COVID-19-associated gastrointestinal (GI) symptoms are often self-limiting; however, gastrointestinal bleeding (GIB) is a critical complication in patients with COVID-19. The present study investigates the etiology, risk factors, esophagogastroduodenoscopy (EGD) findings, and outcomes associated with upper gastrointestinal bleeding (UGIB) in hospital inpatients with COVID-19.

In this retrospective case-control study, 127 patients with COVID-19 in Kerman, Iran, were diagnosed using reverse transcription polymerase chain reaction (RT-PCR) and subsequently divided into case and control groups from January 2022 to July 2022.

This study evaluated 64 patients with COVID-19 with UGIB and 63 patients without. The case group reported previous history of GIB and cirrhosis at 17.2% and 12.5%, respectively (P=0.001 and P=0.01). Melena (37.5%) and peptic ulcer (21.87%) were the most common UGIB symptom and EGD findings, respectively. In the comparison of the case group with the control group, the duration of the patient's stay in the intensive care unit (ICU) (11.58±1.13 vs. 8.29±1.06 days), the need for invasive mechanical ventilation (IMV) (17.2% vs. 8.1%), and the mortality rate (26.6% vs. 18.9%) were recorded (P=0.03, 0.124, and 0.07, respectively).

Patients with COVID-19 and UGIB have a more prevalent ICU stay compared with those without. Melena and peptic ulcer were the most common presentations and EGD findings in these patients. Additionally, liver cirrhosis and a history of previous GIB increased the risk of GIB in patients with COVID-19.

SARS-CoV-2 infects via the respiratory tract, but COVID-19 includes an array of non-respiratory symptoms, among them gastrointestinal (GI) manifestations such as vomiting and diarrhea. Here we investigated the GI pathology of SARS-CoV-2 infections in rhesus macaques and humans. Macaques experienced mild infection with USA-WA1/2020 and shed viral RNA in the respiratory tract and stool, including subgenomic RNA indicative of replication in the GI tract. Intestinal immune cell populations were disturbed, with significantly fewer proliferating (Ki67+) jejunal B cells in SARS-CoV-2-infected macaques than uninfected ones. Modest translocation of bacteria/bacterial antigen was observed across the colonic epithelium, with a corresponding significant increase in plasma soluble CD14 (sCD14) that may be induced by LPS. Human plasma demonstrated significant decreases in interleukin (IL)-6 and sCD14 upon recovery from COVID-19, suggesting resolution of inflammation and response to translocated bacteria. sCD14 significantly positively correlated with zonulin, an indicator of gut barrier integrity, and IL-6. These results demonstrate that GI perturbations such as microbial translocation can occur in even mild SARS-CoV-2 infections and may contribute to the COVID-19 inflammatory state.IMPORTANCEThis study investigates gastrointestinal (GI) barrier disruption in SARS-CoV-2 infections and how it may contribute to disease. We observed bacteria or bacterial products crossing from the colon interior (the lumen) to the lamina propria during SARS-CoV-2 infection in macaques. Bacteria/bacterial products are tolerated in the lumen but may induce immune responses if they translocate to the lamina propria. We also observed a significant increase in soluble CD14, which is associated with an immune response to bacterial products. In addition, we observed that humans recovering from COVID-19 experienced a significant decrease in soluble CD14, as well as the inflammatory marker interleukin (IL)-6. IL-6 and sCD14 correlated significantly across macaque and human samples. These findings suggest that SARS-CoV-2 infection results in GI barrier disruption that permits microbial translocation and a corresponding immune response. These findings could aid in developing interventions to improve COVID-19 patient outcomes.

The pathogenesis of COVID-19 involves a complex interplay between host factors and the SARS-CoV-2 virus, leading to a multitude of clinical manifestations beyond the respiratory system. This chapter provides an overview of the risk factors, genetic predisposition, and multisystem manifestations of COVID-19, shedding light on the underlying mechanisms that contribute to extrapulmonary manifestations. The chapter discusses the direct invasion of SARS-CoV-2 into various organs as well as the indirect mechanisms such as dysregulation of the renin-angiotensin-aldosterone system (RAAS), immune response dysfunctions within the innate and adaptive immune systems, endothelial damage, and immunothrombosis. Furthermore, the multisystem manifestations of COVID-19 across different organ systems, including the cardiovascular, renal, gastrointestinal, hepatobiliary, nervous, endocrine and metabolic, ophthalmic, ear-nose-throat, reproductive, hematopoietic, and immune systems are discussed in detail. Each system exhibits unique manifestations that contribute to the complexity of the disease.

Evidence on long-term associations between coronavirus disease 2019 (COVID-19) and risks of multi-organ complications and mortality in older population is limited. This study evaluates these associations.

