COVID-19 and gut immunomodulation

The disease coronavirus disease 2019 (COVID-19) is a severe respiratory illness that has emerged as a devastating health problem worldwide. The disease outcome is heterogeneous, and severity is likely dependent on the immunity of infected individuals and comorbidities. Although symptoms of the disease are primarily associated with respiratory problems, additional infection or failure of other vital organs are being reported. Emerging reports suggest a quite common co-existence of gastrointestinal (GI) tract symptoms in addition to respiratory symptoms in many COVID-19 patients, and some patients show just the GI symptoms. The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut, which is supported by the fact that (1) The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells; (2) About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract; and (3) SARS-CoV-2 can directly infect gut epithelial cells in vitro (gut epithelial cells and organoids) and in vivo (rhesus monkey). The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically, stool samples of COVID-19 patients possess proinflammatory cytokines (interleukin 8), calprotectin (neutrophils activity), and immunoglobulin A antibodies. In addition to direct immune activation by the virus, impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines, hypoxia, and changes in gut microbiota (dysbiosis) due to infection of the respiratory system, which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive. This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms, their association with disease severity, and potential therapeutic interventions.     

COVID-19 and the gastrointestinal tract: Source of infection or merely a target of the inflammatory process following SARS-CoV-2 infection?

Gastrointestinal (GI) symptoms have been described in a conspicuous percentage of coronavirus disease 2019 (COVID-19) patients. This clinical evidence is supported by the detection of viral RNA in stool, which also supports the hypothesis of a possible fecal-oral transmission route. The involvement of GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is corroborated by the theoretical assumption that angiotensin converting enzyme 2, which is a SARS-CoV-2 target receptor, is present along the GI tract. Studies have pointed out that gut dysbiosis may occur in COVID-19 patients, with a possible correlation with disease severity and with complications such as multisystem inflammatory syndrome in children. However, the question to be addressed is whether dysbiosis is a consequence or a contributing cause of SARS-CoV-2 infection. In such a scenario, pharmacological therapies aimed at decreasing GI permeability may be beneficial for COVID-19 patients. Considering the possibility of a fecal-oral transmission route, water and environmental sanitation play a crucial role for COVID-19 containment, especially in developing countries.     

Current understanding of the impact of COVID-19 on gastrointestinal disease: Challenges and openings

The novel coronavirus disease-2019(COVID-19)is caused by a positive-sense single-stranded RNA virus which belongs to the Coronaviridae family.In March 2019 the World Health Organization declared that COVID-19 was a pandemic.COVID-19 patients typically have a fever,dry cough,dyspnea,fatigue,and anosmia.Some patients also report gastrointestinal(GI)symptoms,including diarrhea,nausea,vomiting,and abdominal pain,as well as liver enzyme abnormalities.Surprisingly,many studies have found severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)viral RNA in rectal swabs and stool specimens of asymptomatic COVID-19 patients.In addition,viral receptor angiotensin-converting enzyme 2 and transmembrane protease serine-type 2,were also found to be highly expressed in gastrointestinal epithelial cells of the intestinal mucosa.Furthermore,SARS-CoV-2 can dynamically infect and replicate in both GI and liver cells.Taken together these results indicate that the GI tract is a potential target of SARS-CoV-2.Therefore,the present review summarizes the vital information available to date on COVID-19 and its impact on GI aspects.     

Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19

Gastrointestinal (GI) symptoms, such as diarrhea, abdominal pain, vomiting, and anorexia, are frequently observed in patients with coronavirus disease 2019 (COVID-19). However, the pathophysiological mechanisms connecting these GI symptoms to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain elusive. Previous studies indicate that the entry of SARS-CoV-2 into intestinal cells leads to downregulation of angiotensin converting enzyme 2 (ACE2) receptors resulting in impaired barrier function. While intestinal ACE2 functions as a chaperone for the amino acid transporter B0AT1, the B0AT1/ACE2 complex within the intestinal epithelium acts as a regulator of gut microbiota composition and function. Alternations to the B0AT1/ACE2 complex lead to microbial dysbiosis through increased local and systemic immune responses. Previous studies have also suggested that altered serotonin metabolism may be the underlying cause of GI disorders involving diarrhea. The findings of elevated plasma serotonin levels and high fecal calprotectin in COVID-19 patients with diarrhea indicate that the viral infection evokes a systemic inflammatory response that specifically involves the GI. Interestingly, the elevated proinflammatory cytokines correlate with elevated serotonin and fecal calprotectin levels further supporting the evidence of GI inflammation, a hallmark of functional GI disorders. Moreover, the finding that rectal swabs of COVID-19 patients remain positive for SARS-CoV-2 even after the nasopharynx clears the virus, suggests that viral replication and shedding from the GI tract may be more robust than that of the respiratory tract, further indicating fecal-oral transmission as another important route of viral spread. This review summarized the evidence for pathophysiological mechanisms (impaired barrier function, gut inflammation, altered serotonin metabolism and gut microbiota dysbiosis) underlying the GI symptoms in patients with COVID-19.     

Gastrointestinal and hepatic manifestations of COVID-19:A comprehensive review

The severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2) that causes coronavirus disease-2019(COVID-19) is a global pandemic, manifested by an infectious pneumonia. Although patients primarily present with fever, cough and dyspnea, some patients also develop gastrointestinal(GI) and hepatic manifestations. The most common GI symptoms reported are diarrhea, nausea,vomiting, and abdominal discomfort. Liver chemistry abnormalities are common and include elevation of aspartate transferase, alanine transferase, and total bilirubin. Studies have shown that SARS-CoV-2 infects the GI tract via its viral receptor angiotensin converting enzyme Ⅱ, which is expressed on enterocytes of the ileum and colon. Viral RNA has also been isolated from stool specimens of COVID-19 patients, which raised the concern for fecal-oral transmission in addition to droplet transmission. Although indirect evidence has suggested possible fecal-oral transmission of SARS-CoV-2, more effort is needed to establish the role of the fecal-oral transmission route. Further research will help elucidate the association between patients with underlying GI diseases, such as chronic liver disease and inflammatory bowel disease, and severity of COVID-19. In this review, we summarize the data on GI involvement to date, as well as the impact of COVID-19 on underlying GI diseases.     

Gastrointestinal manifestations of human immunodeficiency virus and coronavirus disease 2019: Understanding the intersecting regions between the two epidemics

In March 2020, the World Health Organization declared coronavirus disease (COVID-19) a pandemic. As of February 2021, there were 107 million COVID-19 cases worldwide. As a comparison, there are approximately 38 million people living with human immunodeficiency virus (PLHIV) worldwide. The coexistence of both epidemics, and the syndemic effect of both viruses could lead to a delirious impact both at individual and community levels. Many intersecting points were found between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, and HIV; among which, gastrointestinal (GI) manifestations are the most notable.GI manifestations represent a common clinical presentation in both HIV and SARS-CoV-2. The emergence of GI symptoms as a result of SARS-CoV-2 infection provides a new dynamic to COVID-19 diagnosis, management, and infection control measures, and adds an additional diagnostic challenge in case of coinfection with HIV. The presence of GI manifestations in PLHIV during the COVID-19 pandemic could be referred to HIV enteropathy, presence of opportunistic infection, adverse effect of antiretrovirals, or coinfection with COVID-19. Thus, it is important to exclude SARS-CoV-2 in patients who present with new-onset GI manifestations, especially in PLHIV, to avoid the risk of disease transmission during endoscopic interventions.Structural similarities between both viruses adds a valuable intersecting point, which has mutual benefits in the management of both viruses. These similarities led to the hypothesis that antiretrovirals such as lopinavir/Rironavir have a role in the management of COVID-19, which was the target of our search strategy using the available evidence. These similarities may also facilitate the development of an efficient HIV vaccine in the future using the advances in COVID-19 vaccine development.     

