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Inicio Gastroenterología y Hepatología (English Edition) Gastrointestinal symptoms and complications in patients hospitalized due to COVI...
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Vol. 46. Núm. 6.
Páginas 425-438 (junio - julio 2023)
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Vol. 46. Núm. 6.
Páginas 425-438 (junio - julio 2023)
Original Article
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Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project)
Síntomas y complicaciones gastrointestinales en pacientes hospitalizados por COVID-19, estudio internacional, multicéntrico, de cohorte, prospectivo (proyecto TIVURON)
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Karina Cárdenas-Jaéna, Sergio A. Sánchez-Lunab, Alicia Vaillo-Rocamoraa, Micaela Riat Castro-Zocchic, Laura Guberna-Blancoc, Daniel Useros-Brañasd, José M. Remes-Trochee, Antonio Ramos-De la Medinae, Bryan A. Priego-Parrae, José A. Velarde-Ruiz Velascof, Pedro Martínez-Ayalaf, Álvaro Urzúag, Dannette Guiñez-Francoish, Katarzyna M. Pawlaki, Katarzyna Kozłowska-Petriczkoj, Irati Gorroño-Zamalloak, Clara Urteaga-Casaresk, Inmaculada Ortiz-Polol, Adolfo del Val Antoñanal, Edgard E. Lozada-Hernándezm..., Enrique Obregón-Morenom, Guillermo García-Rayadon, María José Domper-Arnaln, Diego Casas-Dezao, Elena I. Esteban-Cabellop, Luis A. Díazq, Arnoldo Riquelmeq, Helena Martínez-Lozanor, Francisco Navarro-Romeros, Ignasi Olivast, Guillem Iborra-Muñozu, Alicia Calero-Amarov, Ibán Caravaca-Garcíav, Francisco J. Lacueva-Gómezv, Rubén Pastor-Mateuw, Berta Lapeña-Muñozx, Violeta Sastre-Lozanoy, Nazaret M. Pizarro-Vegaz, Luigi MelcarneA, Marc Pedrosa-AragónB, José J. MiraC,D, Aurora Mula MStatC, Irene CarrilloD, Enrique de-Madariaa,E,
Autor para correspondencia
emadaria@umh.es

Corresponding author.
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a Gastroenterology Department, Dr. Balmis General University Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
b Basil I, Hirschowitz Endoscopic Center of Excellence, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Alabama at Birmingham, Birmingham, United States
c Gastroenterology Department, La Princesa University Hospital and IIS-Princesa & Biomedical Research Center on Liver and Digestive Diseases Network (CIBEREHD), Madrid, Spain
d Internal Medicine Department, La Princesa University Hospital & IIS-Princesa, Madrid, Spain
e Gastroenterology Department, Spanish Hospital of Veracruz & Medical Biological Research Institute, Veracruz University, Veracruz, Mexico
f Gastroenterology Department, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Mexico
g Gastroenterology Section, Internal Medicine Department, Clinical Hospital University of Chile, Santiago, Chile
h Internal Medicine Department, Clinical Hospital University of Chile, Santiago, Chile
i Gastroenterology Department, Endoscopy Unit, Hospital of the Ministry of Interior and Administration, Szczecin, Poland
j Gastroenterology and Internal Medicine Department, SPWSZ Hospital, Szczecin, Poland
k Gastroenterology Department, University Hospital of Arava, Vitoria-Gasteiz, Spain
l Gastroenterology Unit, Digestive Diseases Department, La Fe University and Polytechnic Hospital, Valencia, Spain
m General Surgery Service, Department of Diseases of the Digestive Tract, Regional Hospital of High Specialty of Bajio, León-Guanajuato, Mexico
n Gastroenterology Department, Lozano Blesa University Clinical Hospital & Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain
o Gastroenterology and Hepatology Department, Miguel Servet University Hospital & Health Research Institute of Aragón (IIS Aragón), Zaragoza, Spain
p Internal Medicine Department, Miguel Servet University Hospital, Zaragoza, Spain
q Gastroenterology Department and Department of Health Sciences, AIRR Working Group, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile
r Gastroenterology Department, Gregorio Marañón General University Hospital & Gregorio Marañón Institute of Health Research, Madrid, Spain
s Internal Medicine Department, Costa del Sol Hospital, Marbella, Spain
t Gastroenterology Department, Hospital Clinic of Barcelona & Centre for Biomedical Research Network on Liver and Digestive Diseases (CIBEReHD) & August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
u Gastroenterology Department, Mataró Hospital, Mataró, Spain
v Surgery Department, Elche General University Hospital, Elche, Spain
w Gastroenterology Department, Valencia General University Hospital Consortium, Valencia, Spain
x Gastroenterology Department, San Pedro Hospital, Logroño, Spain
y Gastroenterology Department, Santa Lucía University Hospital, Cartagena, Spain
z Gastroenterology Department, Fuenlabrada University Hospital, Fuenlabrada, Spain
A Gastroenterology Department, Parc Taulí University Hospital, Sabadell, Spain
B Infectious Diseases Department, Parc Taulí University Hospital, Sabadell, Spain
C ATENEA Research, The Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), Alicante, Spain
D Health Psychology Department, Miguel Hernandez University, Elche, Spain
E Department of Clinical Medicine, Faculty of Medicine, Miguel Hernández University, Elche, Spain
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Table 1. Basal characteristics and differences between severe and non-severe COVID-19, bivariate analysis.
Table 2. Frequency and intensity of gastrointestinal symptoms.
Table 3. Associations of symptoms and complications and other outcome variables with COVID-19 severity; bivariate analysis.
Table 4. Multivariate analysis assessing the association between intensive care unit admission and possible determinants.
Table 5. Multivariate analysis assessing the association between mortality and possible determinants.
Table 6. Bivariate and multivariate analyses assessing the association between length of hospital stay and possible determinants.
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Abstract
Background

Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19.

Methods

This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant.

Results

Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464–0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328–0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms.

Conclusion

GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

Keywords:
COVID-19
Gastrointestinal symptoms
Gastrointestinal complications
Hospitalization
Hepatitis
Abbreviations:
aOR
ACE2
ARBs
AUC
Cis
COVID-19
CRP
GI
ICU
IL-6
IQR
NPV
PCR
PPV
ROC
Se
SOFA
SARS
SARS-CoV2
SAG
Sp
SD
TMPRSS2
WHO
Resumen
Antecedentes

Estudios retrospectivos evidencian que la enfermedad por coronavirus (COVID-19) conlleva síntomas y complicaciones gastrointestinales (GI). Nuestro objetivo fue evaluar prospectivamente las manifestaciones GI de pacientes hospitalizados por COVID-19.

Métodos

Estudio internacional, multicéntrico, de cohorte, prospectivo, que seleccionó a pacientes con COVID-19 en 31 centros de España, México, Chile y Polonia, entre mayo-septiembre de 2020. Los pacientes fueron seguidos hasta 15 días tras el alta y completaron cuestionarios que evaluaban los síntomas y complicaciones GI. Se realizó un análisis descriptivo, bivariante y multivariante de los resultados. Se consideró significativa p<0,05.