The cohorts included patients aged ≥60 year diagnosed with COVID-19 infection (cases), between 16 March 2020 and 31 May 2021 from the UK Biobank; and between 01 April 2020 and 31 May 2022 from the electronic health records in Hong Kong. Each patient was randomly matched with individuals without COVID-19 infection based on year of birth and sex and were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK cohort. Patients with COVID-19 infection over 6 months after the date of last dose of vaccination and their corresponding controls were excluded from our study. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. For evaluating long-term association of COVID-19 with multi-organ disease complications and mortality after 21-days of diagnosis, Cox regression was employed.

10,759 (UKB) and 165,259 (HK) older adults with COVID-19 infection with matched 291,077 (UKB) and 1,100,394 (HK) non-COVID-19-diagnosed older adults were recruited. Older adults with COVID-19 were associated with a significantly higher risk of cardiovascular outcomes [major cardiovascular disease (stroke, heart failure and coronary heart disease): hazard ratio(UKB): 1.4 (95% Confidence interval: 1.1,1.6), HK:1.2 (95% CI: 1.1,1.3)]; myocardial infarction: HR(UKB): 1.8 (95% CI: 1.3,2.4), HK:1.2 (95% CI: 1.0,1.4)]; respiratory outcomes [interstitial lung disease: HR(UKB: 3.4 (95% CI: 2.5,4.5), HK: 4.0 (95% CI: 1.3,12.8); chronic pulmonary disease: HR(UKB): 1.7 (95% CI: 1.3,2.2), HK:1.6 (95% CI: 1.3,2.1)]; neuropsychiatric outcomes [seizure: HR(UKB): 2.6 (95% CI: 1.7,4.1), HK: 1.6 (95% CI: 1.2,2.1)]; and renal outcomes [acute kidney disease: HR(UKB): 1.4 (95% CI: 1.1,1.6), HK:1.6 (95% CI: 1.3,2.1)]; and all-cause mortality [HR(UKB): 4.9 (95% CI: 4.4,5.4), HK:2.5 (95% CI: 2.5,2.6)].

COVID-19 is associated with long-term risks of multi-organ complications in older adults (aged ≥ 60). Infected patients in this age-group may benefit from appropriate monitoring of signs/symptoms for developing these complications.

Dyspepsia still becomes a major challenge in upper gastrointestinal disease in Indonesia. This disease often correlated with Helicobacter pylori infection. However, the prevalence of this bacterium is generally low in Indonesia. Therefore, several considerations should be taken into consideration during the management of dyspepsia and H. pylori infection. "Management of dyspepsia and H. pylori infection in Indonesia: The Indonesian consensus report" comprises information gathered from 22 gastroenterology centers across Indonesia. The experts gathered to evolve a consensus, that consists of the statements, grades of recommendations, evidence levels, and rationales for the dyspepsia and H. pylori infection management for daily clinical practice. The report explains several aspects from the updated epidemiology information to comprehensive management therapy. After the experts worked together on all statements in the recommendations, the results are presented with the final agreement as a consensus to help clinicians in understanding, diagnosing, and treating dyspepsia and H. pylori infection patients in daily clinical practice in Indonesia.

The gastrointestinal (GI) tract is targeted by severe acute respiratory syndrome coronavirus-2. The present review examines GI involvement in patients with long coronavirus disease and discusses the underlying pathophysiological mechanisms that include viral persistence, mucosal and systemic immune dysregulation, microbial dysbiosis, insulin resistance, and metabolic abnormalities. Due to the complex and potentially multifactorial nature of this syndrome, rigorous clinical definitions and pathophysiology-based therapeutic approaches are warranted.

Although many recent studies have examined associations between the gut microbiome and COVID-19 disease severity in individual patient cohorts, questions remain on the robustness across international cohorts of the biomarkers they reported. Here, we performed a meta-analysis of eight shotgun metagenomic studies of COVID-19 patients (comprising 1,023 stool samples) and 23 > 16S rRNA gene amplicon sequencing (16S) cohorts (2,415 total stool samples). We found that disease severity (as defined by the WHO clinical progression scale) was associated with taxonomic and functional microbiome differences. This alteration in gut microbiome configuration peaks at days 7-30 post diagnosis, after which the gut microbiome returns to a configuration that becomes more similar to that of healthy controls over time. Furthermore, we identified a core set of species that were consistently associated with disease severity across shotgun metagenomic and 16S cohorts, and whose abundance can accurately predict disease severity category of SARS-CoV-2 infected subjects, with Actinomyces oris abundance predicting population-level mortality rate of COVID-19. Additionally, we used relational diet-microbiome databases constructed from cohort studies to predict microbiota-targeted diet patterns that would modulate gut microbiota composition toward that of healthy controls. Finally, we demonstrated the association of disease severity with the composition of intestinal archaeal, fungal, viral, and parasitic communities. Collectively, this study has identified robust COVID-19 microbiome biomarkers, established accurate predictive models as a basis for clinical prognostic tests for disease severity, and proposed biomarker-targeted diets for managing COVID-19 infection.

