Introduction
In December 2019, an outbreak of pneumonia caused by a new coronavirus was detected in China, linked to a seafood market in Wuhan [1]. Since then, the virus has spread around the world and the disease caused by this coronavirus disease 2019 (COVID-19) has been declared a global pandemic by the WHO on 11 March 2020 [2]. As of 1 September, over 25 million people had been infected worldwide, including almost 850 thousand deaths [3]. Nevertheless, there is still much that is unknown about this disease.
COVID-19 is usually characterised by respiratory symptoms [4] with some patients developing pneumonia and respiratory failure, hence the new coronavirus being named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, gastrointestinal symptoms have also been reported, ranging from 3 to 79% [5]. In fact, in some patients, digestive symptoms seem to be the presenting clinical picture [6].
Despite several studies from China [7,8] and some from the USA [9,10] describing gastrointestinal manifestations of COVID-19 and its association with outcomes, data from European centres are scarce [11].
The aim of this study was to characterise the gastrointestinal manifestations of a European cohort of COVID-19 patients and their disease course.
Methods
This was a retrospective observational study. Consecutive adult patients with COVID-19 who required hospital admission at our centre during the months of March and April 2020 were included. Diagnosis of COVID-19 was made by identification of SARS-CoV-2 through RT-PCR (commercial kit from Roche, Berlin, Germany) of naso/oropharyngeal swab or sputum. Some patients were already hospitalised at the time of diagnosis for different reasons, but if an accurate report of symptoms was present they were included. All patients without symptoms or those without complete information were excluded.
Patients’ demographics, comorbidities, history of symptoms and laboratory data were collected through a review of electronic clinical records. Patients were divided between those with gastrointestinal symptoms and those without. Day of first gastrointestinal symptoms was defined using the day of all symptom onset as reference. Disease duration until hospital admission was defined as the number of days from the onset of any symptoms until hospital admission. Patients already hospitalised when the diagnosis was made were excluded from this analysis. Gastrointestinal symptom duration was defined as the number of days from onset to resolution of gastrointestinal symptoms. Disease duration was defined as the number of days from any symptom onset until cure. Cure was defined as two negative naso/oropharyngeal swabs, 24 h apart. Patients who died before being cured of COVID-19 were excluded from this analysis. A composite outcome of mechanical ventilation, ICU admission or death was created to define disease severity. Patients who presented none of these criteria were defined as nonsevere.
Statistical analysis
The statistical analysis was performed with IBM SPSS Statistics for Windows, Version 25.0; IBM Corp, Armonk, New York, USA. Continuous variables were presented as median (interquartile range) and categorical variables were presented as frequencies. Association between gastrointestinal symptoms and other variables was performed by the Mann–Whitney test (continuous variables) or chi-square test (categorical variables). Variables found to be associated with severe disease at univariate analysis were included in a logistic regression model to identify independent predictors of severe disease. A P value of 0.05 was considered statistically significant.
Ethics statement and consent
This study was performed in accordance with the Declaration of Helsinki and was approved by the hospital’s health ethics committee. As this was a retrospective study, informed consent was waived by the Data Protection Officer and ethics committee; however, all patient data were carefully anonymised during the data collection and analysis.
Results
A total of 234 patients were admitted to the COVID-19 wards during the study period. Thirty-three patients met the exclusion criteria. The sample was comprised of 201 patients, median age 71 (26) years, with a slight male predominance (56.2%). The sample’s characteristics are depicted in Table 1, as well as differences between patients with and without gastrointestinal symptoms.
