COVID-19 and Gut Injury.

COVID-19 induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic and it has led to more than 620 million patients with 6.56 million deaths globally. Males are more susceptible to COVID-19 infection and associated with a higher chance to develop severe COVID-19 than females. Aged people are at a high risk of COVID-19 infection, while young children have also increased cases. COVID-19 patients typically develop respiratory system pathologies, however symptoms in the gastrointestinal (GI) tract are also very common. Inflammatory cell recruitments and their secreted cytokines are found in the GI tract in COVID-19 patients. Microbiota changes are the key feature in COVID-19 patients with gut injury. Here, we review all current known mechanisms of COVID-19-induced gut injury, and the most acceptable one is that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptor on host cells in the GI tract. Interestingly, inflammatory bowel disease (IBD) is an inflammatory disorder, but the patients with IBD do not have the increased risk to develop COVID-19. There is currently no cure for COVID-19, but anti-viruses and monoclonal antibodies reduce viral load and shorten the recovery time of the disease. We summarize current therapeutics that target symptoms in the GI tract, including probiotics, ACE2 inhibitors and nutrients. These are promising therapeutic options for COVID-19-induced gut injury.

Mechanism and potential treatments for gastrointestinal dysfunction in patients with COVID-19.

The global coronavirus disease 2019 (COVID-19) has become one of the biggest threats to the world since 2019. The respiratory and gastrointestinal tracts are the main targets for severe acute respiratory syndrome coronavirus 2 infection for they highly express angiotensin-converting enzyme-2 and transmembrane protease serine 2. In patients suffering from COVID-19, gastrointestinal symptoms have ranged from 12% to 61%. Anorexia, nausea and/or vomiting, diarrhea, and abdominal pain are considered to be the main gastrointestinal symptoms of COVID-19. It has been reported that the direct damage of intestinal mucosal epithelial cells, malnutrition, and intestinal flora disorders are involved in COVID-19. However, the underlying mechanisms remain unclear. Thus, in this study, we reviewed and discussed the correlated mechanisms that cause gastrointestinal symptoms in order to help to develop the treatment strategy and build an appropriate guideline for medical workers.

Gastrointestinal manifestations of COVID-19: An updated systematic review.

Lack of knowledge about the type and prevalence of gastrointestinal symptoms as a clinical manifestation is one of the reasons for delayed diagnosis and treatment of COVID-19 patients. This review study aimed to systematically review the type and prevalence of gastrointestinal symptoms in COVID-19 patients. To study the gastrointestinal manifestations of COVID-19, we used the 06- PRISMA registered in the CAMARADES-NC3Rs Preclinical Systematic Review and Meta-Analysis Facility (SyRF) database. PubMed, Embase, Web of Science, Google Scholar, and Scopus databases were searched for publications on the gastrointestinal manifestations of COVID-19 with no publication time frame. Articles were found using the following terms and search strategy: ["COVID-19, Coronavirus, 2019-nCoV, Clinical SymptomsGastrointestinal or gastric or intestinal manifestations"]. Out of 27652 papers, 35 papers on a total of 6730 COVID-19 patients up to 2022 met the inclusion criteria. Remarkably, most articles (28 papers, 77.8%) were from China (77.8%). The most common gastrointestinal manifestations were nausea or vomiting (13.1%), diarrhea (11.05%), anorexia (8.7%), and abdominal pain (2.4%), respectively. The findings of the present review revealed that contrary to what was initially assumed in the COVID-19 outbreak, this infection does not manifest only as respiratory symptoms but also as gastrointestinal symptoms. Therefore, clinicians and gastroenterologists must be alert to these unusual cases and fecal-oral transmission during the COVID-19 pandemic and implement preventive strategies.

It Ain't Over 'Til It's Over: SARS CoV-2 and Post-infectious Gastrointestinal Dysmotility.

