Prevalence of gastro-intestinal symptoms among COVID-19 patients and the association with disease clinical outcomes

Aim This study examined the various manifestations of COVID-19 in people's gastro-intestinal system and how gastro-intestinal involvement relates to the progression and outcome of the disease. Methodology A questionnaire survey was used to collect data from 561 COVID-19 patients between February 6 and 6 April 2022. Laboratory data and clinical outcomes were obtained from the patients' medical records. Results 39.9% of patients presented gastro-intestinal symptoms, mainly loss of appetite, nausea, vomiting and diarrhea. Gastro-intestinal symptoms were not linked to poorer outcomes such as mortality, ICU admission or length of hospital stays. Conclusion gastro-intestinal symptoms were common among patients and may manifest with respiratory symptoms. We recommended clinicians to watch out for gastro-intestinal symptoms as related to COVID-19 infection.

difficult to put together an effective healthcare system to combat the spreading pandemic. Additionally, a growth in the number of intensive care beds necessitates an increase in the number of mechanical ventilators and other hospital equipment. COVID-19 has affected many other fields than medicine, including travel, manufacturing, schools, and the workforce. Chronic illnesses account for a disproportionate share of deaths and hospitalizations in Jordan. To aid in the early detection of COVID-19 cases and the prevention of future transmission, a better knowledge of its clinical symptoms is necessary.

Study design & data collection
Following clearance from an institutional review board, a prospective cohort research was conducted between 6 February and 6 April 2022, during the fourth wave of SARS-CoV-2 viral propagation in Jordan. The fourth wave of the COVID-19 pandemic began in early 2022. It was said that this wave was embedded within the wave that preceded it. The omicron mutant was responsible for 55% of new infections on January 20 in Jordan [32].. By mid-February, infections escalated vigorously to reach a peak of ∼30 000 cases per day with Omicron variant dominance.
The participants in this research are people aged 18 years or older who were hospitalized at Prince Hamza Hospital for the purposes of treatment and isolation. PCR swab testing was used to make the diagnosis of COVID-19 in those patients. Patients who had had gastro-intestinal surgery in the past, suffered from mental illness, or were less than 18 years old were not included. We interviewed all patients who were eligible for the study and who had signed a consent form, monitored their progress in the hospital, and analyzed the data from all participants.
The patients' demographic characteristics, their presenting symptoms and signs, including their gastro-intestinal symptoms, as well as their clinical and laboratory investigation results were collected. Upon hospital admission, patients were interviewed using a pre-designed, two-part questionnaire. The interview was conducted with the assistance of a trained nurse who collected information such as patient demographics, comorbid conditions, gastro-intestinal symptoms, respiratory symptoms, gustatory symptoms, and olfactory symptoms.
The first part of the questionnaire consisted of patient demographics and their medical and surgical histories, as well as their medication histories. The researchers calculated the patients' BMI based on self-reported height and weight data.
The second part of the questionnaire consisted of a symptom evaluation, and patients were asked about their major complaints. They were also asked whether they experienced any of the listed symptoms. The listed symptoms were divided into three categories, namely: general symptoms; respiratory symptoms; and gastro-intestinal symptoms. The researchers gathered laboratory data and patient clinical outcomes, such as intensive care unit (ICU) admission, the need for intubation and mechanical ventilation, and the mortality rate, from the patients' medical records.

Patient classification
According to the Guidance for COVID-19 that was published by the National Institutes of Health [33], each of the patients who participated in the research was assigned to one of three different groups based on the severity of their illness, which were as follows: • Mild illness: a patient who does not have shortness of breath, or abnormal chest x-ray or CT scan findings, but who exhibits symptoms consistent with COVID-19. • Moderate illness: Patients whose oxygen saturation (SpO 2 ) less than 94% and who have abnormal radiological results from a chest x-ray or CT scan indicating lower respiratory illness. • Severe illness: In addition to abnormal radiological findings from chest x-rays or CT scans, patients with severe symptoms such as a respiratory rate exceeding 30-times per minute, pulse oxygen saturation levels of 93% or below or rapid pneumonia progression within 24 to 48 hours.

Outcomes
The incidence of gastro-intestinal symptoms at initial presentation in patients with COVID-19 was considered the primary outcome. Secondary analyses were made with regards to associations between gastro-intestinal symptoms and general and respiratory symptoms, laboratory results, patient characteristics, and the length of hospitalization.

