presence of GI Symptoms on Complications of COVID-19

      Patients with COVID-19 and GI symptoms were more likely to have ARDS (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.11, 1.29), sepsis (OR 1.19, 95% CI 1.14, 1.24), AKI (OR 1.30, 95% CI 1.24, 1.36), and VTE (OR 1.36, 95% CI 1.22, 1.52) and less likely to have cardiomyopathy (OR 0.87, 95% CI 0.77, 0.99) and mortality (OR 0.71, 95% CI 0.67, 0.75; Table 2). The mean hospital length of stay was 6.8 days for all patients.

      Presence of GI Symptoms in COVID-19 and Risk of GI Complications

      GI bleed was the most common GI complication (2%) and was more likely in patients with GI symptoms (OR 1.62, 95% CI 1.47, 1.79). Intestinal ischemia, pancreatitis, acute liver injury, and intestinal pseudoobstruction were not associated with GI symptoms (Table 2).

      Factors Associated With Adverse Outcomes in Patients With COVID-19 and GI Symptoms: Mortality, ARDS, Sepsis, and Invasive Mechanical Ventilation or Oxygen Dependence

      In a multivariate analysis of patients with GI symptoms in COVID-19 (Table 3), men had a higher risk of mortality (OR 1.47, 95% CI 1.32, 1.64), ARDS (OR 1.47, 95% CI 1.30, 1.68), and sepsis (OR 1.44, 95% CI 1.33, 1.55). Black race compared with White was not associated with adverse outcomes. A hospital bed size of 500–999 compared with <300 was associated with higher mortality (OR 1.73, 95% CI 1.22, 2.47), ARDS (OR 1.50, 95% CI 1.06, 2.13), and sepsis (OR 2.33, 95% CI 1.82, 2.97). West region compared with the south was associated with higher mortality (OR 1.20, 95% CI 1.04, 1.38), ARDS (OR 2.13, 95% CI 1.81, 2.50), sepsis (OR 1.78, 95% CI 1.62, 1.95), and ventilator requirement or oxygen dependence (OR 1.62, 95% CI 1.34, 1.96). Northeast region was associated with a higher mortality (OR 1.25, 95% CI 1.08, 1.46), sepsis (OR 1.46, 95% CI 1.31, 1.62), and ventilator or oxygen dependence (OR 1.81, 95% CI 1.47, 2.21), whereas Midwest region was associated with lower mortality (OR 0.72, 95% CI 0.57, 0.90) and sepsis (OR 0.45, 95% CI 0.38, 0.55).
      A higher age, particularly age 50 years and above (compared with age 17 years or less) as well as an increasing CCI score (compared with a CCI score of 0) was associated with a higher risk of mortality, ARDS, sepsis, and ventilator or oxygen dependence (Table 3).

      Impact of PPI and H2RA in Patients With GI Symptoms in COVID-19

      PPI use was associated with a higher risk of mortality (OR 1.48, 95% CI 1.32, 1.66), ARDS (OR 2.19, 95% CI 1.91, 2.50), sepsis (OR 1.88, 95% CI 1.73, 2.05), and ventilator or oxygen dependence (OR 1.73, 95% CI 1.48, 2.02). Similarly, the use of H2RA was associated with a higher risk of mortality (OR 1.78, 95% CI 1.57, 2.02), ARDS (OR 3.75, 95% CI 3.29, 4.28), sepsis (OR 2.50, 95% CI 2.28, 2.73), and ventilator or oxygen dependence (OR 1.97, 95% CI 1.68, 2.30).

      Discussion

      In this study of 100,902 patients with COVID-19 presenting to the hospital or ER, 1 in 5 patients had GI symptoms. Patients with GI symptoms were older and more likely to be women. Two-thirds of the patients studied were evaluated at large hospitals. This is likely reflective of the higher usage of Cerner EMR in larger hospitals compared with smaller hospitals. Patients with GI symptoms had a higher comorbidity burden. In addition, concomitant GI conditions and medication use of PPI or H2RA were more common in patients with GI symptoms. This demonstrates that patients with GI symptoms in COVID-19 represent an overwhelmingly sicker patient population. In a previous small study of 150 hospitalized patients with COVID-19, the presence of GI symptoms was not associated with a difference in comorbidities.
      • Ramachandran P.
      • Onukogu I.
      • Ghanta S.
      • et al.
      Gastrointestinal symptoms and outcomes in hospitalized coronavirus disease 2019 patients.
      Conversely, a retrospective study of 2804 patients hospitalized in New York with COVID-19 found a greater comorbidity burden and younger age among patients with GI symptoms.
      • Laszkowska M.
      • Faye A.S.
      • Kim J.
      • et al.
      Disease course and outcomes of COVID-19 among hospitalized patients with gastrointestinal manifestations.

