The pandemic caused by severe acute respiratory syndrome corona virus 2 (SARS-COV-2), initially referred to as the 2019 novel coronavirus and termed COVID 19 by the World Health Organization, it has been impacting the entire world since December 2019 and causing a massive crisis for global health.

The virus is mainly spreads through direct exposure (respiratory droplets, person to person). However, it is also assumed transmitted by contaminated objectifs, airborne transmission and fecal-oral transmission [1]. The COVID 19 is predominantly a respiratory disease, however gastrointestinal (GI) symptoms such diarrhoea, abdominal pain and us vomiting are increasingly being recognized as important manifestations of COVID 19. The distribution of angiotension converting enzyme type 2 receptors in multiple organs in the body and highly in the gastrointestinal tract and the liver provides a possible explanation for the digestive symptoms [1-2] GI symptoms can coexist or even precede respiratory manifestations. Rarely COVID 19 patients can present with only GI symptoms without respiratory symptoms.

It has been an increasing interest in whether GI symptoms are associated with severe disease and it still unclear if the presence of GI symptoms is associated with poor outcomes in COVID 19 or not. Therefore, in our study, we aimed to analyse if the presence of GI symptoms at the time of hospitalization is associated with the severity of disease and poor outcome when compared to those who did not have GI symptoms.

Study Design and Data Source

This is a prospective cohort study conducted in a cohort of COVID19 patients who were admitted to our service, to help COVID 19 patients in the middle of the crisis of the second wave of the disease. We included consecutive patients who were admitted to the hospital with confirmed diagnosis of COVID 19 on nasopharyngeal polymerase chain reaction testing for SARS-COV-2 from 24 October 2021 to 8 January 2022.

Data related to patient’s demographics, clinical symptoms, comorbidities, vitals at presentation, admission laboratory tests, and outcomes were collected.

The definition of positive GI symptoms required that the patients have at least one of the following symptoms: nausea, vomiting and diarrhoea or abdominal pain. GI symptoms were recorded in admission, excluding the influence of other medical therapy and externals factors. We’ve also eliminated all other abdominal emergencies by carrying out a lipase assay and abdominal CT scan (which came back normal) in all our patients with acute abdominal pain.

Demographic variables such as age, sex, smoking status and BMI were obtained. Data multiple comorbid conditions such as the history of hypertension, diabetes, heart disease, chronic liver disease, chronic renal disease or chronic obstructive pulmonary disease, the history of cancer or any condition of immunosuppression was collected. Clinical data included the respiratory symptoms, oxygen status and duration of symptoms. 

laboratory data such as haemoglobin level, hematocrit, WBC , absolute lymphocyte and neutrophils counts , platelet count , ferritin level , C-reactive protein , D-dimer , aspartate aminotransferase , and alanine aminotransferase , creatinine and lactate dehydrogenase were noted . Finally, CT findings were noted too.

Stratification of Study Cohort and Outcomes

In our study, the GI symptoms were defined as the presence of nausea, vomiting, diarrhoea, or abdominal pain at the time of admission. The study cohort was stratified into 2 groups based on the presence of GI symptoms: COVID 19 with symptoms (cases) and COVID-19 without GI symptoms (controls). The primary outcome was death from any cause. Secondary outcomes were identified as total hospital length of stay (LOS) and need for mechanical ventilation during that hospitalization.

Statistical Analysis

Statistical analysis was performed using Jamovi version1.2.27. For continuous variables, mean (SD) and median (IQR) were respectively used for normally and abnormally data, followed by unpaired t-test and non-parametric test when appropriate such as the Mann-Whitney U to compare the groups. Categorical variables were expressed as number with percentages (%) and compared using the χ² test. A two-sided α of < 0.05 was considered statistically significant.