The ongoing pandemic resulting from severe acute respiratory syndrome-caused by coronavirus 2 (SARS-CoV-2)-has posed a multitude of healthcare challenges of unprecedented proportions. Intestinal enterocytes have the highest expression of angiotensin-converting enzyme-2 (ACE2), which functions as the key receptor for SARS-CoV-2 entry into cells. As such, particular interest has been accorded to SARS-CoV-2 and how it manifests within the gastrointestinal system. The acute and chronic alimentary clinical implications of infection are yet to be fully elucidated, however, the gastrointestinal consequences from non-SARS-CoV-2 viral GI tract infections, coupled with the generalized nature of late sequelae following COVID-19 disease, would predict that motility disorders are likely to be seen in these patients. Determination of the chronic effects of COVID-19 disease, herein defined as GI disease which is persistent or recurrent more than 3 months following recovery from the acute respiratory illness, will require comprehensive investigations comprising combined endoscopic- and motility-based evaluation. It will be fascinating to ascertain whether the specific post-COVID-19 phenotype is hypotonic or hypertonic in nature and to identify the most vulnerable target portions of the gut. A specific biological hypothesis is that motility disorders may result from SARS-CoV-2-induced angiotensin-converting enzyme 2 (ACE2) depletion. Since SARS-CoV-2 is known to exhibit direct neuronal tropism, the potential also exists for the development of neurogenic motility disorders. This review aims to explore some of the potential pathophysiologic mechanisms underlying motility dysfunction as it relates to ACE2 and thereby aims to provide the foundation for mechanism-based potential therapeutic options.

Calprotectin: The Link Between Acute Lung Injury and Gastrointestinal Injury in Covid-19: Ban or Boon.

The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and associated hyper-inflammation due to exaggerated immune response. Different experimental and clinical studies revealed that many biomarkers could be used to determine the Covid-19 severity, such as Ddimer, procalcitonin, C-reaction protein (CRP), IL-6, and ferritin. Calprotectin (CP) is associated with intestinal inflammation, intestinal injury, and different respiratory diseases such as cystic fibrosis. Thus, CP might be a possible biomarker linking intestinal injury and acute lung injury (ALI) in Covid-19. Therefore, this study aimed to find a potential role of CP regarding GITI and ALI in Covid-19. CP is a complex protein consisting of S100A8 and S100A9, belonging to the Ca+2-binding proteins S100 family abundant in the cytosol of neutrophils and expressed on the monocyte membranes, macrophages, and intestinal epithelial cells. CP is a proinflammatory protein that acts through activation of the receptor for the advanced glycation end product (RAGE) and toll-like receptor 4 (TLR4). CP is a biomarker of neutrophil activation and is released following the turnover of neutrophils. CP could be controversial; it increases airway inflammation or protects lung and airway epithelium from an exaggerated immune response. Therefore, a high level of CP in different respiratory disorders might be protective and compensate against abnormal immune responses. CP level is high in Covid-19 and correlated with Covid-19 severity and oxygen demand due to activation of proinflammatory cytokines and inflammatory signaling pathways. Therefore, CP level is elevated in both ALI and intestinal inflammation so that it could be a potential biomarker that links the respiratory and intestinal injury in Covid-19.

Intestinal viral infections of nSARS-CoV2 in the Indian community: Risk of virus spread in India.

In December 2019, novel severe acute respiratory syndrome coronavirus 2 (nSARS-CoV-2) virus outbreaks emerged from Wuhan, China, and spread all over the world, including India. Molecular diagnosis of Coronavirus Disease 2019 (COVID) 19 for densely and highly populated countries like India is time-consuming. A few reports have described the successful diagnosis of nSARS-CoV-2 virus from sewage and wastewater samples contaminated with fecal matter, suggesting the diagnosis of COVID 19 from the same to raise an alarm about the community transmission of virus for implementation of evacuation and lockdown strategies. So far, the association between the detection of virus and its concentration in stool samples with severity of the disease and the presence or absence of gastrointestinal symptoms have been rarely reported. We led the search utilizing multiple databases, specifically PubMed (Medline), EMBASE, and Google Scholar. We conducted a literature survey on gastrointestinal infection and the spread of this virus through fecal-oral transmission. Reports suggested that the existence and persistence of nSARS-CoV-2 in anal/rectal swabs and stool specimens for a longer period of time than in nasopharyngeal swabs provides a strong tenable outcome of gastrointestinal contamination and dissemination of this infection via potential fecal-oral transmission. This review may be helpful to conduct further studies to address the enteric involvement and excretion of nSARS-CoV-2 RNA in feces and control the community spread in both COVID-19 patients ahead of the onset of symptoms and in asymptomatic individuals through wastewater and sewage surveillance as an early indication of infection. The existence of the viral genome and active viral particle actively participate in genomic variations. Hence, we comprehended the enteric spread of different viruses amongst communities with special reference to nSARS-CoV-2.