Coronavirus disease–2019 and the intestinal tract: An overview

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can progress to a severe respiratory and systemic disease named coronavirus disease–2019 (COVID-19). The most common symptoms are fever and respiratory discomfort. Nevertheless, gastrointestinal infections have been reported, with symptoms such as diarrhea, nausea, vomiting, abdominal pain, and lack of appetite. Importantly, SARS-CoV-2 can remain positive in fecal samples after nasopharyngeal clearance. After gastrointestinal SARS-CoV-2 infection and other viral gastrointestinal infections, some patients may develop alterations in the gastrointestinal microbiota. In addition, some COVID-19 patients may receive antibiotics, which may also disturb gastrointestinal homeostasis. In summary, the gastrointestinal system, gut microbiome, and gut-lung axis may represent an important role in the development, severity, and treatment of COVID-19. Therefore, in this review, we explore the current pieces of evidence of COVID-19 gastrointestinal manifestations, possible implications, and interventions.     

Gastrointestinal and hepatic involvement during COVID-19 pandemic: A focus on pediatric population and possible future implications

Since the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide, there is still limited knowledge about this condition and its natural history. Children have been relatively spared during COVID-19 pandemic but a novel syndrome known as multisystem inflammatory syndrome (MIS-C) has emerged, following a SARS-CoV-2 infection in children and adolescents. This syndrome can lead to shock and multiple organ failure requiring intensive care. Although COVID-19 clinical research focuses on respiratory symptoms, extrapulmonary involvement such as gastrointestinal (GI) and hepatic manifestations should also be considered. In fact, GI and hepatic involvement play an important role among the most common presenting symptoms of both pediatric and adult COVID-19 and MIS-C. This involvement can not only be one of the most common presenting clinical features but also one of the sequelae of these syndromes. Abdominal ultrasonography monitoring could be very useful to identify a potential involvement of the GI tract and liver. Moreover, long-term follow-up is needed and would be essential to define the long-term outcomes of these patients.     

COVID-19 infection manifesting as a severe gastroparesis flare: A case report

Rationale:Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which commonly presents with symptoms including fever, cough, and dyspnea. More recently, however, some patients have tested positive for COVID-19 after developing gastrointestinal (GI) symptoms either solely or in conjunction with respiratory symptoms. This may be due to SARS-CoV-2 infection of the GI tract. In patients with chronic GI illnesses, COVID-19 may initially present as a flare of their underlying GI conditions as viruses have historically been implicated in exacerbations of GI disorders, including gastroparesis.Patient concerns:We report a case of a 37-year-old female with a history of diabetic gastroparesis who presented to the Emergency Department (ED) with nausea and vomiting similar to her gastroparesis flares.Diagnoses:Her symptoms in the ED failed to improve with fluids and anti-emetic medications. After developing a fever, she was tested and found to be positive for COVID-19.Interventions:She was started on antibiotic, steroid, and antiviral medications.Outcomes:Her symptoms improved, her fever defervesced on day 4 of hospitalization, and she was discharged on day 5 of hospitalization. The patient reported symptom improvement at a follow-up outpatient gastroenterology visit 2 months after hospitalization.Lessons:To the best of our knowledge, at the present time, this is the first report of a patient with COVID-19 presenting with signs and symptoms of a gastroparesis flare. This case illustrates that COVID-19 may present in an exacerbation of symptoms of an underlying disorder, such as a severe gastroparesis flare, in a patient with underlying gastroparesis. Initial presentation of these patients manifesting as a flare of their chronic GI disease, more severe than usual, should prompt an index of suspicion for COVID-19.     

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?     

COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract

The pandemic of coronavirus disease 2019(COVID-19), caused by a newly identified β-coronavirus(SARS-CoV-2) has emerged as a dire health problem, causing a massive crisis for global health. Primary method of transmission was firstly thought to be animal to human transmission. However, it has been observed that the virus is transmitted from human to human via respiratory droplets. Interestingly, SARS-CoV-2 ribonucleic acid(RNA) has been isolated from patient stools, suggesting a possible gastrointestinal(GI) involvement. Most commonly reported clinical manifestations are fever, fatigue and dry cough. Interestingly, a small percentage of patients experience GI symptoms with the most common being anorexia, diarrhea, nausea and vomiting. The presence of viral RNA in stools is also common and fecal tests can be positive even after negative respiratory samples. The exact incidence of digestive symptoms is a matter of debate. The distribution of Angiotensin converting enzyme type 2 receptors in multiple organs in the body provides a possible explanation for the digestive symptoms' mechanism. Cases with solely GI symptoms have been reported in both adults and children. Viral RNA has also been detected in stool and blood samples, indicating the possibility of liver damage, which has been reported in COVID-19 patients. The presence of chronic liver disease appears to be a risk factor for severe complications and a poorer prognosis, however data from these cases is lacking. The aim of this review is firstly, to briefly update what is known about the origin and the transmission of SARS-CoV-2, but mainly to focus on the manifestations of the GI tract and their pathophysiological background, so that physicians on the one hand, not to underestimate or disregard digestive symptoms due to the small number of patients exhibiting exclusively this symptomatology and on the other, to have SARS-CoV-2 on their mind when the "gastroenteritis" type symptoms predominate.     

Gastrointestinal and hepatic diseases during the COVID-19 pandemic: Manifestations,mechanism and management

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered the causative pathogen of coronavirus disease 2019 (COVID-19) and has become an international danger to human health. Although respiratory transmission and symptoms are still the essential manifestations of COVID-19, the digestive system could be an unconventional or supplementary route for COVID-19 to be transmitted and manifested, most likely due to the presence of angiotensin-converting enzyme 2 (ACE2) in the gastrointestinal tract. In addition, SARS-CoV-2 can trigger hepatic injury via direct binding to the ACE2 receptor in cholangiocytes, antibody-dependent enhancement of infection, systemic inflammatory response syndrome, inflammatory cytokine storms, ischemia/reperfusion injury, and adverse events of treatment drugs. Gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea, which are unusual in patients with COVID-19, and some digestive signs may occur without other respiratory symptoms. Furthermore, SARS-CoV-2 can be found in infected patients’ stool, demonstrating the likelihood of transmission through the fecal-oral route. In addition, liver function should be monitored during COVID-19, particularly in more severe cases. This review summarizes the evidence for extra-pulmonary manifestations, mechanisms, and management of COVID-19, particularly those related to the gastrointestinal tract and liver.     

Mechanisms of gastrointestinal barrier dysfunction in COVID-19 patients

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global public health event, resulting in a significant social and economic burden. Although COVID-19 was initially characterized as an upper respiratory and pulmonary infection, recent evidence suggests that it is a complex disease including gastrointestinal symptoms, such as diarrhea, nausea, and vomiting. Moreover, it remains unclear whether the gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or are the result of systemic immune activation and subsequent dysregulation of homeostatic mechanisms. This review provides a brief overview of the mechanisms by which SARS-CoV-2 disrupts the integrity of the gastrointestinal barrier including the mechanical barrier, chemical barrier, microbial barrier, and immune barrier.     

Paediatric gastrointestinal disorders in SARS-CoV-2 infection: Epidemiological and clinical implications

The coronavirus disease 2019 (COVID-19) pandemic is a threat worldwide for individuals of all ages, including children. Gastrointestinal manifestations could be the initial presenting manifestation in many patients, especially in children. These symptoms are more common in patients with severe disease than in patients with non-severe disease. Approximately 48.1% of patients had a stool sample that was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA. Children typically form 1%-8% of all laboratory-confirmed cases of SARS-CoV-2. Gastrointestinal manifestations of COVID-19 in children are not rare, with a prevalence between 0 and 88%, and a wide variety of presentations, including diarrhoea, vomiting, and abdominal pain, can develop before, with or after the development of respiratory symptoms. Atypical manifestations such as appendicitis or liver injury could also appear, especially in the presence of multisystem inflammatory disease. In this review, we discussed the epidemiology of COVID-19 gastrointestinal diseases in children as well as their implications on the diagnosis, misdiagnosis, prognosis, and faecal-oral transmission route of COVID-19 and the impact of gastrointestinal diseases on the gut microbiome, child nutrition, and disease management.     