Statistical Analysis
To conduct the analysis of the study data, the researcher used GraphPad InStat 6.0. For continuous data, means ± standard deviation was calculated based on patient characteristics, COVID-19 manifestations, laboratory data, and hospitalization outcomes. For categorical data, frequencies and proportions were calculated based on patient characteristics and COVID-19 manifestations. Both the Chi-square test and Fisher's exact test were utilized to compare the categorical data, while the two-sample t-test and the Wilcoxon rank-sum test were used to compare the continuous data [12].. Logistic regression was used in the process undertaking multivariable analyses. To determine significant predictors of the gastro-intestinal manifestations of COVID-19 and hospitalization outcomes, logistic regression analyses were carried out. The results of logistic regression analyses were reported as odds ratios (OR) with corresponding 95% confidence intervals (CIs), considering factors such as age, sex, BMI, comorbidities, and the presence of respiratory and constitutional symptoms. These analyses were conducted to determine significant predictors of the gastro-intestinal manifestations of COVID-19 and hospitalization outcomes. In this study, statistical significance was determined to exist when the p value was less than 0.05.

Patient's demographic characteristic
The study involved a total of 561 patients who tested positive for COVID-19. The patients were mostly overweight to obese, with a mean BMI of 29.0 ± 4.5 kg/m 2 . Many of them presented certain cardiovascular risk factors, including coronary artery disease, congestive heart failure, cardiac arrhythmia, and other comorbidities. The most common gastro-intestinal comorbidities among the patients were gastroesophageal reflux disease (18.7% [n = 105]) followed by irritable bowel syndrome (8.4% [n = 47]), inflammatory bowel disease (3.0% [n = 17]) and peptic ulcer disease (6.4% [n = 36]). There was no difference when it came to baseline demographics between those with gastro-intestinal symptoms and those without (Table 1).

Prevalence of gastro-intestinal symptoms
The study showed that about 39.9% of patients reported at least one gastro-intestinal symptom on presentation.

Gastro-intestinal symptoms & patients' clinical presentation
Findings of this study showed that patients with gastro-intestinal symptoms reported statistically significantly lower rates of fatigue (59.4% vs 76.3%; p < 0.0001) and myalgia (27.7% vs 57.3%; p < 0.0001) ( Table 2). Moreover, patients with gastro-intestinal symptoms reported statistically significantly lower rates of some respiratory symptoms, including cough (80.4% vs 86.9%; p = 0.04) and shortness of breath (58.0% vs 72.4%; p < 0.0001). However, patients with gastro-intestinal symptoms reported significantly higher rates of loss of taste (53.3% vs 35.9%; p < .0001). No other gastro-intestinal or respiratory symptoms were found to be statistically different between those with and without gastro-intestinal symptoms. The study also observed that arthralgia, sore throat, and loss of smell were more common among patients with gastro-intestinal symptoms, but not at a statistically significant level.

Gastro-intestinal symptoms & patients' laboratory test results
This study found no significant differences in any of the routine tests done at the time of hospital admission (Table 3). Among the tests performed were blood tests (e.g., leukocyte count, hemoglobin level, and platelet count), coagulation tests (international normalized ratio (INR), partial thromboplastin time (PTT)), liver enzymes (including: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin), and the cardiac enzyme creatinine kinase between patients with and without gastro-intestinal symptoms. Inflammatory markers that were tested in this study were ferritin, D-dimer, and C-reactive protein.

