Diarrhea as a Prognostic Factor for Severe COVID-19

In March of 2020, the WHO has declared the state pandemic of Coronavirus disease (COVID-19) that started in the city of Wuhan, China. The widespread of cases resulted in 2,877,476 cases and 73,582 death reported in Indonesia. It is commonly known that the respiratory system was the main problem in COVID-19, but it is recently reported that gastrointestinal involevment has a higher likelihood to develop into severe cases. Moreover, it is found that diarrhea is the most highly prevalent of the gastrointestinal signs and symptoms in COVID-19 patients. The aim of this evidence-based case report is to understand the association between diarrhea and severe cases of COVID-19. A search on Pubmed, Scopus and Cochrane result in five articles to be appraised using Centre for Evidence-Based Medicine (CEBM) critical appraisal tool. The most recent systematic review by Ghimere S et al (2020), found COVID-19 patients with diarrhea has higher likelihood of developin ginto a severe case (OR = 1.63, 95% CI: 1.11 – 2.38). While the cohort studies showed several prognostic factors that may potentially effect the outcome of severe COVID-19 cases. It is concluded that severe COVID-19 cases were more likely to be found in patients presenting with diarrhea. Thus, Confirmed COVID-19 patients with diarrhea should be carefully evaluated to anticipate worsening of symptoms. prognosis klinis berat (OR = 1.63, 95% CI: 1.11 – 2.38). Sedangkan, studi kohort diinklusi faktor prognostik yang dapat mempengaruhi kasus COVID-19 dengan derajat berat.


INTRODUCTION
In late 2019, there were series of atypical pneumonia cases reported in Wuhan, China. 1 The cases grew exponentially and in March 2020, the WHO declared a pandemic of novel coronavirus. 2 This new coronavirus commonly known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the one responsible for Coronavirus Diseases 2019. 3,4 As of March 2021, there have been 2,877,476 confirmed cases and 73,582 death in Indonesia, widespread cases have disrupted economic, social and health status of the country. 5 Most patients are present with respiratory symptoms such as cough and dyspnea accompanied with systemic symptoms like chills or fever. 6,7 Nevertheless, there is a trend shifting towards gastrointestinal involvement in COVID-19 clinical manifestations. 6,7 While it is known that the general mechanism of gastrointestinal involvement in SARS-CoV-2 infection is mediated by angiotensin converting enzyme-2 (ACE2), the exact mechanism is not yet known. ACE2 play a role as the port of entry of the virus, which are not only localized in the respiratory system but are also found in gastrointestinal linings. 8 There are growing evidence showing how gastrointestinal involvement is associated with severe cases. 6,7,9,10 Moreover, it is also stated early in the early phase of the pandemic that diarrhea is the most prevalent gastrointestinal involvement in COVID-19. 1 Therefore, this paper is interested in looking into diarrhea as an independent prognostic factor by investigating available studies on the association between the presence of diarrhea and severe cases of COVID-19.

CASE ILLUSTRATION
A 28-year -old woman presented with a 2-day history of watery diarrhea five to six times per day. Diarrhea was accompanied by fever and cough. There was a history of contact with a confirmed case within her workplace. On initial presentation, body temperature was 38°celcius there were course bibasal crackles on chest examination and mild abdominal tenderness without rigidity and rebound. Initial workup revealed normocytic normochromic anemia and thrombocytopenia. The patient's polymerase chain reaction (PCR) result was positive for SARS-CoV-2 infection.

METHOD
The search was conducted on three major databases (Pubmed, Scopus and Cochrane) with "COVID-19" "SARS-CoV-2" "diarrhea" "Signs and Symptoms, Gastrointestinal" "prognosis" "severity" as keywords ( Table 1). Studies that were included are full-text articles in English following the eligibility criteria which are studies with confirmed COVID-19 cases as the targeted population comparing ratio of gastrointestinal involvement and case severity as the outcome.
Studies included in this article were limited to systematic reviews/meta-analyses of cohort studies and cohort studies. Chosen articles were assessed using systematic review and cohort study assessment tool from the University of Oxford 2010 Center for Evidence-based Medicine (CEBM). Cochrane 0 0