      Association of GI Symptoms With Adverse Outcomes in COVID-19

      Our study found that the presence of GI symptoms in patients with COVID-19 was associated with a higher risk of ARDS, sepsis, AKI, and VTE. Conversely, GI symptoms were associated with a lower risk of mortality and cardiomyopathy. GI symptoms were not associated with ventilator or oxygen requirements. Few of these associations have been studied before. A previous study of 2804 patients found GI symptoms to be associated with lower mortality and less need for mechanical ventilation.
      • Laszkowska M.
      • Faye A.S.
      • Kim J.
      • et al.
      Disease course and outcomes of COVID-19 among hospitalized patients with gastrointestinal manifestations.
      A meta-analysis of 12,797 patients did not find a difference between the mortality in patients with GI symptoms and overall mortality in COVID-19.
      • Tariq R.
      • Saha S.
      • Furqan F.
      • et al.
      Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis.
      A separate smaller study of 150 patients did not find an association between GI symptoms and mortality or mechanical ventilation in COVID-19.
      • Ramachandran P.
      • Onukogu I.
      • Ghanta S.
      • et al.
      Gastrointestinal symptoms and outcomes in hospitalized coronavirus disease 2019 patients.
      Furthermore, a meta-analysis of 186 articles demonstrated that patients with COVID-19 and GI symptoms had an increased risk of ARDS but not mortality,
      • Gul F.
      • Lo K.B.
      • Peterson J.
      • et al.
      Meta-analysis of outcomes of patients with COVID-19 infection with versus without gastrointestinal symptoms.
      whereas another meta-analysis of 125 articles found that patients with COVID-19 presenting with GI symptoms had a higher risk of mortality, ARDS, AKI, and cardiac injury.
      • Elshazli R.M.
      • Kline A.
      • Elgaml A.
      • et al.
      Gastroenterology manifestations and COVID-19 outcomes: a meta-analysis of 25,252 cohorts among the first and second waves.
      Our findings emphasize the need to consider GI symptoms in the determination of prognosis in COVID-19.

      Association of GI Symptoms With GI Complications in COVID-19

      Among GI complications, GI bleed was more common in those presenting with GI symptoms, but intestinal ischemia, pancreatitis, acute liver injury, or pseudoobstruction was not. Although the causality of the association between COVID-19 and pancreatitis has been questioned,
      • de-Madaria E.
      • Capurso G.
      COVID-19 and acute pancreatitis: examining the causality.
      the association between COVID-19 and liver injury has been previously demonstrated.
      • Tian D.
      • Ye Q.
      Hepatic complications of COVID-19 and its treatment.
      The proposed mechanism of liver injury in COVID-19 is a combination of direct viral invasion as well as inflammatory, hypoxic, and drug-induced effects.
      • Nardo A.D.
      • Schneeweiss-Gleixner M.
      • Bakail M.
      • et al.
      Pathophysiological mechanisms of liver injury in COVID-19.

      Impact of Demographic Factors and Comorbidities on Outcomes in Patients With GI Symptoms in COVID-19