Table 1. -
Sample’s characteristics
| Characteristics |
Total |
Gastrointestinal
symptoms |
Nongastrointestinal
symptoms |
P value |
| Age [median years (IQR)] |
71 (26) |
65.5 (24) |
73 (26) |
0.032
|
| Age group (years) |
|
|
|
|
| 18–29 |
3 (1.5%) |
1 (1.7%) |
2 (1.4%) |
|
| 30–39 |
4 (2.0%) |
1 (1.7%) |
3 (2.1%) |
| 40–49 |
16 (8.0%) |
6 (10.0%) |
10 (7.1%) |
| 50–59 |
31 (15.4%) |
12 (20.0%) |
19 (13.5%) |
| 60–69 |
42 (20.9%) |
14 (23.3%) |
28 (19.9%) |
| 70–79 |
30 (14.9%) |
10 (16.7%) |
20 (14.2%) |
| 80–89 |
47 (23.4%) |
11 (18.3%) |
36 (25.5%) |
| 90–99 |
28 (13.9%) |
5 (8.3%) |
23 (16.3%) |
| Sex (male) |
113 (56.2%) |
28 (46.7%) |
85 (60.3%) |
0.075 |
| Comorbidities |
|
|
|
|
| Cardiovascular |
143 (71.1%) |
42 (70.0%) |
101 (71.6%) |
0.815 |
| Respiratory |
37 (18.4%) |
6 (10.0%) |
31 (22.0%) |
0.045
|
| Renal |
20 (10.0%) |
2 (3.3%) |
18 (12.8%) |
0.041
|
| Hepatic |
3 (1.5%) |
0 (0.0%) |
3 (2.1%) |
0.556 |
| Neurologic |
30 (14.9%) |
4 (6.7%) |
26 (18.4%) |
0.032
|
| Diabetes mellitus |
62 (30.8%) |
17 (28.3%) |
54 (31.9%) |
0.615 |
| Disease duration until admission (n = 189) [median days (IQR)] |
7 (7) |
7 (5) |
6 (6) |
0.033
|
| Severe disease |
79 (39.3%) |
17 (28.3%) |
62 (44.0%) |
0.038
|
| Mechanical ventilation |
25 (12.4%) |
9 (15.0%) |
16 (11.3%) |
0.473 |
| ICU admission |
28 (13.9%) |
11 (18.3%) |
17 (12.1%) |
0.240 |
| Death |
55 (27.4%) |
7 (11.7%) |
48 (34.0%) |
0.001
|
| Disease duration (n = 144) [median days (IQR)] |
41 (18.75) |
41 (21) |
41 (17) |
0.957 |
Significant at P < 0.05 in bold.
IQR, interquartile ratio.
Gastrointestinal symptoms
Digestive symptoms were reported by 60 (29.9%) patients during the disease course, being part of the disease presentation in 34 (16.9%). In fact, they were the only symptoms at presentation in 7 (3.5%) patients, without fever or respiratory complaints. The median first day of gastrointestinal symptoms was 1 [4]. Disease duration until hospital admission was significantly longer in gastrointestinal symptoms group compared to nongastrointestinal symptoms [7 (5) days vs. 6 (6) days; P = 0.033]. Patients with digestive symptoms were younger [65.5 (24) vs. 73 (26); P = 0.032) and presented less respiratory (10 vs. 22%; P = 0.045), renal (3.3 vs. 12.8%; P = 0.041) and neurologic (6.7 vs. 18.4%; P = 0.032) comorbidities.
The most frequent symptom reported was diarrhoea (n = 36; 17.9%), followed by vomiting (n = 22; 10.9%), nausea (n = 14; 7%), ageusia (n = 12; 6%) and abdominal pain (n = 10; 5%). Anorexia was present in 60 (29.9%) patients but it was not included in gastrointestinal symptoms group due to its rather unspecific nature. Gastrointestinal symptom median duration was 9 (12) days.
The laboratory data of patients at admission are displayed in Table 2. Patients with gastrointestinal symptoms had higher haemoglobin levels [13.4 (1.8) vs. 12.6 (2.7); P = 0.002] and lower C-reactive protein [82.5 (122) vs. 115.8 (126.6); P = 0.045] and potassium [3.9 (0.5) vs. 4.1 (0.6); P = 0.004] compared with patients without gastrointestinal symptoms.