COVID-19 and its effects on the digestive system

Coronavirus disease 2019 (COVID-19) is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with typical respiratory symptoms. SARS-CoV-2 invades not only the respiratory system, but also other organs expressing the cell surface receptor angiotensin converting enzyme 2. In particular, the digestive system is a susceptible target of SARS-CoV-2. Gastrointestinal symptoms of COVID-19 include anorexia, nausea, vomiting, diarrhea, abdominal pain, and liver damage. Patients with digestive damage have a greater chance of progressing to severe or critical illness, a poorer prognosis, and a higher risk of death. This paper aims to summarize the digestive system symptoms of COVID-19 and discuss fecal-oral contagion of SARS-CoV-2. It also describes the characteristics of inflammatory bowel disease patients with SARS-CoV-2 infection and discusses precautions for preventing SARS-CoV-2 infection during gastrointestinal endoscopy procedures. Improved attention to digestive system abnormalities and gastrointestinal symptoms of COVID-19 patients may aid health care providers in the process of clinical diagnosis, treatment, and epidemic prevention and control.     

Interferon-lambda: New role in intestinal symptoms of COVID-19

The tremendous public health and economic impact of coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2), has become a huge challenge globally. There is increasing evidence that SARS-CoV-2 induces intestinal infections. Type Ⅲ interferon(IFN-λ) has an antiviral role in intestinal infection, with focused, long-lasting, and non-inflammatory characteristics. This review presents a summary of the structure of SARSCoV-2, including its invasion and i...     

Acute upper limb ischemia in a patient with COVID-19

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with upper and lower respiratory tract symptoms, with complications related to cytokine storm syndrome and acute respiratory distress syndrome. It has also been described to predispose to venous and arterial thromboembolism; however, limited published data is available regarding thrombosis in coronavirus disease 2019 (COVID-19). Here we are presenting a case of arterial thrombosis in a patient with COVID-19 and a systematic review on coagulopathy associated with COVID-19.     

Altered gut microbiota patterns in COVID-19: Markers for inflammation and disease severity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a severe respiratory illness and alters the gut microbiota, which dynamically interacts with the human immune system. Microbiota alterations include decreased levels of beneficial bacteria and augmentation of opportunistic pathogens. Here, we describe critical factors affecting the microbiota in coronavirus disease 2019 (COVID-19) patients. These include, such as gut microbiota imbalance and gastrointestinal symptoms, the pattern of altered gut microbiota composition in COVID-19 patients, and crosstalk between the microbiome and the gut-lung axis/gut-brain-lung axis. Moreover, we have illustrated the hypoxia state in COVID-19 associated gut microbiota alteration. The role of ACE2 in the digestive system, and control of its expression using the gut microbiota is discussed, highlighting the interactions between the lungs, the gut, and the brain during COVID-19 infection. Similarly, we address the gut microbiota in elderly or co-morbid patients as well as gut microbiota dysbiosis of in severe COVID-19. Several clinical trials to understand the role of probiotics in COVID-19 patients are listed in this review. Augmented inflammation is one of the major driving forces for COVID-19 symptoms and gut microbiome disruption and is associated with disease severity. However, understanding the role of the gut microbiota in immune modulation during SARS-CoV-2 infection may help improve therapeutic strategies for COVID-19 treatment.     

Markers Associated with COVID-19 Susceptibility,Resistance, and Severity

In December 2019, the latest member of the coronavirus family, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, leading to the outbreak of an unusual viral pneumonia known as coronavirus disease 2019 (COVID-19). COVID-19 was then declared as a pandemic in March 2020 by the World Health Organization (WHO). The initial mortality rate of COVID-19 declared by WHO was 2%; however, this rate has increased to 3.4% as of 3 March 2020. People of all ages can be infected with SARS-CoV-2, but those aged 60 or above and those with underlying medical conditions are more prone to develop severe symptoms that may lead to death. Patients with severe infection usually experience a hyper pro-inflammatory immune reaction (i.e., cytokine storm) causing acute respiratory distress syndrome (ARDS), which has been shown to be the leading cause of death in COVID-19 patients. However, the factors associated with COVID-19 susceptibility, resistance and severity remain poorly understood. In this review, we thoroughly explore the correlation between various host, viral and environmental markers, and SARS-CoV-2 in terms of susceptibility and severity.