Factors Associated With Severe Gastrointestinal Diagnoses in Children With SARS-CoV-2 Infection or Multisystem Inflammatory Syndrome.

Importance: Severe gastrointestinal (GI) manifestations have been sporadically reported in children with COVID-19; however, their frequency and clinical outcome are unknown. Objective: To describe the clinical, radiological, and histopathologic characteristics of children with COVID-19 presenting with severe GI manifestations to identify factors associated with a severe outcome. Design, Setting, and Participants: A multicenter retrospective cohort study (February 25, 2020, to January 20, 2021) enrolled inpatient and outpatient children (aged <18 years) with acute SARS-CoV-2 infection, confirmed by positive real-time reverse-transcriptase-polymerase chain reaction on nasopharyngeal swab or fulfilling the US Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children (MIS-C). The study was conducted by pediatricians working in primary care or hospitals in Italy participating in the COVID-19 Registry of the Italian Society of Pediatric Infectious Diseases. Main Outcomes and Measures: The occurrence of severe GI manifestations, defined by a medical and/or radiological diagnosis of acute abdomen, appendicitis (complicated or not by perforation and/or peritonitis), intussusception, pancreatitis, abdominal fluid collection, and diffuse adenomesenteritis requiring surgical consultation, occurring during or within 4 to 6 weeks after infection with SARS-CoV-2 infection. Logistic regression was used to estimate odds ratios (ORs) with 95% CIs of factors potentially associated with severe outcomes. Results: Overall, 685 children (386 boys [56.4%]; median age, 7.3 [IQR, 1.6-12.4] years) were included. Of these children, 628 (91.7%) were diagnosed with acute SARS-CoV-2 infection and 57 (8.3%) with MIS-C. The presence of GI symptoms was associated with a higher chance of hospitalization (OR, 2.64; 95% CI, 1.89-3.69) and intensive care unit admission (OR, 3.90; 95% CI, 1.98-7.68). Overall, 65 children (9.5%) showed severe GI involvement, including disseminated adenomesenteritis (39.6%), appendicitis (33.5%), abdominal fluid collection (21.3%), pancreatitis (6.9%), or intussusception (4.6%). Twenty-seven of these 65 children (41.5%) underwent surgery. Severe GI manifestations were associated with the child's age (5-10 years: OR, 8.33; 95% CI, 2.62-26.5; >10 years: OR, 6.37; 95% CI, 2.12-19.1, compared with preschool-age), abdominal pain (adjusted OR [aOR], 34.5; 95% CI, 10.1-118), lymphopenia (aOR, 8.93; 95% CI, 3.03-26.3), or MIS-C (aOR, 6.28; 95% CI, 1.92-20.5). Diarrhea was associated with a higher chance of adenomesenteritis (aOR, 3.13; 95% CI, 1.08-9.12) or abdominal fluid collection (aOR, 3.22; 95% CI, 1.03-10.0). Conclusions and Relevance: In this multicenter cohort study of Italian children with SARS-CoV-2 infection or MIS-C, 9.5% of the children had severe GI involvement, frequently associated with MIS-C. These findings suggest that prompt identification may improve the management of serious complications.

Post-infection functional gastrointestinal disorders following coronavirus disease-19: A case-control study.

BACKGROUND AND AIM: Because acute infectious gastroenteritis may cause post-infection irritable bowel syndrome and functional dyspepsia and the severe acute respiratory syndrome coronavirus-2 affects gastrointestinal (GI) tract, coronavirus disease-19 (COVID-19) may cause post-infection-functional GI disorders (FGIDs). We prospectively studied the frequency and spectrum of post-infection-FGIDs among COVID-19 and historical healthy controls and the risk factors for its development. METHODS: Two hundred eighty patients with COVID-19 and 264 historical healthy controls were followed up at 1 and 3 months using translated validated Rome Questionnaires for the development of chronic bowel dysfunction (CBD), dyspeptic symptoms, and their overlap and at 6-month for IBS, uninvestigated dyspepsia (UD) and their overlap. Psychological comorbidity was studied using Rome III Psychosocial Alarm Questionnaire. RESULTS: At 1 and 3 months, 16 (5.7%), 16 (5.7%), 11 (3.9%), and 24 (8.6%), 6 (2.1%), 9 (3.2%) of COVID-19 patients developed CBD, dyspeptic symptoms, and their overlap, respectively; among healthy controls, none developed dyspeptic symptoms and one developed CBD at 3 months (P < 0.05). At 6 months, 15 (5.3%), 6 (2.1%), and 5 (1.8%) of the 280 COVID-19 patients developed IBS, UD, and IBS-UD overlap, respectively, and one healthy control developed IBS at 6 months (P < 0.05 for all except IBS-UD overlap). The risk factors for post-COVID-19 FGIDs at 6 months included symptoms (particularly GI), anosmia, ageusia, and presence of CBD, dyspeptic symptoms, or their overlap at 1 and 3 months and the psychological comorbidity. CONCLUSIONS: This is the first study showing COVID-19 led to post-COVID-19 FGIDs. Post-COVID-19 FGIDs may pose a significant economic, social, and healthcare burden to the world.