Table 2. -
Laboratory results at admission
|
Median (IQR) |
Gastrointestinal symptoms |
Nongastrointestinal symptoms |
P value |
| Haemoglobin (g/dL) |
12.9 (2.5) |
13.4 (1.8) |
12.6 (2.65) |
0.002
|
| White blood count (×103/μL) |
6.3 (4.8) |
5.75 (3.75) |
6.6 (5.45) |
0.347 |
| Neutrophile count (×103/μL) |
4.7 (4.8) |
4.25 (4.23) |
4.8 (5.4) |
0.269 |
| Lymphocyte count (×103/μL) |
1.0 (0.7) |
1.0 (0.58) |
1.0 (0.7) |
0.562 |
| Platelet count (×103/μL) |
196 (100) |
194.5 (98.25) |
196 (102.5) |
0.494 |
| CRP (mg/L) |
103.2 (134.5) |
82.5 (121.95) |
115.8 (126.55) |
0.045
|
| LDH (U/L) |
322 (194) |
300.5 (189.25) |
327 (178) |
0.188 |
| D-dimer (ng/mL) |
1087 (2120.5) |
886 (957) |
1364 (2575.5) |
0.062 |
| AST (U/L) |
39.5 (31.25) |
39 (24.25) |
40 (31.25) |
0.377 |
| ALT (U/L) |
31 (30) |
33 (24) |
30.5 (31) |
0.760 |
| ALP (U/L) |
66 (40.5) |
65 (34.75) |
69 (42) |
0.530 |
| Total bilirubin (mg/dL) |
0.54 (0.36) |
0.53 (0.28) |
0.55 (0.41) |
0.577 |
| Creatinine (mg/dL) |
0.8 (0.4) |
0.8 (0.3) |
0.85 (0.5) |
0.080 |
| Serum sodium (mmol/L) |
139 (5) |
138 (5) |
139 (6.75) |
0.438 |
| Serum potassium (mmol/L) |
4 (0.6) |
3.9 (0.5) |
4.1 (0.6) |
0.004
|
Significant at P < 0.05 in bold.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; LDH, lactate dehydrogenase.
In terms of disease severity, defined as mechanical ventilation, ICU admission or death, patients with gastrointestinal symptoms had less severe disease (28.3 vs. 44.0%; P = 0.038), which was due to a lower risk of death (11.7 vs. 34.0%; P = 0.001). Besides gastrointestinal symptoms, age (P < 0.001), cardiovascular disease (P = 0.013), diabetes mellitus (P = 0.007), haemoglobin level (P = 0.001), C-reactive protein (P < 0.001), lactate dehydrogenase (LDH) (P < 0.001), AST (P = 0.002) and creatinine levels (P = 0.008) were associated with severe disease. On multivariate analysis, only lower haemoglobin levels [odds ratio (OR) 0.792; 95% confidence interval (CI), 0.637–0.986; P = 0.032] and higher C-reactive protein (OR 1.006; 95% CI, 1.001–1.010; P = 0.015) and LDH (OR 1.005, 95% CI 1.002-1.008, P = 0.002) were predictors of severe disease.
A total of 144 patients had completed the clinical course fulfilling the criteria of cure. There was no difference in terms of disease duration between patients with digestive symptoms and those without [41 (21) vs. 41 (17); P = 0.957].
Liver injury
Regarding liver damage, AST was elevated during hospitalisation in 131 (65.2%) patients and ALT in 126 (62.7%), although most were only slight elevations. If we consider only the patients whose values were two times the upper limit of normal, then only 66 (32,8%) had this increase in AST and 56 (27,9%) in ALT. Abnormal transaminases were more frequent in male patients (AST P = 0.004; ALT P = 0.001). There was no difference in terms of age, comorbidities or frequency of gastrointestinal symptoms between patients with AST and ALT elevation. Increased AST and ALT were more frequent in ventilated patients (AST – 16.8 vs. 4.5%, P = 0.014; ALT – 18.3 vs. 2.9%, P = 0.002) and those who were admitted to ICU (AST – 19.1 vs. 4.5%, P = 0.005; ALT – 19.8 vs. 4.3%, P = 0.003), but there was no difference regarding death (AST – 26.7 vs. 26.9%, P = 0.982; ALT – 23.8 vs. 30.4%, P = 0.314) or the composite outcome (AST – 43.5 vs. 29.9%, P = 0.062; ALT – 41.3 vs. 33.3%, P = 0.276) between patients with abnormal transaminases and those without.