Resultados

Se incluyeron 829 pacientes; 129 (15,6%) presentaron COVID-19 grave, 113 (13,7%) requirieron ingreso en UCI y 43 (5,2%) fallecieron. Al ingreso, los síntomas GI más prevalentes fueron anorexia (n=413; 49,8%), diarrea (n=327; 39,4%), náuseas/vómitos (n=227; 27,4%) y dolor abdominal (n=172; 20,7%), que resultaron de intensidad leve/moderada y se resolvieron durante el seguimiento. Un tercio de los pacientes presentaron daño hepático. La COVID-19 no grave se asoció con la presencia de ≥2 síntomas GI al ingreso (OR 0,679; IC 95%: 0,464-0,995; p=0,046) y/o diarrea durante la hospitalización (OR 0,531; IC 95%: 0,328-0,860; p=0,009). El análisis multivariante reveló que los peores resultados hospitalarios no se asociaron de forma independiente con el daño hepático o los síntomas GI.

Conclusión

Los síntomas GI fueron más frecuentes de lo que se había documentado, resultaron leves, se resolvieron rápidamente y no se asociaron de forma independiente con COVID-19 grave. El daño hepático fue una complicación frecuente en los pacientes hospitalizados que no se asoció de forma independiente con COVID-19 grave.

Palabras clave:
COVID-19
Síntomas gastrointestinales
Complicaciones gastrointestinales
Hospitalización
Hepatitis
Texto completo
Introduction

The initial reports describing COVID-19 disease highlighted respiratory symptoms, fever, and severe acute respiratory syndrome (SARS).1,2 However, further several published retrospective studies and systematic reviews suggest that infected patients commonly exhibit GI symptoms, like diarrhoea, nausea, emesis, abdominal pain, and less specific symptoms, such as anorexia.2–5 The virus can penetrate and infect epithelial gastrointestinal (GI) cells due to their surface expression of angiotensin-converting enzyme 2 (ACE2) receptors and the transmembrane protease serine 2 (TMPRSS2) used for S protein priming.6 Moreover, this explains the detection of virus RNA in faecal samples, and potential changes in GI flora.7,8

Although GI symptoms are recognized within the spectrum of COVID-19 manifestations, the described frequency has widely varied, ranging from 3 to 50%.3–5 Unfortunately, most of published studies are retrospective and have not evaluated the baseline pre-COVID-19 presence of GI symptoms. Moreover, virtually no prospective data are available describing the patient-assessed symptom intensity or their evolution throughout the disease.

Regarding GI complications, liver damage has been reported in approximately 15–35% of patients with COVID-19, especially in critically ill patients.3–5,9 The mechanism underlying this liver damage has not been defined, although a multifactorial origin is postulated, which includes cytopathic effects of the virus, drug-related hepatotoxicity, immune-mediated liver damage, and critical involvement of the patient's liver.10 Other possible GI complications of COVID-19 include acute pancreatitis,11 new-onset inflammatory bowel disease,12 and digestive ischaemic conditions secondary to endotheliitis, hypercoagulability, and systemic inflammation,13,14 such as ischaemic colitis15 or gangrenous cholecystitis.16 However, it is difficult to establish a causal relationship due to biases associated with retrospective studies and the low incidence rates of these complications in the epidemiological context of high COVID-19 occurrence.17

In this international, multicentre, prospective cohort study, we aimed to describe the frequency, intensity, evolution, and impact of digestive symptoms and complications, during hospitalization and after discharge, in patients with COVID-19.

Methods

The prospecTIVe evalUation of gastROintestinal maNifestations of COVID-19 (TIVURON) project was an international, multicentre, prospective, cohort study, developed with the auspice of the Spanish Association of Gastroenterology (AEG). This study was conducted through the collaboration of 31 centres from Spain, Mexico, Chile, and Poland. Patients were recruited from May to September of 2020. The study was approved on May 6th of 2020 (reference PI2020-068) by the central Institutional Review Board (IRB) (Dr. Balmis General University Hospital CEiM, Alicante, Spain), and subsequently by the IRB of each participating centre. Informed consent from patients was required. The STROBE guidelines were followed.

Study end-points

The primary outcome was the prevalence and intensity of GI symptoms and complications in patients hospitalized with COVID-19, as well as their evolution throughout the disease. Secondary outcomes included the associations of GI symptoms and complications with COVID-19 severity and hospital outcomes (hospital stay, need for ICU admission, and mortality).

Patient selection

Inclusion criteria were age ≥18, positive polymerase chain reaction (PCR) test for SARS-CoV-2 in any biological sample, hospital admission, and informed consent to participate in the study. Exclusion criteria were hospital admission due to a non-gastrointestinal disease clearly not related to COVID-19 (e.g., a hip fracture) with a subsequent diagnosis of COVID-19, acute active digestive disease clearly independent of COVID-19 (e.g., choledocholithiasis), acute outbreak of chronic inflammatory digestive disease (e.g., exacerbated chronic pancreatitis) with no apparent relationship to COVID-19, pre-existing digestive or non-digestive active neoplastic disease with abdominal or pelvic involvement, previous admission for COVID-19, or patients recruitment over 72h after admission.

Gastrointestinal symptoms selection

Based on a previously published patient-reported outcome scale,18 a survey was conducted among all collaborating researchers to assess the appropriateness of symptoms to be included in the study, using a numerical scale of 0–10, with 0 indicating no appropriateness, and 10 maximum appropriateness. The mean value for each symptom was calculated, and selected those with an average score of ≥5. Finally, the following nine symptoms were chosen: abdominal pain, gas/bloating/flatulence, diarrhoea, constipation, heartburn/gastroesophageal reflux, nausea/vomiting, hyporexia/anorexia, odynophagia, and dysphagia.

Data acquisition and definitions

Information regarding demographic features (including sex, understood as biological sex); toxic habits; previous comorbidities; chronic treatments; pre-COVID-19 GI symptoms; complications; analytical, radiological, and endoscopic data during admission; specific COVID-19 treatments; ventilatory support; mortality; and hospital stay, were collected. Data were prospectively acquired by researchers involved in direct patient management. Comprehensive symptom questionnaires were completed at different times throughout the disease course. A questionnaire administered at admission asked about GI symptoms at baseline (before COVID-19), and specifically at the time of admission. A questionnaire administered at discharge asked about the presence and higher intensity of GI symptoms during hospitalization, and specifically at the time of discharge. A final interview was performed at 15 days after discharge by phone call, asking about the presence and higher intensity of GI symptoms from discharge to the end of follow-up, and specifically at the time of interview.

The intensity of GI symptoms was defined as mild, moderate, or severe according to the patient's perception. Severe COVID-19 was defined as requiring ICU admission, requiring mechanical ventilation, and/or causing mortality during hospitalization, as previously reported by Colmenero et al.19 The GI complications evaluated during COVID-19 hospitalization and convalescence included esophagitis, oesophageal-gastric-duodenal ulcers, gastritis, duodenitis, acute pancreatitis, acute liver injury, acute liver failure, cholecystitis, cholangitis, enteritis, colitis, and upper or lower gastrointestinal bleeding. Definitions are presented in supplementary content 1.

Sample size

As retrospective reports suggested a high incidence of GI symptoms and complications among COVID-19 patients, here we aimed to provide exploratory high-quality data. However, this observational descriptive study was performed under exceptional circumstances, with a global pandemic collapsing hospital care. Therefore, we did not perform a sample size calculation based on expectations of finding statistically significant differences. Rather, the final sample size depended on the capacities of the centres involved and the time-frame established for data collection.

