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Original Articles: Gastroenterology

Gastrointestinal symptoms are associated with severity of coronavirus disease 2019: a systematic review and meta-analysis

Zeng, Weibiaoa,,*; Qi, Kaia,,b,,*; Ye, Miaoc,,*; Zheng, Lid; Liu, Xinlianga; Hu, Shenga; Zhang, Wenxionga; Tang, Wenjingb; Xu, Jianjuna; Yu, Donglianga; Wei, Yipinga

Author Information
European Journal of Gastroenterology & Hepatology: February 2022 - Volume 34 - Issue 2 - p 168-176
doi: 10.1097/MEG.0000000000002072

Abstract

Introduction

Coronavirus disease 2019 (COVID-19) is a widespread infectious disease that was first reported in December 2019 [1,2]. As of 12 May 2020, it has infected more than 4 088 848 persons, resulting in 283 153 deaths [3]. The pathogen of COVID-19 is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4], which belongs to the betacoronavirus genus, along with severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus [5,6]. Previous studies have shown that coronaviruses can be transmitted from person to person through droplets and contact [7]. The main symptoms of COVID-19 are fever, cough, sputum, and other upper respiratory symptoms, while gastrointestinal symptoms are relatively uncommon [8–10].

Gastrointestinal symptoms in patients with COVID-19 mainly include diarrhea, abdominal pain, nausea, and vomiting; the incidence reported by different studies varies widely, from 3 to 39% [11,12]. Although most studies have suggested that COVID-19 patients with gastrointestinal symptoms have shown more severe symptoms of pneumonia and taken longer to turn negative for nucleic acid detection [13,14], there have also been some studies showing that such COVID-19 patients are associated with mild illness and lower mortality [10,15]. Due to the low incidence of gastrointestinal symptoms in patients with COVID-19, the sample size of related studies has been limited, so there are still many controversies regarding the relationship between gastrointestinal symptoms and the severity of COVID-19 [16,17]. In this meta-analysis, we reviewed all current evidence to explore the relationship between gastrointestinal symptoms and COVID-19 disease severity by analyzing the severe rate of COVID-19 in patients with gastrointestinal symptoms, and the odds ratio (OR) of association between gastrointestinal symptoms and severe COVID-19.

Methods

This systematic review was registered on PROSPERO and can be accessed at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42020176862. We performed and reported this systematic review and meta-analysis according to the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines [18]. The MOOSE Checklist is provided in Supplementary Table 1, Supplemental digital content 1, https://links.lww.com/EJGH/A659 in supplemental data Files.

Search strategy and selection criteria

Two investigators (Z.L. and L.X.L.) independently carried out a comprehensive systematic search of PubMed, Web of Science, Embase, Science Direct, and Google Scholar to find relevant literature published between 1 December 2019 and 16 October 2020. The details of the search strategy are presented in Supplementary Table 2, Supplemental digital content 1, https://links.lww.com/EJGH/A659 in supplement. In addition, the references of the included articles were searched manually. There were no restrictions on the language of publication: we can fully understand Chinese and English, and we sought the help of professional translators for articles in other languages.

Articles that met the following conditions were included in our study: (1) study types: randomized controlled trials, cross-sectional studies, case-control studies, and cohort studies; (2) subjects: COVID-19 patients with gastrointestinal symptoms, which could be one or more of diarrhea, abdominal pain, nausea, and vomiting; (3) parameters: the severity of COVID-19 needed to be reported in patients with gastrointestinal symptoms. Because Covid-19 severity was not defined consistently across different studies, we defined ‘severe COVID-19’ as either meeting the criteria for severe or critical type according to the Chinese guideline of management of COVID-19 (version 7) [19], or requiring intensive care. Case reports, reviews, and articles on special groups such as children and pregnant women, as well as articles with no available data were excluded. Two researchers (Z.L. and L.X.L.) independently screened the title and abstract of each study and then read the full text to determine whether the study qualified for inclusion. Any disagreement was finally resolved by the third reviewer (W.Y.P.).

Data extraction and paper quality evaluation

Two investigators (T.W.J. and H.S.) independently screened and extracted all the documents from included studies. The contents of data extraction included lead author, time of publication, country, information about the study population (the total sample size, the number of COVID-19 patients with gastrointestinal symptoms, and the number of patients with severe disease), and information related to the risk-of-bias assessment. The quality of all the included studies was scored independently by the two reviewers using the Newcastle–Ottawa Scale (NOS) [20]. NOS analyzed selection, comparability, and results to evaluate the quality of the study. The full score is 9, a total score of 8 or 9 indicates high quality, and a total score of 6 or 7 indicates medium quality. Disagreements were resolved by consensus. The disagreements between two investigators were resolved through discussion or through help from the third investigator (W.Y.P.).