      Previous large studies have shown older age to be associated with a higher risk of mortality and mechanical ventilation in COVID-19.
      • Fried M.W.
      • Crawford J.M.
      • Mospan A.R.
      • et al.
      Patient characteristics and outcomes of 11,721 patients with COVID19 hospitalized across the United States.
      ,
      • Ioannou G.N.
      • Locke E.
      • Green P.
      • et al.
      Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection.
      In our study of patients with COVID-19 and GI symptoms, the odds of mortality were approximately 4-fold, 10-fold, 20-fold, and 37-fold in age groups 35–49, 50–64, 65–79, and ≥80, respectively. Increasing age also had higher odds of ARDS, sepsis, and ventilator requirement or oxygen dependence, dropping respectively to 6.3-, 1.6-, and 1.9-fold in the age group ≥80 years. A previous study of hospitalized patients with risk factors for ARDS postulated that the anatomical, physiological, and immunological differences in those more than 80 years of age conferred protection against ARDS; in addition, more conservative goals of care led to less aggressive testing for ARDS along with less use of mechanical ventilation.
      • Reynolds D.
      • Kashyap R.
      • Wallace L.
      • et al.
      Older adult patients are at lower risk of ARDS compared to younger patients at risk: secondary analysis of a multicenter cohort study.
      Male sex has been associated with mechanical ventilation in previous studies on COVID-19, whereas its association with mortality has been inconsistent.
      • Fried M.W.
      • Crawford J.M.
      • Mospan A.R.
      • et al.
      Patient characteristics and outcomes of 11,721 patients with COVID19 hospitalized across the United States.
      ,
      • Ioannou G.N.
      • Locke E.
      • Green P.
      • et al.
      Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection.
      In our study of COVID-19 with GI symptoms, men had higher odds of mortality, ARDS, and sepsis but not ventilator requirement or oxygen dependence. The results of previous studies exploring the relationship between COVID-19 mortality and race have been incongruent. Black race or Hispanic ethnicity was not found to be associated with mortality in a previous study of 10,131 veterans with COVID-19.
      • Ioannou G.N.
      • Locke E.
      • Green P.
      • et al.
      Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection.
      A University of Michigan study of 5698 patients with COVID-19 also did not find mortality differences by race.
      • Gu T.
      • Mack J.A.
      • Salvatore M.
      • et al.
      Characteristics associated with racial/ethnic disparities in COVID-19 outcomes in an academic health care system.
      A study using the same CRWD COVID-19 database of patients with COVID-19 found increased mortality in non-Hispanic Black or African American patients.
      • Qeadan F.
      • VanSant-Webb E.
      • Tingey B.
      • et al.
      Racial disparities in COVID-19 outcomes exist despite comparable Elixhauser comorbidity indices between Blacks, Hispanics, Native Americans, and Whites.
      In our study of patients with COVID-19 with GI symptoms, Black race was not associated with adverse outcomes. This is likely because, in addition to studying a subset of patients with GI symptoms, we also adjusted for different variables, including the use of PPI/H2RA. Overall, being in the West and Northeast regions predicted worse outcomes, and the Midwest region had better outcomes compared with the Southern region in our study. This is consistent with earlier reports of worse mortality outcomes in COVID-19 in the Northeast region
      • Fried M.W.
      • Crawford J.M.
      • Mospan A.R.
      • et al.
      Patient characteristics and outcomes of 11,721 patients with COVID19 hospitalized across the United States.
      and the relationship of mortality with COVID-19 disease burden.
      • Ioannou G.N.
      • Locke E.
      • Green P.
      • et al.
      Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US veterans with SARS-CoV-2 infection.
      We found that an increase in CCI score was associated with increasing mortality, ARDS, sepsis, as well as ventilator requirement/oxygen dependence in patients with GI symptoms and COVID-19. Previous studies have found CCI score to be associated with mortality and poor outcomes in COVID-19.
      • Tuty Kuswardhani R.A.
      • Henrina J.
      • Pranata R.
      • et al.
      Charlson comorbidity index and a composite of poor outcomes in COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Imam Z.
      • Odish F.
      • Gill I.
      • et al.
      Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States.
      A previous meta-analysis found that patients with COVID-19 and severe disease had a higher prevalence of abnormal liver function.
      • Dong Z.Y.
      • Xiang B.J.
      • Jiang M.
      • et al.
      The prevalence of gastrointestinal symptoms, abnormal liver function, digestive system disease and liver disease in COVID-19 infection: a systematic review and meta-analysis.
      We did not find an independent association between acute liver injury and severe outcomes, including respiratory failure and death in patients with COVID-19 who had GI symptoms.