MIS-C among return visits for fever in a pediatric emergency department during the COVID-19 pandemic.

Return visits (RV) to a pediatric emergency department (PED) can be secondary to illness progression, parental concerns, call backs or rarely due to a diagnostic error during the first visit. Fever accounts for nearly half of these RVs and is also one of the most common presenting complaints of Corona Virus Disease 2019 (COVID- 19) due to severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection in children. Although majority of children with COVID 19 have a mild illness, severe complications such as Multisystem inflammatory syndrome in children (MIS-C) can occur. These children are often critically ill with a mortality rate of 2-4%. Initial symptoms of MIS- C are non- specific and mimic other viral illness making early diagnosis challenging. We report five patients who were evaluated for fever and discharged from our PED and were subsequently diagnosed with MIS-C (n = 3) or Kawasaki Disease (n = 2) during their RV within 7 days. All patients presented with fever during the initial visit and three of the five children had gastrointestinal symptoms. They were all noted have persistent tachycardia during the index visit. Three patients presented in cardiogenic shock and echocardiographic abnormalities were noted in four patients during the RV. Significant interventions were required in majority of these children (PICU admission: 4, inotropes: 3, mechanical ventilation:2). Clinicians need to maintain a high index of suspicion for diagnosis of MIS-C especially in those who present with persistent fever and have abnormal vital signs during the COVID-19 pandemic.

Gastrointestinal symptoms in patients with COVID-19: Is there a relationship with mortality and new variations of SARS-CoV-2?

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although, respiratory symptoms are typical the digestive system is also a susceptible target with gastrointestinal symptoms present even in the absence of respiratory symptoms. The gastrointestinal symptoms of COVID-19 include diarrhea, abdominal pain, anorexia, and nausea among other symptoms. Some questions that remain to be answered include: Do patients with gastrointestinal symptoms have a higher mortality? SARS-CoV-2 variants are already a global reality: Do these variants present with a greater prevalence of gastrointestinal symptoms? Do patients with these symptoms warrant more intensive care unit care?

Complication and Sequelae of COVID-19: What Should We Pay Attention to in the Post-Epidemic Era.

COVID-19 is widespread worldwide and seriously affects the daily life and health of humans. Countries around the world are taking necessary measures to curb the spread. However, COVID-19 patients often have at least one organ complication and sequelae in addition to respiratory symptoms. Controlling the epidemic is only a phased victory, and the complication and sequelae of COVID-19 will need more attention in the post-epidemic era. We collected general information from over 1000 articles published in 2020 after the COVID-19 outbreak and systematically analyzed the complication and sequelae associated with eight major systems in COVID-19 patients caused by ACE2 intervention in the RAS regulatory axis. The autoimmune response induced by 2019-nCoV attacks and damages the normal tissues and organs of the body. Our research will help medical workers worldwide address COVID-19 complication and sequelae.

Gastrointestinal manifestations of coronavirus disease 2019.