Statistical analysis

All analyses were performed using Stata version 15. The Cochran Chi-square test and I2 were used to evaluate the heterogeneity of studies. We use a random-effects model for combined analysis when calculating the severe rate of COVID-19 patients with each gastrointestinal symptom and its 95% confidence interval (CI). When we calculated the OR of association between each gastrointestinal symptom and severe COVID-19, a fixed-effects model was selected if I2 ≤ 50% and P > 0.1, which indicated that the heterogeneity was acceptable, whereas a random-effects model was used if I2 > 50% or P < 0.1, which indicated that the heterogeneity was obvious. Sensitivity analysis was done to identify the stability of the overall results with regard to the contribution from each study. The subgroup analysis considered the effects of study region and study type on the relationship between diarrhea and the severity of COVID-19. Publication bias was assessed by funnel plot asymmetry and Egger’s test [21,22]. P < 0.05 was considered statistically significant.

Results

Study selection and characteristics

A total of 3351 articles were obtained in the initial examination; 1884 articles were retained after removal of duplicate records, 1740 articles were excluded after reading of titles and abstracts, and 122 articles were excluded after full-text reading. Of the latter, 31 articles were case reports, 59 articles did not have data on severity, and 33 articles did not provide extractable data. Finally, 21 articles [9,13,15,23–39] with a total of 5285 COVID-19 patients were included in our analysis (Fig. 1): 15 of these articles were case-control studies, five were cohort studies, and one was a cross-sectional study. Most of the selected studies were from China, one from the United States, one from Mexico and one from Egypt. Sample sizes ranged from 29 to 1099 patients. The patient characteristics and demographic data included in each study are shown in Table 1, and the specific data for each gastrointestinal symptom are shown in Supplementary Table 3, Supplemental digital content, https://links.lww.com/EJGH/A659 in supplemental data files.

Table 1. - Characteristics and demographic data of the included studies
Author Year Country Study type Age (years) Male/female Total cases Gastrointestinal
symptoms
NOS score
C.Huang 2020 China Case-control study Median age 49 30/11 41 1 9
D.Wang 2020 China Case-control study Median Age 56 75/63 138 1234 9
G.Zhang 2020 China Case-control study Median age 55 108/113 221 12 7
JJ.Zhang 2020 China Case-control study Median age 57 69/72 140 1234 9
L.Mao 2020 China Case-control study Mean age 52.7 87/127 214 12 9
L.Pan 2020 China cross-sectional Average age 52.9 55/48 103 124 8
L.Zhang 2020 China Cohort study Median age 60 286/278 564 1 8
Q.Chen 2020 China Case-control study Average age 47.5 79/66 145 1234 7
R.He 2020 China Case-control study Median age 49 79/125 204 1 7
R.Zhang 2020 China Case-control study Mean age 45.4 43/77 120 1 7
W.Guan 2020 China Case-control study Median age 47 639/460 1099 1 9
Y.Wan 2020 China Cohort study Median age 47·5 129/101 230 1 8
Nobel 2020 America Case-control study >18 253/263 516 1 8
Ghweil 2020 Egypt Case-control study Mean age 55.5 48/18 66 1 8
J.Huang 2020 China Case-control study >18 151/157 308 1 9
Ortiz-Brizuela 2020 Mexico Cohort study Median age 43 85/55 140 124 7
L.Yang 2020 China Case-control study Mean age 55 98/102 200 1 8
J.Zhang 2020 China Cohort study Mean age 55.6 321/342 663 1234 9
J.Zhao 2020 China Case-control study Median age 56.0 14/15 29 1 7
Z.Zhong 2020 China Case-control study >10 31/17 48 1 7
S.Zheng 2020 China Cohort study Median age 55 58/38 96 134 9
1 Diarrhea 2 Abdominal pain 3 Nausea 4 vomiting.

F1
Fig. 1.:
Flow diagram of the study selection process.

Quality assessment

All included studies received at least seven points on the NOS. Seven studies scoring 7 were considered of medium quality; six studies scoring 8 and eight studies scoring 9 were considered of high quality. The NOS scoring details are shown in Supplementary Table 4, Supplemental digital content, https://links.lww.com/EJGH/A659 in supplemental data files.