Statistical analysis

Statistical analyses were performed using IBM-SPSS V 25.0 software (IBM, Armonk, NY, USA). Quantitative variables are expressed as mean and standard deviation (SD) or median and interquartile range (IQR), and qualitative variables as number and percentage. Normality was assessed using the Shapiro–Wilk test. Quantitative variables were compared with qualitative variables using Student's t-test and the Mann–Whitney U-test for two categories, or using ANOVA and Kruskal–Wallis tests for over two categories. Qualitative variables were compared using the Chi-square test or Fisher's exact test if needed.

The Wilcoxon signed-rank test with continuity correction was used to make pairwise comparisons for each GI symptom at the five evaluated time-points, determining the difference compared to baseline GI symptoms (before COVID-19). Multivariate analysis was performed with binary logistic regression. Prevalence, odds ratio (OR), and adjusted odds ratio (aOR) with 95% confidence intervals (CIs) were calculated as measures of the frequency and strength of association. The Nagelkerke R2 statistic was calculated to assess the proportion of variance of the dependent variable explained by the model. For bivariate and multivariate models, GI symptoms during hospitalization were considered with adjustment according to baseline (before COVID-19), with the analysis excluding patients who presented the GI symptom before COVID-19. The multivariate models included the patients’ baseline characteristics, Charlson Comorbidity Index adjusted by age, GI and non-GI symptoms, GI complications, Sepsis-related organ failure assessment (SOFA) score, and C-reactive protein (CRP) level as a marker of systemic inflammation. A p-value of <0.05 was considered statistically significant.

Results

This study enrolled a total of 829 hospitalized patients, including 486 (58.6%) from Spain, 203 (24.5%) from Mexico, 97 (11.7%) from Chile, and 43 (5.2%) from Poland. The median age was 57 years (IQR 44–70 years), 481 (58.0%) were male, and the median Charlson Comorbidity Index adjusted per age was 2 points (IQR 0–4 points). Table 1 shows the patients’ baseline characteristics. Male gender, Charlson score, diabetes, and moderate-to-severe chronic renal disease were associated with severe COVID-19. The median time from symptom onset to admission was 7 days (IQR 4–10 days), and the median hospitalization length was 8 days (IQR 5–12 days). A total of 129 (15.6%) patients had severe COVID-19, 113 (13.7%) required ICU admission after a median of 1 day (IQR 0–3 days), 64 (7.7%) required orotracheal intubation, and 43 (5.2%) died.

Table 1.

Basal characteristics and differences between severe and non-severe COVID-19, bivariate analysis.

Basal characteristics  TotalN=829  Severe COVID-19*,129 (15.6)  Non-severe COVID-19,689 (83.1)  Bivariate analysis
        OR  95% CIp 
          Lowest  Highest   
Age, years  57 (44–70)  58 (48–71)  56 (43–69)  1.008  0.997  1.018  0.163 
Gender, male  481 (58.0)  89 (69.0)  387 (56.3)  1.725  1.153  2.579  0.007 
Active smoking  60 (7.2)  11 (8.5)  49 (7.1)  1.214  0.613  2.403  0.578 
Active alcohol intake  122 (14.7)  17 (13.2)  105 (15.3)  0.841  0.485  1.459  0.538 
BMI, kg/m2  28.2 (25.2–31.9)  29.1 (25.2–33.3)  28.2 (25.2–31.9)  1.027  0.996  1.059  0.130 
Charlson Comorbidity Index  2 (0–4)  2 (1–4)  2 (0–3)  1.086  1.003  1.171  0.030 
Comorbidities
Arterial hypertension  325 (39.2)  56 (43.4)  263 (38.2)  1.243  0.849  1.818  0.263 
Dyslipidaemia  185 (22.3)  24 (18.6)  156 (22.6)  0.781  0.484  1.260  0.310 
Heart disease  90 (10.9)  11 (8.5)  59 (8.6)  0.995  0.508  1.951  0.989 
Peripheral vascular disease  21 (2.5)  6 (4.7)  14 (2.0)  2.352  0.887  6.238  0.077 
Cerebrovascular disease  28 (3.4)  6 (4.7)  19 (2.8)  1.720  0.673  4.394  0.263 
Dementia  22 (2.7)  6 (4.7)  15 (2.2)  2.192  0.834  5.759  0.124 
Chronic pulmonary disease  72 (8.7)  10 (7.8)  60 (8.7)  0.881  0.439  1.770  0.722 
Thromboembolic disease  9 (1.1)  1 (0.8)  7 (1.0)  0.761  0.093  6.239  1.000 
Connective tissue disease  11 (1.3)  2 (1.6)  9 (1.3)  1.190  0.254  5.572  0.688 
Diabetes  187 (22.6)  42 (32.6)  141 (20.5)  1.876  1.242  2.833  0.002 
Moderate–severe CRD, Cr >3mg/dL  29 (3.5)  9 (7.0)  19 (2.8)  2.645  1.169  5.984  0.016 
Any tumour without metastasis  34 (4.1)  5 (3.9)  29 (4.2)  0.918  0.348  2.417  0.862 
Metastatic solid tumour  5 (0.6)  1 (0.8)  4 (0.6)  1.338  0.148  12.067  0.577 
Leukaemia  7 (0.8)  2 (1.6)  5 (0.7)  2.154  0.413  11.226  0.305 
Lymphoma  4 (0.5)  0 (0.0)  4 (0.6)  0.000  0.000  –  1.000 
AIDS  4 (0.5)  0 (0.0)  3 (0.4)  0.000  0.000  –  1.000 
Chronic treatments
ARBs  160 (19.3)  26 (20.2)  130 (18.9)  1.085  0.678  1.738  0.733 
ACE inhibitors  110 (13.3)  20 (15.5)  86 (12.5)  1.287  0.759  2.180  0.348 
NSAIDs  45 (5.4)  3 (2.3)  41 (6.05)  0.376  0.115  1.234  0.133 
Corticosteroids  29 (3.5)  2 (1.6)  26 (3.8)  0.402  0.094  1.713  0.292 
Oral antidiabetics  149 (18.0)  29 (22.5)  118 (17.1)  1.403  0.887  2.219  0.146 
Heparin  6 (0.7)  1 (0.8)  5 (0.7)  1.069  0.124  9.224  0.952 
Insulin  61 (7.4)  17 (13.2)  43 (6.2)  2.280  1.256  4.140  0.006 
Oral anticoagulants  47 (5.7)  11 (8.5)  32 (4.6)  1.914  0.939  3.903  0.070 
Statins  165 (19.9)  20 (15.5)  139 (20.2)  0.726  0.435  1.211  0.219 
Proton pump inhibitors  178 (21.5)  23 (17.8)  151 (21.9)  0.773  0.476  1.256  0.298 
Previous GI disease
Peptic ulcer  25 (3.0)  3 (2.3)  20 (2.9)  0.795  0.233  2.716  1.000 
Gastroesophageal reflux  76 (9.2)  7 (5.4)  67 (9.7)  0.530  0.238  1.183  0.115 
Eosinophilic esophagitis  1 (0.1)  0 (0.0)  1 (0.1)  0.000  0.000  –  1.000 
Gastritis/duodenitis  15 (1.5)  0 (0.0)  14 (2.0)  0.000  0.000  –  0.143 
Functional disorders  85 (10.3)  11 (8.5)  70 (10.2)  0.823  0.423  1.601  0.566 
H. pylori-associated disease  34 (4.1)  1 (0.8)  31 (4.5)  0.166  0.022  1.226  0.078 
Chronic liver disease**  47 (5.7)  6 (4.7)  40 (5.8)  0.791  0.328  1.907  0.835 
Symptomatic cholelithiasis  36 (4.4)  3 (2.3)  32 (4.6)  0.489  0.147  1.621  0.342 
Acute cholecystitis  16 (1.9)  1 (0.8)  15 (2.2)  0.351  0.046  2.681  0.490 
Choledocholithiasis  2 (0.2)  0 (0.0)  2 (0.3)  0.000  0.000  –  1.000 
Cholangitis  1 (0.1)  0 (0.0)  1 (0.1)  0.000  0.000  –  1.000 
Acute pancreatitis  4 (0.5)  0 (0.0)  3 (0.4)  0.000  0.000  –  1.000 
Chronic pancreatitis  1 (0.1)  0 (0.0)  1 (0.1)  0.000  0.000  –  1.000 
Celiac disease  1 (0.1)  1 (0.8)  0 (0.0)  8.6×109  0.000  –  1.000 
Diverticulosis/diverticulitis  14 (1.7)  0 (0.0)  13 (1.9)  0.000  0.000  –  0.999 
Inflammatory bowel disease  5 (0.6)  0 (0.0)  5 (0.7)  0.000  0.000  –  1.000 
Cholangiocarcinoma  1 (0.1)  0 (0.0)  1 (0.1)  0.000  0.000  –  1.000 
Hepatocellular carcinoma  1 (0.1)  1 (0.8)  0 (0.0)  8.6×109  0.000  –  1.000 
Colorectal cancer  8 (1.0)  1 (0.8)  7 (1.0)  0.761  0.093  6.239  1.000 

