In December 2019, an outbreak of pneumonia of unknown etiology in Wuhan, Hubei province, China led to the identification of a new betacoronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. SARS-CoV-2 is the seventh identified coronavirus that is able to infect humans2. In addition to animal origin it shares up to 80% of the gene sequence with other members of coronavirus family, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)2,3. Our understanding of SARS human-to-human transmission is still evolving, but is currently believed to occur through air droplets, although fecal oral spread and airborne transmission may be other sources of transmission4,5. In a short time, the highly contagious virus has caused a pandemic, destabilizing health systems, economies, and governments around the world6. SARS-CoV-2 infection can be asymptomatic or be associated with the coronavirus disease 2019 (COVID-19), which has a spectrum of respiratory clinical manifestations ranging from fever, dry cough, and dyspnea to pneumonia,pulmonary oedema, acute respiratory distress syndrome (ARDS), and multiple organ failures, requiring hospitalization in intensive care unit (ICU) and leading to death in severe cases7. Less common symptoms include headache, haemoptysis, nausea, vomiting, and diarrhea8. Although initially found in a small percentage of cases, an increasing number of patients present with diarrhea9. Diarrhea is a frequent symptom in coronavirus infections; it was detected in up to 30% of patients with MERS-CoV and 10.6% of patients with SARS-CoV10,11. The purpose of this review is to examine the literature on the epidemiology, clinical symptoms, mechanism of action, management, and prevention of COVID 2019 associated diarrhea in order to better characterize this symptom and to identify any preventive measures for patients exposed to virus.
Epidemiology of COVID -19 associated diarrhea
Epidemiological data of COVID-19 patients with diarrhea are summarized in Table 1. The medical records of the National Health Commission of China allowed to evaluate the data of 1099 Chinese patients with an established diagnosis of COVID-19 up to 31 January 202023. Forty-two subjects experienced diarrhea (3.8%) and the primary composite outcome (admission to ICU, use of mechanical ventilation, or death) occurred in 4 patients with diarrhea (6%)23. In a retrospective study by Xu et al.24 diarrhea occurred in 3/62 patients (4.8%). A symptom duration-based analysis showed that diarrhea was experienced only in patients who had symptoms for more than 10 days (3/33, 9%), while those who had a shorter duration had no diarrhea24. In a cross-sectional, Chinese
7 multicenter study9 enrolling 204 patients until early March 2020, diarrhea occurred in 29 cases (29.3%). The time between symptom onset and admission to the hospital was significantly longer in patients with digestive symptoms than in patients without gastrointestinal manifestations (9 vs. 7.3 days, p=0.02)9. Most patients had non-dehydrating loose stools and had an average of 3 evacuations per day9. No cases of severe diarrhea were detected, although a clinical relationship was reported between diarrhea and worsening of COVID-19 symptoms9. Wu et al. investigated a cluster of subjects exposed to the infection at the same time, documenting the presence of diarrhea in 15% of positive patients25. In the experience of Huang et al.26, only one out of 41 (3%) patients had diarrhea as initial symptom, while another Chinese study conducted in the Zhejiang province
7 multicenter study9 enrolling 204 patients until early March 2020, diarrhea occurred in 29 cases (29.3%). The time between symptom onset and admission to the hospital was significantly longer in patients with digestive symptoms than in patients without gastrointestinal manifestations (9 vs. 7.3 days, p=0.02)9. Most patients had non-dehydrating loose stools and had an average of 3 evacuations per day9. No cases of severe diarrhea were detected, although a clinical relationship was reported between diarrhea and worsening of COVID-19 symptoms9. Wu et al. investigated a cluster of subjects exposed to the infection at the same time, documenting the presence of diarrhea in 15% of positive patients25. In the experience of Huang et al.26, only one out of 41 (3%) patients had diarrhea as initial symptom, while another Chinese study conducted in the Zhejiang province