Discussion
This study showed that of the 561 patients who were hospitalized with COVID-19, 39.9% manifested gastrointestinal symptoms including diarrhea, nausea, vomiting, and abdominal pain. "Loss of appetite" came at the top of the list, followed by nausea or vomiting and diarrhea, 7.6% of the patients had heartburn. The researchers found no significant differences between patients with and without gastro-intestinal symptoms with regards to patient demographic characteristics or their comorbid diseases. In this cohort of patients, gastro-intestinal symptoms were not the initial presentation symptoms.
Since the outbreak of COVID-19 in Wuhan, China, more and more people, particularly health workers, are becoming aware of gastro-intestinal manifestations in COVID-19 patients. When COVID-19 was first detected in Wuhan, diarrhea was reported in only 3% of the cases [28]. However, subsequent studies from Wuhan showed diarrhea cases to rise to 10% and to 25% of all cases in a study from Singapore [25,34]. As health workers became more aware of gastro-intestinal manifestations in COVID-19 patients, reports of gastro-intestinal symptoms in subsequent studies also increased. One study found a higher frequency (39.6%) of gastro-intestinal symptoms, with nausea being reported as the most prevalent symptom [35]. Meanwhile, Pan, et al.'s Chinese-based research [24] indicates that more than half of the study's patient population experienced gastro-intestinal symptoms.
Our own study showed a prevalence of gastro-intestinal symptoms at 39.9% among COVID-19 patients, which was considerably lower than that reported by other studies from the USA and China, which ranged from 50.5% to 61.3% [24,36,37]. In such studies, the inclusion of anorexia in the list of gastro-intestinal symptoms may explain the higher reported incidence of gastro-intestinal symptoms overall. However, the present study did not include anorexia as a gastro-intestinal symptom since it is non-specific and may alternatively be associated with other infectious or inflammatory processes. A study in Wuhan, China, reported that 50% of their subjects had gastrointestinal symptoms, but most of these patients (78.6%) had anorexia [24]. However, when anorexia was taken out of the equation, only 18.6% came up as having specific gastro-intestinal symptoms.
The most common gastro-intestinal symptoms found in our study were loss of appetite (21.2%) and nausea (17.3%) followed by vomiting, diarrhea, and abdominal pain (16.2, 15.5 and 14.3%, respectively). A study in Wuhan, China, by Damaso, Oliveira, Massarani, Moussatché [38] showed similar results, wherein almost half, or 49.5% of the 305 COVID-19 patients reported having had diarrhea. The same study reported an incidence of nausea at 29.4%, vomiting at 15.9% and abdominal pain at a relatively low 6.0%. Other studies from Wuhan that involved COVID-19 patients reflected similar outcomes, showing nausea, vomiting, and diarrhea as the main gastro-intestinal symptoms among patients [25,39,40].
Our research has shown that heartburn is experienced by 7.6% of patients who have gastro-intestinal symptoms, and that 18.7% of our patient cohorts had the comorbidity of gastroesophageal reflux (GOR) disease. Since ACE-2 through which SARS-CoV-2 enters the host cells is highly expressed in upper part of gastro-intestinal tract [41], we might postulate that (micro)aspiration through GOR is a possible pathway for the transmission of SARS-CoV-2 from the stomach to the lungs. GOR is a common condition defined by a retrograde flow of stomach contents into the esophagus [42,43]. GOR may be a physiological process that many individuals experience routinely, but it can also be pathological, leading to GOR disease characterized by an abnormally high level of GOR [44,45].
Evidence of an infectious virus, not only viral RNA, was found in the stool of a patient with severe COVID-19 illness, according to a study from the US Centers for Disease Control and Prevention (CDC) [46]. The discovery of 'live' viruses in human stool was also reported in a separate investigation [47]. According to other research, approximately 50% of COVID-19 patients have detectable viral RNA in their feces, even when the virus is not present in other organ systems [48].. This may indicate the gastro-intestinal system as a major portal for SARS-CoV-2 infection with the possibility of fecal-oral or gut to lung transmission. Further research is warranted on the possibility that SARS CoV-2 is being aspirated into the lungs from a stomach reservoir, as suggested by our data.
Our prior studies have hinted at a potentially substantial stomach infection etiology in cystic fibrosis (CF), as well as a potential reservoir of microorganisms [49,50]. This link between gastric juice microflora and sputum samples from cystic fibrosis (CF) patients has revealed a correlation between the two [49,50]. Furthermore, supporting the concept of microbial transmission between the respiratory and gastro-intestinal systems is evidence from a study of CF patients in children by Palm, Sawicki, and Rosen [49] showing a link between lower-airway pseudomonas aeruginosa infection and GOR. Independent of the flora in the oropharynx, another study also revealed microbial translocation from the gastro-intestinal tract to the lungs [51]. The importance of GOR and the potential function of microaspiration in the spread of COVID-19 has never previously been investigated. Therefore, further studies are needed.
Our own study showed that gastro-intestinal symptoms were not linked to poorer outcomes such as increased mortality, a longer hospital stay, or increased mechanical intubation of COVID-19 patients, with the tendency toward a milder form of infection in patients with gastro-intestinal symptoms. We also found no difference in the results of laboratory tests between patients with gastro-intestinal symptoms and those without. Earlier studies have reported conflicting findings with regards to the presence of gastro-intestinal symptoms and poor outcomes. One study from Wuhan, China showed that patients who had digestive symptoms had longer hospital stays (9 vs 7.3 days, p = 0.013). Another study by Zhou et al. [52] showed that as the severity and duration of COVID-19 increased, gastro-intestinal symptoms increased as well. In a multicenter study of 191 patients [52], the presence of gastro-intestinal symptoms was associated with elevated C-reactive protein, elevated alanine aminotransferase, and lower hemoglobin levels when compared with patients without gastro-intestinal symptoms. However, another study by Redd [36], showed no difference in clinical outcomes in patients with or without gastro-intestinal symptoms. It also showed no significant differences in the leukocyte count, hemoglobin, platelets, coagulation, and liver tests among patients with or without gastro-intestinal symptoms [36]. This disparity between different studies could be related to different study design and sampling approaches as well as the variation in clinical features of different SARS-CoV-2 variants.
There are still gaps in our knowledge as to what specific processes caused gastro-intestinal manifestations in COVID-19. There are many proffered theories. One theory touched on the fact that intestinal tropism has been associated with SARS-CoV-2, which could be due to its strong affinity for ACE-2 receptors. ACE-2 receptors are highly expressed in the esophagus and intestinal epithelial cells [53]. Hence, there is a strong possibility of direct small bowel involvement resulting in direct cytopathic effects causing gastro-intestinal symptoms. Similar to another study [36], we found that loss of smell (anosmia) and loss of taste (ageusia) were commonly found among patients with gastro-intestinal symptoms. While the exact cause of this association is unclear, it could be due to damage to olfactory and gustatory receptors during viral entry through nasal and oral routes [53]. In a separate study from Hong Kong, patients with diarrhea on presentation had higher rates of stool RNA positivity when compared with those without diarrhea (38.5 vs 8.7%, p = 0.02). This implies a direct effect of SARS-CoV-2 on the gastro-intestinal 10.2144/fsoa-2023-0040 Future Sci. OA (2023) FSO858 future science group tract [54]. The viral infection can cause altered intestinal permeability, resulting in malabsorption [55]. Another theory suggested that the inflammatory response from a cytokine storm in severe COVID-19 patients can cause hypoxia-induced bowel ischemia, resulting in diarrhea and other gastro-intestinal symptoms.