The values in bold are those results that have reached statistical significance (p < 0.05).

Data were missing or unavailable for 11 patients that could not be classified as having severe or non-severe COVID-19.

Qualitative variables expressed as absolute number (%). Quantitative variables expressed as mean and standard deviation (SD) or median and interquartile range (IQR). ACE inhibitors: angiotensin-converting enzyme inhibitors; AIDS: acquired immunodeficiency syndrome; ARBs: angiotensin II receptor blockers; BMI: body mass index; CI: confidence intervals; Cr: creatinine; CRD: chronic renal disease; H. pylori: Helicobacter pylori; IQR: interquartile range; NSAIDs: non-steroidal anti-inflammatory drugs; OR: odds ratio.

*

Severe COVID-19 was defined as the need for ICU admission, need for mechanical ventilation, and/or mortality during hospitalization.

**

Types of chronic liver disease prior to COVID-19: non-alcoholic fatty liver disease 27 (42.6%); alcoholic liver disease 6 (12.8%), chronic VHB liver disease 8 (18.0%); chronic VHC liver disease 6 (12.8%); primary biliary cholangitis 1 (2.1%); idiopathic liver disease 2 (4.3%).

Prevalence, intensity, and evolution of GI symptoms due to COVID-19

All patients presented in the emergency room due to fever and/or respiratory symptoms. Upon admission, 660 (73.3%) patients had at least one GI symptom, and 406 (49.0%) had two or more GI symptoms, when anorexia was considered a GI symptom. When excluding anorexia, 544 (65.6%) patients had at least one GI symptom and 299 (36.1%) presented two or more. All GI symptoms, except constipation, were more frequent at admission compared to baseline (before COVID-19) (Table 2). The most prevalent GI symptoms at admission were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%) (Table 2). Patients who reported diarrhoea had a median of 3 bowel movements/day (IQR 2–4), with a mean Bristol scale consistency of 6 (IQR 5–6). Patients with constipation had a median of 1 bowel movement/day (IQR 0–1), with a mean Bristol scale consistency of 2 (IQR 1–4). In most cases, the intensity of GI symptoms was mild or moderate (Table 2). In general, the prevalence and intensity of GI symptoms were maximal at admission and progressively decreased, returning to baseline pre-COVID-19 status between discharge and 15 days post-discharge (Fig. 1 and Table 2). GI symptoms at baseline did not significantly differ from those at discharge, between discharge and 15 days post-discharge, or at 15 days after discharge—with the exception that the frequency of diarrhoea was lower at 15 days after discharge compared to at baseline.

Table 2.

Frequency and intensity of gastrointestinal symptoms.