Diarrhea

A total of 21 studies including 682 COVID-19 patients with diarrhea were reported. Meta-analysis showed that the severe rate of COVID-19 patients with diarrhea was 41.1% (95% CI: 31.0–51.5%), and there was some heterogeneity between the studies (I2 = 78.0%, P = 0, Fig. 2a). Using a random-effects model, the pooled OR of association between diarrhea and severe COVID-19 was 1.41 (95% CI: 1.06–1.89). Heterogeneity was I2 = 50.1%, P = 0.005 (Fig. 2d). The results of sensitivity analysis showed that after excluding the article of Wan et al., [13] the combined result of OR and 95% CI were changed significantly (Fig. 2f). In the meta-analysis conducted after excluding the study by Wan et al., the pooled OR = 1.22 (95% CI: 0.96–1.56), and the heterogeneity also decreased to I2 = 23.4% (Supplementary Figure 2, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files). The above analysis results and the sensitivity analysis results (Fig. 2c and f) showed that the pooled result of OR was not stable. The results of subgroup analysis conducted in different study region showed that, in the study conducted in Wuhan, the severe rate of COVID-19 patients with diarrhea was 41.2% (95%: 30.1–52.7%, I2 = 75.7%, P = 0) (Fig. 3a), the pooled OR of association between diarrhea and severe COVID-19 was 1.11 (95% CI: 0.82–1.49, I2 = 34.2%, P = 0.116) (Fig. 3b). In the study conducted in China outside Wuhan, the severe rate of COVID-19 patients with diarrhea was 58.0% (95%: 31.1–83.0%, I2 = 78.9%, P = 0) (Fig. 3a), the pooled OR of association between diarrhea and severe COVID-19 was 3.17 (95% CI: 2.02–4.96, I2 = 0%, P = 0.470) (Fig. 3b); In the study conducted in outside China, the severe rate of COVID-19 patients with diarrhea was 14.4% (95%: 5.8–25.0%, I2 = 0%, P = 0) (Fig. 3a), the pooled OR of association between diarrhea and severe COVID-19 was 1.23 (95% CI: 0.70–2.14, I2 = 0%, P = 0.773) (Fig. 3b). These results suggested regional differences in the relationship between diarrhea and the severity of COVID-19. No significant difference was found in the subgroup analysis based on the study type (Supplementary Figure 3, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files). No publication bias was found by Egger’s test (P = 0.497; P = 0.269) and funnel plots (Fig. 2b and e).

F2
Fig. 2.:
Meta-analysis for coronavirus disease 2019 (COVID-19) patients with diarrhea: (a) Forest plot of severe rate; (b) Funnel plot of severe rate; (c) Sensitivity analysis of severe rate; (d) Forest plot of odds ratio; (e) Funnel plot of odds ratio; (f) Sensitivity analysis of odds ratio.
F3
Fig. 3.:
Subgroup analysis of the relationship between diarrhea and coronavirus disease 2019 (COVID-19) severity based on study region: (a) Subgroup analysis of severe rate (Mainly from Wuhan, Mainly from outside Wuhan, from outside China); (b) Subgroup analysis of odds ratio (Mainly from Wuhan, Mainly from outside Wuhan, from outside China).

Abdominal pain

A total of 55 COVID-19 patients with abdominal pain were reported in eight studies. The results of meta-analysis showed that there was a high proportion of COVID-19 patients with abdominal pain developing into severe infection (59.3%, 95% CI: 41.3–76.4%), with mild heterogeneity among studies (I2 = 25.4%, P = 0.227) (Fig. 4a). The OR of association between abdominal pain and severe COVID-19, calculated by a fixed-effects model, was 2.76 (95% CI: 1.59–4.81) (Fig. 4c), indicating that there was a significant correlation between abdominal pain and the severity of COVID-19. The heterogeneity between studies was not obvious (I2 = 7.4%, P = 0.373). No significant publication bias was found by Egger’s test (P = 0.169; P = 0.591) and funnel plots (Fig. 4b and d).

F4
Fig. 4.:
Meta-analysis for coronavirus disease 2019 (COVID-19) patients with abdominal pain: (a) Forest plot of severe rate; (b) Funnel plot of severe rate; (c) Forest plot of odds ratio; (d) Funnel plot of odds ratio.