RESULTS
The research yielded twenty-two studies from the three major databases. After the removal of duplicates, eighteen studies were screened based on their title and abstract. Thirteen studies were excluded for not meeting the eligibility criteria ( Figure 1). Overall qualities of selected studies were adequate though some are better than the others (Table 2 and  Table 3). Between the three systematic reviews Wang H et al (2020) has the least quality due to the absence of quality assessment within included studies. A systematic review by Ghimere S et al (2020) was the most recent one and it involves studies located in multiple centers around the world. Additionaly Wang H et al (2020) fail to involve more than one database. Deane K et al (2021) as one of the cohort studies selected, fail to describe the initial point of disease within the cohort and did not adjust for potentially important prognostic factors.
Out of all five studies, two studies by Ghimire

DISCUSSION
This evidence-based case report aims to identify the prognosis of confirmed COVID-19 presenting with diarrhea. The main question here is best answered from the highest available article, which is the systemic reviews. A systematic review done by Ghimere S et al (2020) found all except only one of the evidence in their meta-analysis showed significance between diarrhea and disease severity of COVID-19. 9 Although Mao R et al (2020) and Wang H et al (2020) did not find significant results regarding diarrhea as a prognostic factor. 1, 12 Mao R et al found that gastrointestinal involvement (including nausea, vomiting and abdominal pain) and abdominal pain alone were a significant predictor of severe COVID-19 cases. 1 Different results between the three studies can be explained by evidence showing an increase of Protein S mutation in a late phase of the pandemic, resulting in a higher case of gastrointestinal involvement in SARS-CoV-2 infection. 13 Where in the latest systematic review, the meta-analysis show significance of diarrhea as a prognostic factor for severe COVID-19 cases.
A retrospective study by Hegazy MA et al (2021) found significant factors between the mild and severe cohorts. 10 Where age, sex, presence of chronic lung diseases and metabolic comorbidities were factors that have a significant impact on COVID-19 severity. 10 These factors were then used to adjust the analysis of diarrhea as an independent prognostic factor. 10 Between the two cohort studies, one has clinical significance while the other does not.
Cohorts in the Hegazy MA et al (2021) showed participants with diarrhea has a 2.7 times higher likelihood of requiring ICU admission. 10 The study also identifies age, sex and metabolic comorbidities as predictors of severe cases. 10 This finding is in accordance with the previous studies as older age, male and metabolic comorbidities were associated with a higher prevalence of severe manifestations. 14-17 Additionally Deane K et al report an increase in the duration of hospitalization in participants with diarrhea, nausea and vomiting collectively, this finding is in line with previous studies. 1,11 arch stratergy flowchart and study selection  The results of this evidence-based case reported varied results on the prevalence of diarrhea in COVID-19 cases. This finding is in accordance with the previous observation by D'amico et al which also reported a wide range of 2% to 50%. It is ought to believe that the difference was due to the lack of ability to identify diarrhea clinically and theoretically as there are various incorrect definitions of diarhea. 12,13,18,19 Furthermore, the mechanism of diarrhea in COVID-19 infection is explained by previous evidence that suggested SARS-CoV-2 alters the permeability of the gastrointestinal tract causing malabsorption within the enterocytes. 20 There is also evidence demonstrating ACE2 involvement in the gastrointestinal linings directly disrupts the homeostasis of gut microbes. 21 Nevertheless, the pathophysiology of diarrhea in severe cases of COVID-19 has not been fully understood.
Though an article proposed that cytokine storm play a role in causing hypoxia and later ischemia of the intestine which will promote diarrhea. 22 Additionally, Wang H et al implied that investigation towards the side effects of diarrhea from antivirus consumption should be done because it is known that some antibiotics and antivirus caused drug-induced diarrhea. 12

CONCLUSION
Severe COVID-19 infection is more likely to be found in confirmed cases presenting with diarrhea. Although this study assessed a wide range of corresponding literature, the result of the studies involved was mainly limited to those being admitted to a hospital. Therefore, confirmed COVID-19 patients presenting to the hospital with diarrhea should be carefully evaluated to anticipate a worsening condition.