Symptoms  TotalN (%)  MildN (%)  ModerateN (%)  SevereN (%)  p valuea 
Diarrhoea
Before COVID-19  55 (6.6)  34 (4.1)  18 (2.2)  3 (0.4)   
At admission  327 (39.4)  169 (20.3)  128 (15.4)  30 (3.6)  <0.001 
During hospitalization  263 (31.7)  174 (21.0)  82 (9.9)  7 (0.8)  <0.001 
At discharge  74 (8.1)  67 (8.1)  7 (0.9)  0 (0.0)  1.0 
From discharge to 15 days post-discharge  64 (7.7)  52 (6.3)  11 (1.3)  1 (0.1)  1.0 
15 days post-discharge  33 (4.0)  29 (3.5)  3 (0.4)  1 (0.1)  0.01 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 21 (2.5%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Constipation
Before COVID-19  71 (8.6)  42 (5.1)  22 (2.7)  7 (0.8)   
At admission  71 (8.6)  29 (3.5)  36 (4.3)  6 (0.7)  1.0 
During hospitalization  117 (14.1)  53 (6.4)  48 (5.8)  16 (1.9)  <0.001 
At discharge  87 (10.5)  56 (6.8)  22 (2.7)  9 (1.1)  1.0 
From discharge to 15 days post-discharge  71 (8.6)  48 (5.8)  13 (1.6)  10 (1.2)  1.0 
15 days post-discharge  47 (5.7)  29 (3.5)  15 (1.8)  3 (0.4)  1.0 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 22 (2.7%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Nausea & vomiting
Before COVID  30 (3.6)  21 (2.5)  8 (1.0)  1 (0.1)   
At admission  227 (27.4)  134 (16.2)  75 (9.0)  18 (2.2)  <0.001 
During hospitalization  140 (16.9)  104 (12.5)  32 (3.9)  4 (0.5)  <0.001 
At discharge  32 (3.9)  28 (3.4)  4 (0.5)  0 (0.0)  1.0 
From discharge to 15 days post-discharge  34 (4.1)  28 (3.4)  4 (0.5)  2 (0.2)  1.0 
15 days post-discharge  20 (2.4)  18 (2.2)  1 (0.1)  1 (0.1)  0.3 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 22 (2.7%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Abdominal pain
Before COVID  47 (5.7)  37 (4.5)  6 (0.7)  4 (0.5)   
At admission  172 (20.7)  92 (11.1)  63 (7.6)  17 (2.1)  <0.001 
During hospitalization  141 (17.0)  96 (11.6)  41 (4.9)  4 (0.5)  <0.001 
At discharge  38 (4.6)  30 (3.6)  8 (1.0)  0 (0.0)  1.0 
From discharge to 15 days post-discharge  55 (6.6)  44 (5.3)  7 (0.8)  4 (0.5)  1.0 
15 days post-discharge  30 (3.6)  21 (2.5)  8 (1.0)  1 (0.1)  0.9 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 22 (2.7%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Anorexia
Before COVID  73 (8.8)  50 (6.0)  15 (1.8)  8 (1.0)   
At admission  413 (49.8)  143 (17.2)  162 (19.5)  108 (13.0)  <0.001 
During hospitalization  339 (40.9)  154 (18.6)  145 (17.5)  40 (4.8)  <0.001 
At discharge  181 (21.8)  140 (16.9)  30 (3.6)  11 (1.3)  1.0 
From discharge to 15 days post-discharge  113 (13.6)  85 (10.3)  23 (2.8)  5 (0.6)  1.0 
15 days post-discharge  49 (5.9)  38 (4.6)  9 (1.1)  2 (0.2)  0.04 
Missing data. Before COVID-19: 5 (0.6%); at admission: 4 (0.5%); during hospitalization: 22 (2.7%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Gas/bloating/flatulence
Before COVID  63 (7.6)  51 (6.2)  12 (1.4)  0 (0.0)   
At admission  113 (13.6)  70 (8.4)  39 (4.7)  4 (0.5)  <0.001 
During hospitalization  121 (14.6)  77 (9.3)  37 (4.5)  7 (0.8)  <0.001 
At discharge  65 (7.8)  47 (5.7)  18 (2.2)  0 (0.0)  0.9 
From discharge to 15 days post-discharge  85 (10.3)  76 (9.2)  9 (1.1)  0 (0.0)  0.2 
15 days post-discharge  57 (6.9)  51 (6.2)  6 (0.7)  0 (0.0)  0.9 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 22 (2.7%); at discharge: 23 (2.8%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Odynophagia
Before COVID  9 (1.0)  6 (0.7)  2 (0.2)  1 (0.1)   
At admission  49 (5.9)  28 (3.4)  17 (2.1)  4 (0.5)  <0.001 
During hospitalization  29 (3.5)  20 (2.4)  7 (0.8)  2 (0.2)  0.02 
At discharge  18 (2.2)  12 (1.4)  5 (0.6)  1 (0.1)  0.6 
From discharge to 15 days post-discharge  6 (0.7)  3 (0.4)  2 (0.2)  1 (0.1)  1.0 
15 days post-discharge  6 (0.7)  4 (0.5)  2 (0.2)  0 (0.0)  1.0 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 23 (2.8%); at discharge: 24 (2.9%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Heartburn/gastroesophageal reflux
Before COVID  41 (4.9)  35 (4.2)  6 (0.7)  0 (0.0)   
At admission  61 (7.4)  38 (4.6)  19 (2.3)  4 (0.5)  <0.001 
During hospitalization  51 (6.2)  38 (4.6)  11 (1.3)  2 (0.2)  0.5 
At discharge  35 (4.2)  27 (3.3)  8 (1.0)  0 (0.0)  1.0 
From discharge to 15 days post-discharge  43 (5.2)  32 (3.9)  8 (1.0)  3 (0.4)  1.0 
15 days post-discharge  34 (4.1)  23 (2.8)  9 (1.1)  2 (0.2)  1.0 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 23 (2.8%); at discharge: 24 (2.9%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).
Dysphagia
Before COVID  8 (1.0)  5 (0.6)  3 (0.4)  0 (0.0)   
At admission  22 (2.7)  11 (1.3)  9 (1.1)  2 (0.2)  0.003 
During hospitalization  28 (3.5)  16 (1.9)  9 (1.1)  3 (0.4)  0.003 
At discharge  21 (2.5)  16 (1.9)  4 (0.5)  1 (0.1)  0.08 
From discharge to 15 days post-discharge  10 (1.2)  9 (1.1)  1 (0.1)  0 (0.0)  0.2 
15 days post-discharge  7 (0.9)  6 (0.7)  1 (0.1)  0 (0.0)  0.6 
Missing data. Before COVID-19: 4 (0.5%); at admission: 3 (0.4%); during hospitalization: 23 (2.8%); at discharge: 24 (2.9%); from discharge to 15 days post-discharge: 71 (8.6%); at 15 days post-discharge: 71 (8.6%).

The values in bold are those results that have reached statistical significance (p < 0.05).

a

Pairwise comparisons using Wilcoxon signed-rank test with continuity correction: each symptom during COVID-19 was compared to the pre-COVID-19 baseline presence of the symptom. Qualitative variables expressed as absolute number (%). Intensity during hospitalization and from discharge to 15 days post-discharge: higher intensity reported by the patient during those periods.

Figure 1.

Frequency of gastrointestinal symptoms, from pre-COVID-19 baseline presence of the symptoms (baseline) to 15 days post-discharge.

(0.19MB).
Development of GI complications due to COVID-19

GI complications were infrequent—except for acute liver injury or worsening of previous liver disease, which was present in 267 (32.1%) patients, 251 (94.0%) of whom already had it upon admission (supplementary content 2). Among the patients with liver damage, 238 (89.1%) presented mild hypertransaminasemia, 29 (10.9%) severe hypertransaminasemia, 246 (29.7%) elevated enzymes of cholestasis, 17 (6.4%) any increase of bilirubin level, and 2 (0.7%) an INR increase to >1.5IU (not related to liver failure). Patients with liver injury exhibited the following median maximum values of liver laboratory parameters: aspartate-aminotransferase (AST) 63 (IQR 44–108)U/L, alanine-aminotransferase (ALT) 73 (IQR 50–135)U/L, gamma-glutamyl transpeptidase (GGT) 144 (IQR 102–267)U/L, alkaline phosphatase (AF) 146 (IQR 124–202)U/L, and bilirubin 1.6 (IQR 1.3–2.0)mg/dL. No patient developed acute liver failure. Supplementary content 2 summarizes other exceptional GI complications that occurred and their suspected causes.

Association between GI symptoms/complications and COVID-19 severity

Table 1 summarizes the baseline characteristics associated with severe COVID-19. Bivariate analysis revealed that severe COVID-19 was associated with dysphagia (OR 4.384; 95% CI 1.899–10.118; p<0.001), odynophagia (OR 10.182; 95% CI 4.637–22.356; p<0.001), and liver injury (OR 1.762; 95% CI 1.200–2.587; p=0.004). In contrast, non-severe COVID-19 was associated with the presence of ≥2 gastrointestinal symptoms upon admission (OR 0.679; 95% CI 0.464–0.995; p=0.046) and diarrhoea during hospitalization after adjustment for baseline diarrhoea (OR 0.531; 95% CI 0.328–0.860; p=0.009) (Table 3).

Table 3.

Associations of symptoms and complications and other outcome variables with COVID-19 severity; bivariate analysis.