Nausea

Five studies reported 98 COVID-19 patients with symptoms of nausea. About 41.4% (95% CI: 23.2–60.7%, I2 = 67.7%, P = 0.015) of COVID-19 patients with nausea had severe disease (Supplementary Figure 4a, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files), but no correlation between nausea and COVID-19 severity was found (OR = 0.92, 95% CI: 0.59–1.43, I2 = 46.6%, P = 0.112) (Supplementary Figure 4c, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files). The funnel plots (Supplementary Figure 4b, Supplemental digital content 2, https://links.lww.com/EJGH/A660 and Supplementary Figure 4d, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files) and Egger’s test (P = 0.904; P = 0.445) suggested that there was no notable evidence of publication bias.

Vomiting

Seven studies reported 59 patients with COVID-19 who had symptoms of vomiting. The meta-analysis results showed that 51.3% (95% CI: 36.8–65.8%, I2 = 0%, P = 0.450) of patients with vomiting had severe COVID-19 (Supplementary Figure 5a, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files). A fixed-effects model was used to calculate the OR and found that vomiting was not significantly related to the severity of COVID-19 (OR = 1.68, 95% CI: 0.97–3.08, I2 = 0%, P = 0.587) (Supplementary Figure 5c, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files). The funnel plots (Supplementary Figure 5b, Supplemental digital content 2, https://links.lww.com/EJGH/A660 and Supplementary Figure 5d, Supplemental digital content 2, https://links.lww.com/EJGH/A660 in supplemental data files) and Egger’s test (P = 0.477; P = 0.934) showed that there was no publication bias in the study.

Discussion

The widespread spread of COVID-19 has led to a worldwide shortage of medical resources, especially those necessary for critically ill patients such as intensive care and ventilators [40]. Clinical predictors are urgently needed to identify potentially critically ill patients for close monitoring and early intervention before the disease worsens, thereby reducing the morbidity and mortality from COVID-19 and relieving the shortage of medical resources [41]. This meta-analysis provides important evidence for the relationship between gastrointestinal symptoms and the severity of COVID-19. The severe rate was more than 40% in COVID-19 patients with gastrointestinal symptoms, and abdominal pain was associated with a 2.8-fold increased risk of severe COVID-19 infection; the relationship between diarrhea and the severity of COVID-19 was regionally different; the increased risk of nausea and vomiting need to be verified. Considering the incidence of gastrointestinal symptoms, the data from the studies with small sample sizes did not conform to a normal distribution, so we use a random-effects model to pool the severity rate [42]. Sensitivity analysis was carried out on the pooled analysis of each result to make our conclusion robust.

Studies have shown that the surfaces of gastrointestinal cells have high expression levels of the angiotensin-converting enzyme II receptor [43,44]. These cells were easily invaded by coronavirus, resulting in gastrointestinal flora imbalance and inflammation, which leads to gastrointestinal symptoms. Gastrointestinal symptoms have been common in patients with SARS and MERS [45,46] but have been relatively rare and mild in COVID-19 patients. As the number of COVID-19 patients with gastrointestinal symptoms has increased with the spread of the pandemic, attention has been paid to the relationship between gastrointestinal symptoms and the severity of COVID-19. A study of 74 COVID-19 patients with gastrointestinal symptoms found that the disease in these patients was more severe and more contagious [14], and often was accompanied by severe pneumonia symptoms. The report by Wang et al. showed that ICU patients had a higher percentage of gastrointestinal symptoms [26], although other studies have shown that COVID-19 with gastrointestinal symptoms was not associated with a higher incidence of severe pneumonia [9,47]. To accurately evaluate the severe rate of COVID-19 patients with gastrointestinal symptoms, this study separately analyzed the four common gastrointestinal symptoms, including diarrhea, abdominal pain, nausea, and vomiting. The results showed that the severe rates of these four gastrointestinal symptoms were all over 40%, which was significantly higher than the 19.1% reported by the Chinese Center for Disease Control and Prevention [48]. But in the subsequent pooled analysis of OR, we found that only abdominal pain was significantly associated with increased COVID-19 severity, while diarrhea, vomiting, and nausea were not. This suggests that among COVID-19 patients with gastrointestinal symptoms, patients with abdominal pain have a higher risk of developing severe pneumonia, while patients with diarrhea, vomiting, and nausea do not have an elevated risk.