      Impact of GERD, PPI, and H2RA in Patients With GI Symptoms in COVID-19

      In patients with GI symptoms in COVID-19, GERD appeared to be protective against ARDS and mortality but had no association with ventilator requirement or oxygen dependence or sepsis. Hypochlorhydria has been hypothesized to be conducive to COVID-19 GI infection.
      • Dibner J.J.
      Direct COVID-19 infection of enterocytes: the role of hypochlorhydria.
      Perhaps, a conversely increased acidic environment associated with GERD suppresses COVID-19 viral load at the gastrointestinal point of entry, favoring a milder disease course.
      In a nationwide Korean study of 132,316 patients, the use of PPI was associated with an increased risk of a composite outcome of critical care requirements, mechanical ventilation, and mortality.
      • Lee S.W.
      • Ha E.K.
      • Yeniova A.
      • et al.
      Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching.
      The effect of H2RA on COVID-19 outcomes has been controversial in previous studies.
      • Shoaibi A.
      • Fortin S.P.
      • Weinstein R.
      • et al.
      Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
      ,
      • Freedberg D.E.
      • Conigliaro J.
      • Wang T.C.
      • et al.
      Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study.
      A recent study of 295 patients with COVID-19 elucidated that PPI use before hospitalization was associated with mortality and ARDS.
      • Ramachandran P.
      • Perisetti A.
      • Gajendran M.
      • et al.
      Pre-hospitalization proton pump inhibitor use and clinical outcomes in COVID-19.
      The presence of GI symptoms in our study cohort likely marks the presence of SARS-CoV-2 in the GI tract in these patients. A possible explanation is that the suppression of gastric acid favors increased viral load and enterocyte invasion by SARS-CoV-2 and a possible greater cytokine storm as previously hypothesized.
      • Lee S.W.
      • Ha E.K.
      • Yeniova A.
      • et al.
      Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching.
      In addition, a recent study found PPI to be associated with GI symptoms and discussed a possible role of PPI-related dysbiosis in the clinical course of COVID-19.
      • Marasco G.
      • Cremon C.
      • Barbaro M.R.
      • et al.
      Prevalence of gastrointestinal symptoms in severe acute respiratory syndrome coronavirus 2 infection: results of the prospective controlled multinational GI-COVID-19 study.
      These hypotheses in part could explain our study findings that PPI and H2RA were associated with a higher risk of ARDS, mortality, sepsis, as well as ventilator requirement or oxygen dependence in patients with COVID-19 and GI symptoms. We were unable to confirm the role of PPI and H2RA in the causation of these adverse outcomes, however, and future studies are needed that account for the indications for the use of PPI and H2RA, whether such use is a modifiable factor or unavoidable use due to medical necessity, and for the cause of death.

      Strengths and Limitations

      To our knowledge, this is the largest study to date evaluating the characteristics and outcomes in patients with COVID-19 and GI symptoms and the first study to explore the detailed predictors of specific adverse outcomes, including ARDS, sepsis, mortality, and ventilator requirement or oxygen dependence in this subset of patients. Our study is not without limitations, however. The CRWD COVID-19 database includes COVID-19 patients with an ER or inpatient encounter and omits those treated at home. This confers a bias toward patients with a more aggressive disease course. Moreover, a comparison group without COVID-19 was not available using the CRWD COVID-19 database.
      Another limitation is the potential for coding errors and variations in coding practices among the hospitals captured by the database, as well as limitations in the reconciliation of such variations using coding-based queries retrospectively. There is also the possibility of unmeasured individual patient-level confounders not captured by International Classification of Diseases codes or the CRWD COVID-19 database. We were unable to ascertain if the differences in an individual patient and/or family values, preferences, goals of care, and decisions such as palliative care or hospice affected the ventilator requirements and/or mortality. Finally, we could not account for the differences in treatment protocols by individual hospitals and clinicians, as well as the temporal changes in treatment protocols.

      Conclusion

      Patients with COVID-19 and GI symptoms have a higher comorbidity burden and overall worse in-hospital complications but lower mortality and cardiomyopathy than patients without GI symptoms. A higher age and comorbidity burden, as well as the use of PPI and H2RA, are associated with poor outcomes in patients with COVID-19 that have GI symptoms. Factors associated with adverse outcomes specific to this subset of patients could guide further disease management, prognostication, and resource utilization decisions.

      Authors' Contributions

      Nikita Patil contributed to conceptualization, methodology, and writing, reviewing, and editing the article. Pankush Kalgotra contributed to data curation, formal analysis, software, and reviewing and editing the article. Suneha Sundaram contributed to conceptualization, methodology, and reviewing and editing the article. Stephanie Melquist contributed to methodology and writing, reviewing, and editing the article. Sravanthi Parasa contributed to conceptualization, methodology, supervision, and reviewing and editing the article. Madhav Desai contributed to conceptualization, methodology, and reviewing and editing the article. Prateek Sharma contributed to conceptualization, methodology, supervision, and reviewing and editing the article.

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