Variables  TotalN=829 (%)  Severe COVID-19*,129 (15.6%)  Non severe COVID-19,689 (83.1%)  Bivariate analysis
        OR  95% CIp 
          Lowest  Highest   
Treatments
Hydroxychloroquine  42 (5.1)  3 (2.3)  39 (5.7)  0.396  0.121  1.302  0.131 
Azithromycin  331 (39.9)  65 (50.4)  265 (38.5)  1.621  1.111  2.365  0.012 
Lopinavir/ritonavir  82 (9.9)  7 (5.4)  75 (10.9)  0.469  0.211  1.042  0.058 
Tocilizumab  81 (9.8)  16 (12.4)  65 (9.4)  1.357  0.758  2.430  0.303 
Anakinra  3 (0.4)  2 (1.6)  1 (0.1)  10.819  0.974  120.206  0.067 
Steroids  549 (66.2)  115 (89.1)  429 (62.3)  4.959  2.788  8.820  <0.001 
GI symptoms at admission
1 GI symptom  616 (74.3)  98 (76.0)  510 (74.0)  1.097  0.708  1.701  0.679 
≥2 GI symptoms  406 (49.0)  53 (41.1)  348 (50.5)  0.679  0.464  0.995  0.046 
Type of GI symptom
Abdominal pain  123 (14.8)  17 (13.2)  105 (15.2)  0.919  0.528  1.599  0.765 
Nausea/vomiting  128 (15.5)  13 (10.1)  112 (16.3)  0.626  0.340  1.153  0.130 
Anorexia  298 (35.9)  48 (37.2)  248 (36.0)  1.186  0.796  1.766  0.401 
Diarrhoea  237 (28.6)  23 (17.8)  213 (30.9)  0.531  0.328  0.860  0.009 
Constipation  90 (10.9)  11 (8.5)  79 (11.5)  0.780  0.402  1.514  0.462 
Gas/bloating/flatulence  92 (11.1)  9 (7.0)  81 (11.8)  0.609  0.297  1.249  0.172 
Dysphagia  24 (2.9)  10 (7.8)  14 (2.0)  4.384  1.899  10.118  <0.001 
Odynophagia  28 (3.4)  17 (13.2)  11 (1.6)  10.182  4.637  22.356  <0.001 
Heartburn/GE reflux  34 (4.1)  6 (4.7)  28 (4.1)  1.242  0.503  3.067  0.638 
Respiratory symptoms
Dyspnoea  430 (51.9)  101 (78.3)  329 (47.8)  5.736  3.436  9.576  <0.001 
Cough  480 (57.9)  89 (69.0)  390 (56.6)  2.172  1.404  3.358  <0.001 
Expectoration  147 (17.7)  33 (25.6)  114 (16.5)  1.900  1.213  2.95  0.005 
Other non-GI symptoms
Ageusia  195 (23.5)  26 (21.7)  167 (24.4)  0.856  0.536  1.367  0.516 
Anosmia  177 (21.4)  22 (18.3)  154 (22.5)  0.773  0.470  1.269  0.307 
Disorientation  75 (9.0)  35 (29.2)  40 (5.8)  6.640  4.000  11.023  <0.001 
Decreased level of consciousness  71 (8.6)  37 (30.8)  34 (5.0)  8.535  5.081  14.337  <0.001 
Headache  228 (27.5)  37 (30.8)  190 (27.7)  1.161  0.762  1.771  0.487 
Myalgia  254 (30.6)  32 (26.7)  221 (32.3)  0.763  0.494  1.180  0.223 
Skin lesions  25 (3.0)  2 (1.7)  23 (3.4)  0.488  0.114  2.097  0.565 
Fever  259 (31.2)  59 (49.2)  200 (29.2)  2.345  1.582  3.478  <0.001 
Liver damage, SOFA score, and CRP
Liver damage  267 (32.2)  56 (43.4)  209 (30.3)  1.762  1.200  2.587  0.004 
Deep vein thrombosis  7 (0.8)  3 (2.3)  4 (0.6)  4.077  0.902  18.438  0.083 
Pulmonary thromboembolism  26 (3.1)  4 (3.1)  22 (3.2)  0.970  0.329  2.864  1.000 
New onset arrhythmia  15 (1.8)  8 (6.2)  7 (1.0)  6.442  2.294  18.091  0.001 
SOFA score (points)  1 (0–2)  4 (2–6)  1 (0–2)  6.852  5.025  9.344  <0.001 
CRP mg/dL  6.3 (2.0–14.0)  12.7 (5.3–24.5)  5.6 (1.7–12.4)  1.010  1.003  1.017  <0.001 
Hospital stay length
Hospital stay length  8 (5–12)  13 (9–20)  7 (5–10)  1.112  1.083  1.143  <0.001 

The values in bold are those results that have reached statistical significance (p < 0.05).

Data were missing or unavailable data for 11 patients who could not be classified as having severe or non-severe COVID-19.

GI symptoms were adjusted by the baseline pre-COVID-19 presence of the symptoms, eliminating those cases in which the symptom presented before COVID-19. Qualitative variables expressed as absolute number (%). Quantitative variables expressed as mean and standard deviation (SD) or median and interquartile range (IQR). CI: confidence interval; CRP: C-reactive protein; GE reflux: gastroesophageal reflux; GI: gastrointestinal; OR: odds ratio; SOFA score: sepsis-related organ failure assessment score.

*

Severe COVID-19 was defined as a need for ICU admission, need for mechanical ventilation, and/or mortality during hospitalization.

Despite the associations revealed by bivariate analysis, multivariate analysis evaluating hospital outcomes showed that only odynophagia during hospitalization was an independent risk factor for ICU admission (aOR 7.038; 95% CI 1.900–26.068; p=0.003) and mortality (aOR 9.942; 95% CI 1.523–64.875; p=0.016) (Tables 4 and 5). GI symptoms and complications were not independently associated with hospital stay (p>0.05) (Table 6).

Table 4.

Multivariate analysis assessing the association between intensive care unit admission and possible determinants.

Need for ICU admission, N=113 (13.7%)
  ICU  Not ICU  Bivariate  Multivariate
      p  aOR  95% CIp 
          Lowest  Highest   
Age, years  55 (47–66)  57 (43–70)  0.510  0.982  0.954  1.010  0.209 
Sex, male  79 (70.5)  399 (56.3)  0.004  0.895  0.471  1.701  0.735 
Charlson Index, points  2 (1–4)  2 (0–4)  0.673  0.846  0.666  1.073  0.167 
BMI, kg/m2  29.3 (25.5–33.6)  28.1 (25.2–31.8)  0.035  1.031  0.983  1.080  0.207 
Alcohol intake  15 (13.3)  107 (15.1)  0.614  0.944  0.405  2.198  0.893 
Smoking  10 (8.8)  50 (7.1)  0.495  0.932  0.292  2.972  0.905 
Abdominal pain  12 (11.5)  111 (15.8)  0.258  0.604  0.225  1.624  0.318 
Nausea/vomiting  11 (10.6)  117 (16.7)  0.113  0.515  0.202  1.311  0.164 
Anorexia  40 (38.5)  258 (36.8)  0.744  0.859  0.457  1.613  0.636 
Diarrhoea  21 (20.2)  216 (30.7)  0.028  0.938  0.447  1.969  0.866 
Constipation  8 (7.7)  82 (11.7)  0.228  0.784  0.296  2.076  0.624 
Abdominal bloating  7 (6.7)  85 (12.1)  0.108  0.386  0.111  1.342  0.134 
Dysphagia  9 (8.7)  15 (2.1)  0.002  2.835  0.818  9.831  0.100 
Odynophagia  15 (14.4)  13 (1.9)  <0.001  7.038  1.900  26.068  0.003 
Heartburn/reflux  5 (4.8)  29 (4.1)  0.792  0.565  0.137  2.325  0.429 
Dyspnoea  87 (82.9)  343 (48.9)  <0.001  2.878  1.342  6.172  0.007 
Cough  76 (72.4)  404 (57.5)  0.004  0.943  0.469  1.896  0.869 
Expectoration  26 (24.8)  121 (17.2)  0.061  0.789  0.353  1.764  0.564 
Liver damage  51 (46.4)  214 (30.2)  0.001  1.013  0.540  1.899  0.968 
SOFA score, points  4 (2–6)  1 (0–2)  <0.001  5.115  3.494  7.486  0.000 
CRP, mg/dL  14.2 (7.8–25.1)  5.5 (1.7–12.4)  <0.001  1.010  1.002  1.018  0.014 

The values in bold are those results that have reached statistical significance (p < 0.05).