Most studies that reported abdominal pain have observed a close relationship between abdominal pain and severe COVID-19 [24,26]. The mechanism by which COVID-19 patients with gastrointestinal symptoms may be susceptible to severe pneumonia is unclear. The ‘gut-lung axis’, which has been confirmed in influenza infection, may be one of the potential mechanisms [49], which would mean that the virus invades gastrointestinal cells, resulting in changes in the composition and function of gastrointestinal flora, and that these changes affect the respiratory tract through immune regulation. Viral load, gastrointestinal status, and immune function all affect the gut-lung axis. Considering the close relationship between viral load and the severity of COVID-19 [39], we speculate that the viral load in the gastrointestinal tract of patients with abdominal pain is higher than that of COVID-19 patients with diarrhea, nausea, and vomiting [27]. The incidence of abdominal pain is only 0.4% [27], which may be because there must be enough viral load to cause abdominal pain symptoms. Because patients with comorbidities are also prone to abdominal pain, we collected comorbidities of the investigated patients (showed in Supplementary Table 5, Supplemental digital content 1, https://links.lww.com/EJGH/A659) and used a scatter plot to describe the correlation of severe rate between patients with abdominal pain and comorbidities (showed in Supplementary Figure 6, Supplemental digital content 2, https://links.lww.com/EJGH/A660), the results showed that there was no significant correlation between the two. Therefore, we believe that abdominal pain is indeed a sign of subsequent severe disease, rather than a common manifestation in patients with comorbidities.

The incidence of diarrhea was 5–30% [50], and there were 21 studies on diarrhea, more than for any of the other gastrointestinal symptom studies. However, the conclusions of these studies varied widely [23,24]. The appearance of diarrhea symptoms is mainly due to viral invasion of the absorptive epithelial cells in the intestine, where such cells are the most vulnerable, resulting in malabsorption and intestinal secretion disorders [51,52]. In addition, heavy use of antibiotics and antiviral drugs can also cause diarrhea in some patients [53], which are almost impossible to cause abdominal pain. The subgroup analysis of the relationship between diarrhea and COVID-19 severity suggested that comparing with Wuhan, patients with diarrhea in China outside Wuhan had higher severe rate and significantly elevated risk of severe illness, which was an interesting but inexplicable phenomenon. We carefully reviewed these two sets of articles and found that the studies outside Wuhan were later than those in Wuhan. Considering the limited knowledge about the treatment of COVID-19 in the early stage, the more serious condition of patients in Wuhan, and the need for patients to be discharged as soon as possible, Wuhan hospitals may use antibiotics and antiviral drugs more frequently than outside Wuhan hospitals.

We conducted sensitivity analysis to determine the stability of results and the source of heterogeneity. The sensitivity analysis of the pooled results for diarrhea identified the study by Wan et al. as a source of heterogeneity. We found that the study by Wan et al. was a multicenter study involving 10 hospitals, and there were many confounding factors. It included patients in Guangdong, Jiangxi, and other regions, while other studies mostly focused on patient data in Wuhan. The study of Wan et al. is a cohort study, while most of the other studies are case-control studies. These factors may lead to obvious heterogeneity in that result. Our own research also has some inevitable sources of heterogeneity in observational research. First, all of the included studies were retrospective. Second, the studies varied in their definitions of severe COVID-19 and judgment criteria for assessing gastrointestinal symptoms.

Limitations

Several limitations of our meta-analysis need to be pointed out. First, some patients’ gastrointestinal symptoms were caused by factors other than coronaviruses, such as long-term use of antibiotics, ulcerative colitis, and other intestinal underlying diseases. Insufficiency of data to analyze these patients separately limited the quality score of this article. Second, most of the data we have included were from China, and only three studies come from regions outside of China. Studies have reported that the gastrointestinal symptoms of the U.S. population are different from those in Chinese patients [54], so more data from the Americas or Europe are needed to verify our conclusion and clarify how generalizable it is.

Conclusion

The severe rate was more than 40% in COVID-19 patients with gastrointestinal symptoms. Abdominal pain was associated with a 2.8-fold increased risk of severe COVID-19 infection and may be used as clinical predictor of severe COVID-19; the relationship between diarrhea and the severity of COVID-19 was regionally different; nausea and vomiting were limited in their association with severe COVID-19. Our conclusions, based mostly on data from China, call for confirmation or refinement by data from COVID-19 patients with gastrointestinal symptoms in other regions.

Acknowledgements

The authors would like to thank the authors of the studies included for providing additional information.

X.J.J. and W.Y.P. designed the study. Q.K., M.Y. and Z.W.B. interpreted data and wrote the article. Z.L. and L.X.L. screened literature. T.W.J. and H.S. extracted data. Z.W.X. and Y.D.L. conducted statistical analyses. W.Y.P. reviewed the results and made critical comments on the article. All authors approved the final version of the article.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

abdominal pain; COVID-19; diarrhea; gastrointestinal symptoms

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