PURPOSE OF REVIEW: The ubiquitous expression of angiotensin-converting enzyme-2 receptors and its significance as the origin of viral entry have assisted in comprehending the pathophysiology of extrapulmonary manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, we focus on the clinical significance of gastrointestinal manifestations. RECENT FINDINGS: The global pandemic, a result of the widespread implications of SARS-CoV-2, remains a significant burden to current healthcare systems. Fever, dyspnea, and tussive symptoms have primarily been recognized as the most common presenting signs/symptoms. During the past one year our scope of practice has transcended beyond the management of the respiratory system to incorporate other varying systemic manifestations such as anorexia, nausea, vomiting, diarrhea, and abdominal pain. The outcomes reported by recent studies suggest an association between the presence of gastrointestinal symptoms and important clinical factors such as delay in presentation, disease severity, and mortality. SUMMARY: We provide a summarization of the most recent in-depth investigations of coronavirus disease 2019 with gastrointestinal manifestations and their conclusions. Although the pathophysiology remains an area of evolving interest, a better understanding of this disease process may allow for early recognition, efficient triage, and improved prognostication for those presenting with gastrointestinal manifestations of SARS-CoV-2.

Functional gastrointestinal and somatoform symptoms five months after SARS-CoV-2 infection: A controlled cohort study.

BACKGROUND: Gastrointestinal infections represent a risk factor for functional gastrointestinal and somatoform extraintestinal disorders. We investigated the prevalence and relative risk (RR) of gastrointestinal and somatoform symptoms 5 months after SARS-CoV-2 infection compared with a control cohort. METHODS: One hundred and sixty-four SARS-CoV-2 infected patients and 183 controls responded to an online questionnaire about symptoms and signs during the acute phase of the infection and after 4.8 ± 0.3 months. Presence and severity of gastrointestinal symptoms, somatization, anxiety, and depression were recorded with standardized questionnaires. Stool form and presence of irritable bowel syndrome (IBS) were also recorded. Any association between exposure to infection and symptoms was evaluated by calculating crude and adjusted RR values and score differences with 95% confidence intervals (CI). KEY RESULTS: Fever, dyspnea, loss of smell/taste/weight, diarrhea, myalgia, arthralgia, and asthenia were reported by more than 40% of patients during the acute phase. Compared with controls, adjusted RRs for loose stools, chronic fatigue, and somatization were increased after infection: 1.88 (95% CI 0.99-3.54), 2.24 (95% CI 1.48-3.37), and 3.62 (95% CI 1.01-6.23), respectively. Gastrointestinal sequelae were greater in patients with diarrhea during the acute phase. CONCLUSIONS & INFERENCES: Mild gastroenterological symptoms persist 5 months after SARS-CoV-2 infection, in particular in patients reporting diarrhea in the acute phase. Infected patients are at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somatoform disorders may have a common biological origin.

Pediatric COVID-19 and Gastrointestinal Symptoms in Africa.

One year into the coronavirus disease 2019 (COVID-19) pandemic, the African continent still seems to be spared from the devastating effects the disease had in other continents. Africa's COVID-19 seems to be of a milder nature both in adults and children. However, lack of data from Africa is significant, and more studies are needed to validate the disease status, clinical manifestations, and future implications for Africa. In this study, we report pediatric COVID-19 features in Africa represented by 8 countries.

Virus load and incidence of olfactory, gustatory, respiratory, gastrointestinal disorders in COVID-19 patients: A retrospective cohort study.

OBJECTIVES: This study investigated the relationship between viral load and the incidence of olfactory and gustatory dysfunction (OD and GD), the incidence of respiratory and gastrointestinal symptoms and the recovery of OD and GD in COVID-19 patients. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: This study was conducted on 599 outpatients' cases in Golestan province between February and June 2020. MAIN OUTCOME MEASURES: The incidence, severity (complete or partial) and recovery time of OD and GD and their associations with cycle threshold (CT) values of SARS-CoV-2 polymerase chain reaction were assessed. RESULTS: The mean age of patients was 38.27 ± 13.62 years. The incidence of general symptoms included myalgia 70.1%, headache 51.8%, fever 47.7% and dyspnoea 21.4%. 41.9% of patients had gastrointestinal symptoms, including abdominal pain 26.5%, diarrhoea 25.2%, nausea 20.5% and vomiting 12.9%. 12.2% of patients had comorbidity. The trimester recovery rates of OD and GD were 93.94% and 94.74% respectively. The mean recovery time of OD and GD was 14.56 ± 13.37 and 13.8 ± 3.77 days respectively. The mean CT value in all patients was 27.45 ± 4.55. There were significant associations between the mean of CT value with headache (p = 0.04), GD (p = 0.002) and OD (p = 0.001). CONCLUSIONS: The finding of this study indicates a possible association between viral load with incidence of OD and GD in COVID-19 patient's cases and assures the recovery of OD/GD in these patients.