Analysis included 751 patients with no missing data for any of the variables. R2 Nagelkerke: 50.1%.

GI symptoms were adjusted by the baseline pre-COVID-19 presence of the symptoms, eliminating cases in which the symptom presented before COVID-19. Qualitative variables expressed as absolute number (%). Quantitative variables expressed as mean and standard deviation (SD) or median and interquartile range (IQR). Sex representing the biological sex. BMI: body mass index; CI: confidence intervals; CRP: C-reactive protein; OR: odds ratio; SOFA score: sepsis-related organ failure assessment score.

Table 5.

Multivariate analysis assessing the association between mortality and possible determinants.

Mortality during hospitalization, N=43 (5.2%)
  Death  Not death  Bivariate  Multivariate
      p  aOR  95% CIp 
          Lowest  Highest   
Age, years  72 (58–85)  56 (43–68)  <0.001  1.098  1.041  1.159  0.001 
Sex, male  32 (74.4)  446 (57.5)  0.028  4.343  1.072  17.600  0.040 
Charlson Index, points  4 (2–6)  2 (0–3)  <0.001  1.030  0.954  1.112  0.445 
BMI, kg/m2  27.2 (24.8–30.2)  28.4 (25.3–32.0)  0.162  1.002  0.883  1.138  0.976 
Alcohol intake  2 (4.7)  120 (15.5)  0.049  0.496  0.070  3.487  0.481 
Smoking  5 (11.6)  55 (7.1)  0.235  8.901  0.817  96.925  0.073 
Abdominal pain  7 (19.4)  115 (15.0)  0.467  0.517  0.066  4.053  0.530 
Nausea/vomiting  4 (11.1)  121 (15.8)  0.638  1.102  0.175  6.957  0.918 
Anorexia  11 (30.6)  285 (37.2)  0.419  0.278  0.068  1.134  0.074 
Diarrhoea  8 (22.2)  228 (29.7)  0.336  4.221  0.960  18.563  0.057 
Constipation  2 (5.6)  88 (11.5)  0.416  0.799  0.100  6.374  0.832 
Abdominal bloating  0 (0.0)  90 (11.7)  0.026  0.000  0.000  –  0.996 
Dysphagia  0 (0.0)  24 (3.1)  0.620  0.000  0.000  –  0.997 
Odynophagia  5 (13.9)  23 (3.0)  0.006  9.942  1.523  64.875  0.016 
Heartburn/reflux  0 (0.0)  34 (4.4)  0.395  0.000  0.000  –  0.997 
Dyspnoea  33 (91.7)  397 (51.7)  <0.001  9.339  1.278  68.235  0.028 
Cough  28 (77.8)  451 (58.6)  0.022  2.520  0.531  11.951  0.245 
Expectoration  9 (25.0)  138 (17.9)  0.284  0.919  0.221  3.821  0.907 
Liver damage  20 (46.5)  247 (31.7)  0.044  0.705  0.195  2.555  0.595 
SOFA score, points  6 (4–6)  1 (0–2)  <0.001  6.448  3.479  11.951  <0.001 
CRP, mg/dL  9.8 (3.1–18.1)  6.2 (2.0–13.6)  0.057  0.937  0.878  1.000  0.050 

The values in bold are those results that have reached statistical significance (p < 0.05).

Analysis included 751 patients with no missing data for any of the variables. R2 Nagelkerke: 65.8%.

GI symptoms were adjusted by the baseline pre-COVID-19 presence of the symptoms, eliminating cases that presented the symptom before COVID-19. Qualitative variables expressed as absolute number (%). Quantitative variables expressed as mean and standard deviation (SD) or median and interquartile range (IQR). Sex representing the biological sex. BMI: body mass index; CI: confidence interval; CRP: C-reactive protein; OR: odds ratio; SOFA score: sepsis-related organ failure assessment score.

Table 6.

Bivariate and multivariate analyses assessing the association between length of hospital stay and possible determinants.

Length of hospitalization >8 days, N=347 (41.9%)
  >8 days  <8 days  Bivariate  Multivariate
      p  aOR  95% CIp 
          Lowest  Highest   
Age, years  61 (49–73)  54 (41–66)  <0.001  1.011  1.000  1.022  0.042 
Sex, male  207 (60.0  269 (56.9)  0.370  0.908  0.647  1.273  0.574 
Charlson Index, points  2 (1–4)  1 (0–3)  <0.001  1.019  0.973  1.067  0.429 
BMI, kg/m2  28.2 (25.2–31.9)  28.3 (25.3–32.0)  0.916  1.013  0.986  1.042  0.344 
Alcohol intake  40 (11.6)  82 (17.3)  0.022  0.662  0.410  1.067  0.090 
Smoking  20 (5.8)  40 (8.5)  0.147  0.698  0.356  1.372  0.297 
Abdominal pain  47 (14.1)  76 (16.1)  0.430  0.860  0.525  1.408  0.549 
Nausea/vomiting  49 (14.7)  79 (16.7)  0.429  0.790  0.489  1.275  0.334 
Anorexia  123 (36.9)  175 (37.1)  0.968  0.995  0.700  1.414  0.976 
Diarrhoea  90 (26.9)  147 (31.1)  0.204  1.086  0.747  1.579  0.664 
Constipation  35 (10.5)  55 (11.7)  0.602  0.714  0.421  1.209  0.210 
Abdominal bloating  35 (10.5)  57 (12.1)  0.482  0.786  0.453  1.363  0.392 
Dysphagia  16 (4.8)  8 (1.7)  0.011  2.020  0.753  5.416  0.163 
Odynophagia  18 (5.4)  10 (2.1)  0.012  2.152  0.817  5.670  0.121 
Heartburn/reflux  17 (5.1)  17 (3.6)  0.296  1.543  0.713  3.336  0.271 
Dyspnoea  203 (60.6)  227 (48.1)  <0.001  1.360  0.957  1.934  0.086 
Cough  186 (55.5)  294 (62.2)  0.059  0.573  0.400  0.821  0.002 
Expectoration  65 (19.4)  82 (17.3)  0.453  1.119  0.712  1.760  0.626 
Liver damage  127 (37.0)  137 (29.0)  0.015  1.202  0.844  1.711  0.308 
SOFA score, points  2 (0–2)  1 (0–1)  <0.001  1.953  1.551  2.460  <0.001 
CRP, mg/dL  7.3 (2.4–16.2)  5.7 (1.7–12.4)  0.002  1.004  0.997  1.010  0.255 

The values in bold are those results that have reached statistical significance (p < 0.05).

Analysis included 751 patients with no missing data for any of the variables. R2 Nagelkerke:17.8%.