reported a low rate of diarrhea onset in COVID-19 patients (2%). A study by Xiao et al.27 analyzed stool samples from 73 COVID-19 patients to assess the clinical significance of measuring SARS-CoV-2 RNA in the feces. Diarrhea was found in 26 patients and the fecal test remained positive until 12 days after the disease onset27. It is worth mentioning that in 17 patients (23.3%) the stool test was still positive despite negative respiratory tests27. In addition, in a 78-year-old patient with severe respiratory distress treated with veno-venous extracorporeal membrane oxygenation (VV-ECMO), endoscopic procedures were performed following signs of bleeding (coffee ground material from the nasogastric tube and positive fecal occult blood test)27. No mucosal damage was identified, but multiple esophageal, gastric, duodenal, and rectal biopsies were performed27. Histological analysis revealed a high percentage of ACE2 protein in the glandular cells of all examined segments, with the exception of the esophagus (mainly characterized by squamous cells), supporting the theory of a possible effect of the virus on these organs27. An 81-year-old Japanese woman with COVID-19 had watery diarrhea and the virus was detected in the stool for up to 15 days after disease onset28. In a descriptive case series29 of the first 18 COVID-19 cases in Singapore, 3 patients had diarrhea (16.6%). None of these 3 patients had complications and none required supplemental oxygen29. Stool samples were tested by real-time reverse transcriptase – polymerase chain reaction (RT-PCR) and SARS-CoV-2 was found in 4/8 patients (50%) from day 1 to day 72
In a small case series30,
8 data from 5 patients tested positive for both SARS-CoV-2 and influenza virus were analyzed, reporting diarrhea in 2 cases (40%). An analysis on the clinical characteristics of 30 medical members (22 doctors and 8 nurses) with COVID-19 showed the presence of diarrhea in 9/30 subjects (30%)31. Recently, the first study specifically designed to evaluate patients with gastrointestinal symptoms at disease onset was published32. One hundred eighty-three patients were included, and diarrhea was detected in 68 cases (37.1%). COVID-19 epidemiological data in children are lacking, however in a recent analysis33 of 171 children with a median age of 6.7 years, diarrhea was reported in 8.8% (15) of cases. Furthermore, a recent systematic review and meta-analysis of case studies34 assessed the epidemiological characteristics of 1995 patients with COVID-19, showing a diarrhea rate of 4.8%. Finally, we performed a pooled analysis of all avaliable studies revealing an overall diarrhea rate of 10.4% in patients with COVID-19
8 data from 5 patients tested positive for both SARS-CoV-2 and influenza virus were analyzed, reporting diarrhea in 2 cases (40%). An analysis on the clinical characteristics of 30 medical members (22 doctors and 8 nurses) with COVID-19 showed the presence of diarrhea in 9/30 subjects (30%)31. Recently, the first study specifically designed to evaluate patients with gastrointestinal symptoms at disease onset was published32. One hundred eighty-three patients were included, and diarrhea was detected in 68 cases (37.1%). COVID-19 epidemiological data in children are lacking, however in a recent analysis33 of 171 children with a median age of 6.7 years, diarrhea was reported in 8.8% (15) of cases. Furthermore, a recent systematic review and meta-analysis of case studies34 assessed the epidemiological characteristics of 1995 patients with COVID-19, showing a diarrhea rate of 4.8%. Finally, we performed a pooled analysis of all avaliable studies revealing an overall diarrhea rate of 10.4% in patients with COVID-19
In the current SARS-CoV-2 pandemic, most of the attention is still exclusively focused on the respiratory symptoms of the disease. However, it is important to emphasize that the number of COVID-19 patients experiencing diarrhea is significant and cannot be overlooked.We found high variability among published studies in the percentage of patients with diarrhea, ranging from 2% to 50% of cases. Our pooled analysis of the available data revealed an overall diarrhea rate of about 10% in COVID-19 patients. This value is lower than the percentage of diarrhea reported with other coronaviruses40,44, but it is very possible that the available data may underestimate the burden of diarrhea associated with COVID-1961. For example, none of the studies we reviewed provided an explicit definition for diarrhea. The World Health Organization (WHO) defines diarrhea as 3 or more loose / liquid stools per day or an increase in the number of evacuations compared to the usual62. Given the subjective nature, it is not surprising that there is marked heterogeneity in the estimates of patients with diarrhea symptoms61. The collection of reliable epidemiological information is fundamental,and it should be obtained in the shortest possible time to guarantee adequate preventive measures and to allow the best pandemic management. Data should be recorded with explicit diarrhea definition and characterization of number and duration of evacuations, specifying whether the symptom occurred at the onset or during the course of the disease. The use of the so-called "big data", could be a valid alternative to capture the growing