Limitations
There are some limitations to this study, one of which is the lack of a validated symptom questionnaire survey. Another was that it was limited to a single-center hospital-based study, which could result in regional bias. We advise other researchers to exercise caution before generalizing our experience. Moreover, the presence of SARS-CoV-2 RNA in stool could not be correlated with gastro-intestinal symptoms because the relevant test was not routinely performed at the researchers' institution.
In addition, this study did not use a control group composed of patients who tested negative for COVID-19, which the researchers acknowledge would have provided further empirical insight into the representation of gastro-intestinal symptoms in patients with COVID-19. However, notwithstanding these limitations, this study has certain strengths, including its prospective design using a predesigned questionnaire and the large study sample. The researchers believe that these factors overcome some of the inherent bias found in studies that focus on retrospective chart reviews.
The significance and implications of this study lie in its confirmation of the involvement of the gastro-intestinal system in COVID-19 infection, which can mimic a range of gastro-intestinal differential diagnoses. In patients with gastro-intestinal symptoms, failing to acknowledge the possibility that the patient is infected with COVID-19 may not only lead to diagnostic issues, but also failing to isolate the patient accordingly can prolong the spread of the disease [56]. Such isolation delays risk unnecessarily exposing people to the COVID-19 virus, including the patient's family members and friends, other hospital patients, and clinical staff. Failing to identify COVID-19 infection in gastro-intestinal symptomatic patients can also impact virus transmission as a result of underestimating the incidence of the virus. Moreover, finding of this study suggested that there is a need for further studies to explore the role of GOR and aspiration in the transmission of COVID-19 and the impact of reflux on lung involvement.

Conclusion
We found that gastro-intestinal symptoms were routinely encountered among hospitalized COVID-19 patients. Certain gastro-intestinal symptoms such as loss of appetite, nausea, vomiting, and diarrhea were found to be widely prevalent among COVID-19 patients. This study showed that the presence of gastro-intestinal symptoms was not linked to poorer outcomes such as increased mortality, longer hospital stays, or increased mechanical intubation of COVID-19 patients. It seemed that gastro-intestinal symptoms could potentially be a precursor or determining factor in the diagnosis of COVID-19. The authors of this study recommend that more extensive studies be made to evaluate the effects of gastro-intestinal symptoms on COVID-19 outcomes and that epidemiologic studies involving a larger population sample should be carried out to further confirm this study's findings.

Summary points
• COVID-19 is a new disease that primarily affects the respiratory system However, it was found to impact on other organ systems particularly the gastro-intestinal system. • The study showed that 39.9% (244/561) of patients involved in the study presented gastro-intestinal symptoms.
• The most common gastro-intestinal symptoms were loss of appetite, nausea, vomiting and diarrhea.
• The presence of gastro-intestinal symptoms was not linked to poorer clinical we recommended for clinicians to watch out for gastro-intestinal symptoms and to be aware of the fecal-oral route of transmission so that precautionary measures may be established to prevent further development of the disease.
Author contributions H Al-Momani was responsible for the study design, analyzing data, preparing the figure and tables, and writing the manuscript.
M Almasri and S Mashal: responsible for data collection. S Mashal and I Aolymat: responsible for study design and co-wrote the manuscript.