GI symptoms were adjusted by the baseline pre-COVID-19 presence of the symptoms, eliminating cases in which the symptom presented before COVID-19. Qualitative variables expressed as absolute number (%). Quantitative variables expressed as mean and standard deviation (SD) or median and interquartile range (IQR). Sex representing the biological sex. BMI: body mass index; CI: confidence intervals; CRP: C-reactive protein; OR: odds ratio; SOFA score: sepsis-related organ failure assessment score.

A sub-analysis performed to evaluate possible confounding factors revealed that patients who presented with odynophagia and dysphagia during hospitalization (after adjustment for pre-COVID-19 symptoms) more frequently required orotracheal intubation during hospitalization: 8 (28.6%) patients with odynophagia versus 47 (6.0%) without odynophagia, and 8 (33.3%) patients with dysphagia versus 47 (6.0%) without dysphagia (p<0.05). In contrast, odynophagia and dysphasia at admission did not predict poorer hospital outcomes (data not shown).

Discussion

To our knowledge, this is one of the first international prospective observational study designed specifically to evaluate the frequency of GI symptoms and complications in patients hospitalized due to COVID-19. We have particularly focused on assessing the presence of pre-COVID-19 GI symptoms, the patient-reported intensity of GI symptoms, and monitoring the evolution of these symptoms throughout the disease.

The most frequent COVID-19-related GI symptoms were anorexia, diarrhoea, nausea/vomiting, and abdominal pain, as previously published.2-5,20,21 However, our cohort presented a higher frequency of GI symptoms than has been earlier described in hospitalized patients. Among our patients, 74.3% presented at least one GI symptom, and 49.0% with two or more GI symptoms at the time of admission. In contrast, early retrospective published studies report prevalence rates of ∼10%,2-4,21 and later publications report prevalence rates of up to 50%.5,20 This disparity could be explained by previous studies’ logical focus on respiratory symptoms, as well as their retrospective nature, with a bias towards more severe GI symptoms (as milder ones would not be included on clinical records), and the inherent design drawbacks of frequent data loss, low-quality assessments, and short follow-up.

Consistent with our results, among the few published prospective studies, the prevalence of GI symptoms were similar to ours. Thus, the prospective case–control studies by Marasco et al.,22 including 871 patients (575 COVID+ and 296 COVID−), and Chen et al.,23 including 340 patients (101 COVID+ and 239 COVID−), showed a significantly higher prevalence of GI symptoms (p<0.001 both studies) in COVID-19 patients. This way, the prevalence of GI symptoms was 59.7% in the study by Marasco et al. vs 65.6% in our study (anorexia was not included as a symptom); and 74% in the study by Chen et al. vs 74.3% in ours (anorexia was included as a symptom). Although in this second study most of the patients were not hospitalized (different population), it is an obvious example of higher prevalence of GI symptoms reported in prospective studies focus specifically in them. By comparison, another Moroccan study involving 713 patients with COVID-19 described lower prevalences of GI symptoms (14.3%). In this case, the results are likely to be biased by the population included (64 children, 17 pregnant women, 30-years mean age of the cohort).24

Besides, in our study GI symptoms were mostly perceived as mild or moderate, as intuited by Elmunzer et al.,5 tended to resolve early, similar to the study by Marasco et al.,22 and were not associated with severe COVID-19 or worse hospital outcomes (understood as need for ICU admission, longer hospital stay or death). Thus, contrary to speculations of the earliest studies,4 our present findings suggest that GI symptoms are mild manifestations of COVID-19 that do not predict a more aggressive course,5,25 and point that persistent GI symptoms due to COVID-19 are very rare.

Only odynophagia and dysphagia during hospitalization were associated with poorer outcomes. However, a sub-analysis revealed that patients reporting these symptoms more frequently required orotracheal intubation during admission, such that they may be a consequence of this invasive treatment.

Future studies should be directed to elucidate whether these symptoms are due to the direct effect of the virus, secondary aspects of the disease (e.g., odynophagia due to incubation, constipation due to immobility) or adverse effects of the medication.

Regarding GI complications, our study population showed no cases of cholecystitis, pancreatitis, enteritis, duodenitis, cholangitis, debut of inflammatory bowel disease, or GI vascular complications—contrary to the findings of some retrospective studies.12,13,16,17,26–29 Special attention should be paid to acute or worsening liver injury, which affected up to 1/3 of the included patients and mainly presented as mild hypertransaminasemia,3–5 consistent with the suggestions of retrospective studies.10,29,30 Furthermore, bivariate analysis showed that liver injury was more prevalent in patient with severe COVID-19, need for ICU admission, large hospital stay, and mortality. However, when adjusting this condition for other potential confounders, liver injury was not an independent predictor of worse hospital outcomes, in contrast to the suggestions of previous studies.5,10,31,32 It is worth mentioning, Weber et al. found that increased risk of ICU admission was associated with any abnormal liver parameter, after adjusting for age, gender, and relevant comorbidities.32 This difference could be explained by the variables considered in the logistic regression. In our study, these variables also included respiratory symptoms, organ failure, and inflammation, which seem to be the main determinants of disease severity in our cohort. Despite these results, more studies focused on liver damage should be performed to clarify this possible association and the etiopathogenesis of liver injury.

The strengths of this study include its international multicentre nature and its prospective design with a large sample size (higher number of COVID-19 patients included than other prospective studies). Additionally, it was specifically designed to study GI symptoms, assessed using comprehensive questionnaires that enabled proper evaluation of their frequency and intensity as perceived by patients. Finally, the prevalence of GI symptoms at each time point evaluated was compared with the baseline situation of patients, before COVID-19 (not with a control group without COVID, but with other pathologies requiring admission or follow-up in a health centre), allowing us to better discern the magnitude of symptoms caused by COVID-19. A weakness of this study is that the patient sample may be underpowered to detect rare COVID-19 gastrointestinal complications.

In conclusion, GI symptoms were more common than previously documented in hospitalized COVID-19 patients. They mostly presented as mild to moderate and tended to rapidly resolve. Our findings suggest that GI symptoms are a mild manifestation of COVID-19 that do not predict severity. Their isolated presentation as a cause of admission is exceptional, and its persistence outside the acute episode is very rare. Our results also sustain that liver injury is a prevalent complication among hospitalized patients while the rest of digestive complications previously described in the context of COVID-19 seem to be infrequent.

Authors’ contributions

All authors were involved in data acquisition and critical revision of the manuscript. E. de-Madaria and K. Cárdenas-Jaén conceptualized and designed the study. A. Vaillo monitored the study. K. Cárdenas-Jaén, J.J. Mira, A. Mula, I. Carrillo, and E. de-Madaria performed the primary analysis and interpretation of the data. K. Cárdenas-Jaén, S.A. Sánchez-Luna, J.J. Mira, A. Mula, I. Carrillo, and E. de-Madaria prepared the initial draft of the manuscript. All authors have approved the final version of the manuscript.

Funding

This project received financial support from the Alicante Institute for Health and Biomedical Research (ISABIAL) (reference 2020-0355). Karina Cárdenas-Jaén was supported by a Río Hortega research contract from the Instituto de Salud Carlos III, Madrid, Spain, (reference CM19/00157).

Competing interests

The authors declare no conflict of interests for this article.

Appendix A
Supplementary data

The following are the supplementary data to this article:

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