Studies suggest that metformin is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemics. We assessed if metformin is associated with reduced incidence of severe COVID-19 for patients with prediabetes or polycystic ovary syndrome (PCOS), common diseases that increase the risk of severe COVID-19.

This observational, retrospective study utilized EHR data from 52 hospitals for COVID-19 patients with PCOS or prediabetes treated with metformin or levothyroxine/ondansetron (controls). After balancing via inverse probability score weighting, associations with COVID-19 severity were assessed by logistic regression.

In the prediabetes cohort, when compared to levothyroxine, metformin was associated with a significantly lower incidence of COVID-19 with "mild-ED" or worse (OR [95% CI]: 0.636, [0.455-0.888]) and "moderate" or worse severity (0.493 [0.339-0.718]). Compared to ondansetron, metformin was associated with lower incidence of "mild-ED" or worse severity (0.039 [0.026-0.057]), "moderate" or worse (0.045 [0.03-0.069]), "severe" or worse (0.183 [0.077-0.431]), and "mortality/hospice" (0.223 [0.071-0.694]). For PCOS, metformin showed no significant differences in severity compared to levothyroxine, but was associated with a significantly lower incidence of "mild-ED" or worse (0.101 [0.061-0.166]), and "moderate" or worse (0.094 [0.049-0.18]) COVID-19 outcome compared to ondansetron.

Metformin use is associated with less severe COVID-19 in patients with prediabetes or PCOS.

The Omicron variant (B.529) of COVID-19 caused disease outbreaks worldwide because of its contagious and diverse mutations. To reduce these outbreaks, therapeutic drugs and adjuvant vaccines have been applied for the treatment of the disease. However, these drugs have not shown high efficacy in reducing COVID-19 severity, and even antiviral drugs have not shown to be effective. Researchers thus continue to search for an effective adjuvant therapy with a combination of drugs or vaccines to treat COVID-19 disease. We were motivated to consider melatonin as a defensive agent against SARS-CoV-2 because of its various unique properties. Over 200 scientific publications have shown the significant effects of melatonin in treating diseases, with strong antioxidant, anti-inflammatory, and immunomodulatory effects. Melatonin has a high safety profile, but it needs further clinical trials and experiments for use as a therapeutic agent against the Omicron variant of COVID-19. It might immediately be able to prevent the development of severe symptoms caused by the coronavirus and can reduce the severity of the infection by improving immunity.

Describe the incidence and associated outcomes of gastrointestinal (GI) manifestations of acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in hospitalized children (MIS-C).

Retrospective review of the Viral Infection and Respiratory Illness Universal Study registry, a prospective observational, multicenter international cohort study of hospitalized children with acute COVID-19 or MIS-C from March 2020 to November 2020. The primary outcome measure was critical COVID-19 illness. Multivariable models were performed to assess for associations of GI involvement with the primary composite outcome in the entire cohort and a subpopulation of patients with MIS-C. Secondary outcomes included prolonged hospital length of stay defined as being >75th percentile and mortality.

Of the 789 patients, GI involvement was present in 500 (63.3%). Critical illness occurred in 392 (49.6%), and 18 (2.3%) died. Those with GI involvement were older (median age of 8 yr), and 18.2% had an underlying GI comorbidity. GI symptoms and liver derangements were more common among patients with MIS-C. In the adjusted multivariable models, acute COVID-19 was no associated with the primary or secondary outcomes. Similarly, despite the preponderance of GI involvement in patients with MIS-C, it was also not associated with the primary or secondary outcomes.

GI involvement is common in hospitalized children with acute COVID-19 and MIS-C. GI involvement is not associated with critical illness, hospital length of stay or mortality in acute COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) is primarily considered to be a respiratory ailment. Hitherto, abdominal symptoms have been reported with variable frequency in acute COVID-19. The purpose of this study was to estimate the frequency of abdominal symptoms at presentation among patients hospitalised with COVID-19 infection, and to determine their association with disease severity. This was a single-centre cross-sectional observational study conducted at a COVID-19 tertiary care hospital (CTRI/2021/10/037195, registered on 08/10/2021). Consecutive patients hospitalised with acute COVID-19 illness during the study period were included in the study. Their demographic information, abdominal symptoms, comorbidities and category of COVID-19 illness were elicited. All patients had serum inflammatory markers tested on the day of hospitalisation. Among the 685 participants, 214 patients had mild-to-moderate category illness whereas the rest 471 had severe COVID-19 illness. Abdominal complaints were present among 132/685 (18.3%) patients with distension of abdomen (8.03%) being the most common symptom, followed by vomiting (6.72%) and abdominal pain (3.94%). At admission to the hospital, abdominal complaints were commoner among patients with severe disease than in those with mild-to-moderate disease (101/471 vs. 31/214; p=0.029). Abdominal symptoms were associated with a higher neutrophil to lymphocyte ratio (p=0.029). The mortality among COVID-19 patients with abdominal symptoms was higher (9.09 vs. 3.25%; p = 0.007). This study demonstrates the spectrum of abdominal symptoms that can be a part of acute COVID-19 at hospitalisation and also highlights their prognostic potential in acute COVID-19 infection.