Baseline Demographics and clinical characteristics

A total of 93 patients were hospitalized with confirmed COVID-19 during the study period from 24 October 2021 to 08 January 2022. 2 patients were excluded because of unavailability of records.  A total of 91 patients met the inclusion criteria and formed our final study population. Of these, 34 (37.4%) patients presented with at least one GI symptoms (nausea, vomiting, abdominal pain and diarrhoea) , and 57 ( 62.6%) had no GI symptoms ( controls) (Table 1-2).

Table 1: prevalence of GI symptoms in the entire cohort.

Table 2: Prevalence of individual gastrointestinal (GI) symptoms in the COVID-19 cohort with GI symptoms (cases).

In detail, Diarrhoea was the most common GI symptoms, which was reported in 14.3% of the cohort, followed by vomiting or nausea, reported in 9.8% of patients and abdominal pain was find in 6.6%. In addition, five patients (5.5%) had all the GI symptoms of diarrhoea, vomiting and abdominal pain, while only three had the symptoms of both vomiting and diarrhoea. For history of contact with patient COVID 19, in controls, we reported 24.6% of the patients compared to 17.6% in the counterparts but there was no statistic significant difference (p=0.441).

Patients were predominantly males in two groups with a mean age was 57.5 years in cases as compared to 63.1 years in controls without any significant difference, while comparing the 2 groups with age > 60 years we find out that patients without GI symptoms are much older from patients with GI symptoms with significant difference (p<0.05). (Table 3).

Table 3: Demographic and epidemiological characteristics of patients with COVID-19 with and without GI symptoms.

COPD: chronic obstructive pulmonary disease.

The mean BMI and the percentage of current smokers were similar in the two groups (23.7). Comorbidities such as hypertension, diabetes, chronic liver or renal disease, heart disease, obstructive pulmonary disease and cancer were similarly distributed between the two groups without any significant difference. (Table 3)

The clinical characteristics of patients with GI symptoms are shown in (Table 4). Fever, cough, fatigue and dyspnea were the most common symptoms but there was no difference in the presence of other symptoms between the two groups. Our patients with acute abdominal pain demonstrate evidence of COVID19 incidentally through abdominal CT imaging at the lung bases. All abdominal CT imaging were normal. Furthermore, we’ve analysed the association between patients with abdominal pain and the risk of having pulmonary embolism and interestingly we find out that patients with abdominal pain were more likely to present pulmonary embolism (risk x 4.27) compared with those with other symptoms. (Table 5). Laboratory Data and CT findings (Table 6).

Table 4: Clinical characteristics of patients with COVID-19 with and without GI symptoms.

Table 5: association between acute abdominal pain and risk of pulmonary embolism in binomial logistic regression.

Table 6: Laboratory tests CT findings of both cohorts at the time of admission.

There was no statistical difference between the two groups in values of laboratory data such as leucocytes, lymphocytes, platelets, haemoglobin and haematocrits. Concerning infected related markers, such as C-reactive protein, there was no significant difference between medians (83.5 mg/l in cases vs 97.5 mg/l in controls with p =0.853 > 0.05). The median ferritin level, LDH level and Albumin level were lower in cases than in controls but did not reach statistical significance (p of the three parametric was > 0.05). Median of D-Dimers, Aspartate aminotransferase (ASAT) and Total bilirubin were higher but no statistically significant in both groups as noted in table 5. Finally, Althrough most radiographic presentation were similar between the 2 groups and same for the severity of the lesions (p = 0.569 > 0.05).

Outcomes (Table5-7)

As shown in table 6, 3 (8.8%) patients in cases had a complication of ARDS and six others (17.6 %) had pulmonary embolism, these rates were higher than the other groups of seven (12.2%) and four (7%) in patients without GI symptoms, respectively.  Four (11.8 %) patients with GI symptoms needed mechanical ventilation and 12 (35.3%) were treated with non-invasive ventilation which was lower compared to rate of 21.8% and 47.4% in the patients COVID19 without GI symptoms. No significant difference were noted in mean LOS (7 days (7-10) vs 9 days (7-14), p=0.114) and mortality (five (14.7%) vs 13(23.2%), p= 0.328). But there was a significant correlation between mortality and abdominal pain in multiple logistic regression.