14 amoutn of data in a short period as proven in a single Chinese experience63. In addition, some patients have diarrhea in the absence of respiratory symptoms, and this may lead to underestimation of COVID-19 cases, as further investigations may not be performed in patients with mild symptoms.Another limitation is related to the diagnostic method. The analysis of respiratory tract samples does not allow identification of all infections, resulting in diagnostic delays or undiagnosedcases64. A recent study used a mathematical model to simulate the dynamics of infection in China65. It was estimated that around 86% of the infections were not documented and thatpatients with undocumented cases led to the contagion of most of the identified patients (79%)65. SARS-CoV-2 is similar to SARS-CoV and MERS-CoV, but it is transmitted faster than its predecessors and for this reason a rapid and optimal diagnostic approach is essential to contain the virus dissemination66. The evidence of SARS-CoV-2 in the stools and in gastrointestinal histological samples and its prolongedpersistence at the stool compared to nasopharyngeal swabs strongly suggests that oro-fecal transmission is possible, justifying the execution of fecal PCR in suspect patients27. The homology between SARS-CoV-2 and SARS-CoV and MERS-CoV and the high capacity of these viruses to resist for long periods (even two weeks) at low temperatures and for a few days at temperatures between 20°C and 30 °C is a further confirmation of possible orofecal tranmission and requires an enhancement of preventive hygiene measures67. In conclusion, the presence of diarrhea should generate suspicion of a possible SARS-CoV-2 infection and should be investigated in order to reach an early diagnosis of COVID-19.The incidence of diarrhea is currently underestimated and further studies are needed to quantify the exact burden of diarrhea to compare the sensitivity of fecal and nasopharyngeal tests, to evaluate whether diarrhea is a predictive factor for prognosis, and to clarify the effects of COVID-19 in patients with underlying gastrointestinal diseases
14 amoutn of data in a short period as proven in a single Chinese experience63. In addition, some patients have diarrhea in the absence of respiratory symptoms, and this may lead to underestimation of COVID-19 cases, as further investigations may not be performed in patients with mild symptoms.Another limitation is related to the diagnostic method. The analysis of respiratory tract samples does not allow identification of all infections, resulting in diagnostic delays or undiagnosedcases64. A recent study used a mathematical model to simulate the dynamics of infection in China65. It was estimated that around 86% of the infections were not documented and thatpatients with undocumented cases led to the contagion of most of the identified patients (79%)65. SARS-CoV-2 is similar to SARS-CoV and MERS-CoV, but it is transmitted faster than its predecessors and for this reason a rapid and optimal diagnostic approach is essential to contain the virus dissemination66. The evidence of SARS-CoV-2 in the stools and in gastrointestinal histological samples and its prolongedpersistence at the stool compared to nasopharyngeal swabs strongly suggests that oro-fecal transmission is possible, justifying the execution of fecal PCR in suspect patients27. The homology between SARS-CoV-2 and SARS-CoV and MERS-CoV and the high capacity of these viruses to resist for long periods (even two weeks) at low temperatures and for a few days at temperatures between 20°C and 30 °C is a further confirmation of possible orofecal tranmission and requires an enhancement of preventive hygiene measures67. In conclusion, the presence of diarrhea should generate suspicion of a possible SARS-CoV-2 infection and should be investigated in order to reach an early diagnosis of COVID-19.The incidence of diarrhea is currently underestimated and further studies are needed to quantify the exact burden of diarrhea to compare the sensitivity of fecal and nasopharyngeal tests, to evaluate whether diarrhea is a predictive factor for prognosis, and to clarify the effects of COVID-19 in patients with underlying gastrointestinal diseases
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