Discussion
This is one of the first studies to address gastrointestinal manifestations of COVID-19 in Europe. Although the first Eastern studies on this subject reported lower figures [4], growing awareness of these symptoms has probably contributed to increased diagnosis [5]. As high as 79% [12] of patients have been reported to present with digestive symptoms. However, these occasionally include anorexia, which we felt to be a rather ubiquitous symptom, not necessarily a digestive tract affliction, being excluded from the analysis. Consequently, our study found that nearly 30% of patients develop gastrointestinal symptom during the disease course, which is in line with several articles [8,9,13]. A recent meta-analysis [6], including over 6000 patients concluded that 15% present gastrointestinal symptoms. This slightly lower number could be due to the previously mentioned fact that early studies, which reported less gastrointestinal manifestations, were also included in this meta-analysis. In addition, most studies were Chinese, therefore demographical, epidemiological and cultural differences may play a role in explaining these differences. In fact, studies from the USA described higher frequency of gastrointestinal symptoms (35–61%) [9,10], which have been confirmed in European studies (28–59%) [11,14]. We also found that patients with gastrointestinal symptoms were younger, with less comorbidity. This is an interesting finding but should be confirmed in further studies.
Diarrhoea was the main gastrointestinal symptom which is in agreement with numerous studies (once anorexia is excluded) [7,8,10,13,14]. Remarkably, ageusia has drawn some attention, since it seems to be a very specific symptom in the pandemic era, often associated with anosmia [15,16]. In our cohort, 6% of patients reported loss of taste. It is similar to an Eastern study [17], but considerably lower than other European cohorts [16,18]. Besides under-reporting, it is possible that this symptom might be more pronounced in mild to moderate cases which are treated as outpatients, as opposed to hospitalised patients that comprised this study sample. Finally, it is important to emphasise that digestive symptoms are usually present from the beginning of the disease as the median first day of gastrointestinal symptoms was the first day of symptom onset.
Regarding disease severity, we found that patients with digestive symptoms had more frequently a nonsevere clinical course. This seems to be a matter of some controversy. Again, although in initial reports severe disease had higher prevalence of gastrointestinal symptoms [6], a study from the USA found that patients with gastrointestinal symptoms have less risk of severe disease or death [13], while another showed no difference between the two groups [10]. A small Italian study that included only 34 patients positive for COVID-19 also found that patients with digestive symptoms had a better outcome [19]. Moreover, a larger European study reported that gastrointestinal symptoms were inversely associated with the risk of clinical deterioration (ICU or death) [11]. On the other hand, another Italian group reached opposite conclusions, describing gastrointestinal symptoms as a predictor of critical clinical course [14]. Further prospective studies are needed to accurately address this issue. Finally, on multivariate analysis lower haemoglobin levels, higher C-reactive protein and LDH at admission were predictors of severe disease. It is not surprising, since LDH and C-reactive protein are known prognostic markers in COVID-19, and have been included in mortality risk models [20–22].
Since the virus has been detected in stool of infected patients, faecal–oral transmission has also been suggested [23]. However, the clinical significance of this finding is still a matter of debate [24,25]. We did not collect stool samples due to lack of testing capacity.
The frequency of abnormal liver enzymes was quite high in our study. Even though it is difficult to establish comparisons between different studies due to different cutoff values, the rate of liver injury seems to be around 15% [24]. Nevertheless, this is not the first report with such a high number, as the study from New York found that 62% have some degree of liver injury [13].
It is of the utmost importance to deepen the knowledge about COVID-19 in order to diminish the disease burden worldwide. Bearing in mind that gastrointestinal symptoms may be the disease presentation can help reaching an early diagnosis and set up infection control measures to control transmission rate. It is even more important to keep a high level of suspicion in a patient with gastrointestinal complaints and without respiratory symptoms.
This study has several limitations: firstly, its retrospective design, but whenever the lack of information compromised the data accuracy patients were excluded. The sample could be larger, even though it is reasonably well sized to draw some conclusions. In future studies, it would be important to test stool samples for SARS-CoV-2 to clarify the role of faecal-oral transmission of COVID-19.
In conclusion, we found that 30% of patients present gastrointestinal symptoms, which may sometimes be the only complaint early in the disease course. These patients seem to have a less severe disease when compared with patients without gastrointestinal symptoms.
Acknowledgements
T.L. was responsible for the design of the study, acquisition and analysis of the data and drafting of the article. E.C. contributed to data acquisition and analysis and critical revision of the work for important intellectual content. B.A., R.G. and J.A. performed the interpretation of the data for the work and the critical revision of the article for important intellectual content. All authors approved the final version to be published and agreed to be accountable for all aspects of the work.
This article has not been published in its current form or a substantially similar form (in print or electronically, including on a website), has not been accepted for publication elsewhere and is not under consideration by another publication.
Conflicts of interest
There are no conflicts of interest.
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