Table 7: Outcome data of both cohorts in patients with COVID-19 with and without GI symptoms.

All laboratory values are presented as medians (IQR=interquartile).

SARS-Cov-2 may cause digestive symptoms either by direct viral invasion in target cell and/or immune-mediated symptoms tissue and end organ injury. However, symptoms of COVID19 might be indirectly caused by infection –induced respiratory complications, which lead to tissue hypoxia, loss of cell integrity, cell injury and finally cell death [3]. The reports of GI symptoms increased in studies as much as the awareness increasing among health care workers about them.  Our study shows that 37.4% of the patients hospitalized with COVID19 presented with at least one GI symptom. In literature, approximately 5-70% of patients COVID19 reported GI symptoms [4-5], this big variation in proportion of patient with GI symptoms among different studies might be related to geographical region and whether symptom were reported on admission or during hospitalization [4], and it worth mentioning that different studies have adopted different criteria for what constitutes gastrointestinal symptoms. Of the gastrointestinal symptoms, diarrhoea, nausea, vomiting, anorexia, and abdominal pain are the main symptoms found in the majority of studies. We excluded anorexia from our study because it’s a nonspecific symptom that could be related to an overall infectious or inflammatory process.

While rarer, researchers have also found cases of acid reflux, upper gastrointestinal bleeding, hematochezia, constipation, and melena [4-5], In our study, we in terms of patient demographics, we found that patients with GI symptoms were younger, with less comorbidities, this is an interesting finding which line with an European study [7]. There has been controversy regarding the presence of gastrointestinal symptoms and the poor outcomes of these patients. Our results were similar to many studies such as Preethi's R. et All involving 150 patients [8], moreover, in a meta-analysis involving a total of 78 studies with 12797 patients found that mortality in patients with gastrointestinal symptoms was similar to that of the overall mortality and death in patients with COVID19 could be due to the infection itself or to underlying co-morbidities [8-9].

 Contrarily, a study of Alexandra and colleagues that has proved by using human intestinal biopsy tissues obtained from patients with COVID19 and uninfected control individuals for microscopic examination, that there is an absence of a pro-inflammatory response in the GI tract despite detection of SARS-COV-2[9-10]. In parallel, disease severity and mortality were examined in patients with and without GI symptoms in 2 large independent cohorts of hospitalized patients, one in the USA (n=634) and other in Europe (n=287) using multivariate logistic regression and they find the same results of reduced mortality in patients with COVID19 presenting with GI symptoms. They suppose that there is a potential role of GI tract in attenuating SARS-COV-2 associated inflammation that needs to be further examined [9-11]. Furthermore, we find out that acute abdominal pain could be associated with risk of pulmonary embolism and then mortality. Three studies, including 380 patients, were analysed in a meta-analysis [11]. The results suggest that patients with severe SARS-CoV-2 infection were almost seven times more likely to have abdominal pain than their counterparts with non-severe disease. Based on these results, abdominal pain could potentially be used as an indicator of severity in patients infected with COVID-19 to aid triage. A meta-analysis of gastrointestinal manifestations of COVID19 pooled data from 17 studies concluded that patients with severe disease are more likely have abdominal pain as compared with patients with non-severe disease [12-13]. Acute abdominal pain which is known as regular symptom of basal pulmonary embolism that could explain partially this association, so we must be aware about this eventuality and pay more attention for these patients.

The results of this study suggest that COVID 19-related digestive manifestations occur mainly in young subjects and that their presence is non-specific and unrelated to the severity of the disease, and does not increase the mortality rate. After ruling out other digestive emergencies, pulmonary embolism should be considered in the presence of acute abdominal pain complicated by respiratory distress.

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