Corona virus disease-19 (COVID-19) is the latest global pandemic. COVID-19 is mainly transmitted through respiratory droplets and, apart from respiratory symptoms, patients often present with gastrointestinal symptoms and liver involvement. Given the high percentage of COVID-19 patients that present with gastrointestinal symptoms (GIS), in this review, we report a practical up-to-date reference for the physician in their clinical practice with patients affected by chronic gastrointestinal (GI) diseases (inflammatory bowel disease, coeliac disease, chronic liver disease) at the time of COVID-19. First, we summarised data on the origin and pathogenetic mechanism of SARS-CoV-2. Then, we performed a literature search up to December 2020 examining clinical manifestations of GI involvement. Next, we illustrated and summarised the most recent guidelines on how to adhere to GI procedures (endoscopy, liver biopsy, faecal transplantation), maintaining social distance and how to deal with immunosuppressive treatment. Finally, we focussed on some special conditions such as faecal-oral transmission and gut microbiota. The rapid accumulation of information relating to this condition makes it particularly essential to revise the literature to take account of the most recent publications for medical consultation and patient care.

To characterize outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19) who present with gastrointestinal (GI) symptoms.Clinical outcomes in patients with COVID-19 associated with GI symptoms have been inconsistent in the literature.The study design is a retrospective analysis of patients, age 18 years or older, admitted to the hospital after testing positive for COVID-19. Clinical outcomes included intensive care unit requirements, rates of discharges to home, rates of discharges to outside facilities, and mortality.Seven hundred fifty patients met the inclusion criteria. Three hundred seventy three (49.7%) patients presented with at least one GI symptom and 377 (50.3%) patients presented with solely non-GI symptoms. Patients who presented with at least one GI symptom had significantly lower ICU requirements (17.4% vs 20.2%), higher rates of discharges home (77.2% vs 67.4%), lower rates of discharges to other facilities (16.4% vs 22.8%), and decreased mortality (6.4% vs 9.8%) compared with patients with non-GI symptoms. However, patients who presented with solely GI symptoms had significantly higher ICU requirements (23.8% vs 17.0%), lower rates of discharges home (52.4% vs 78.7%), higher rates of discharges to facilities (28.6% vs 15.6%), and higher mortality (19.0% vs 5.7%) compared with those with mixed GI and non-GI symptoms.Although patients with COVID-19 requiring hospitalization with GI symptoms did better than those without GI symptoms, those with isolated GI symptoms without extra-GI symptoms had worse clinical outcomes. COVID-19 should be considered in patients who present with new onset or worsening diarrhea, nausea, vomiting, and abdominal pain even without pulmonary symptoms.

Aim: To identify the predictors of in-hospital mortality in patients with coronavirus disease of 2019 (COVID-19) and acute renal impairment (ARI) or chronic kidney disease (CKD), and to evaluate the performance and inter-reader concordance of chest CT total severity scores (TSSs). Methods: This retrospective single-center study was conducted on symptomatic COVID-19 patients with renal impairment (either acute or chronic) and a serum creatinine of >2 mg/dL at the time of admission. The patients’ demographic characteristics, clinical data, and laboratory data were extracted from the clinical computerized medical records. All chest CT images obtained at the time of hospital admission were analyzed. Two radiologists independently assessed the pulmonary abnormalities and scored the severity using CT chest total severity score (TSS). Univariate logistic regression analysis was used to determine factors associated with in-hospital mortality. A receiver operating characteristic (ROC) curve analysis was performed for the TSS in order to identify the cut-off point that predicts mortality. Bland−Altman plots were used to evaluate agreement between the two radiologists assessing TSS. Results: A total of 100 patients were included, with a mean age of 60 years, 54 were males, 53 had ARI, and 47 had CKD. In terms of in-hospital mortality, 60 patients were classified in the non-survivor group and 40 were classified in the survivor group. The mortality rate was higher for those with ARI compared to those with CKD (p = 0.033). The univariate regression analysis showed an increasing odds of in-hospital mortality associated with higher respiratory rate (OR 1.149, 95% CI 1.057−1.248, p = 0.001), total bilirubin (OR 2.532, 95% CI 1.099−5.836, p = 0.029), lactate dehydrogenase (LDH) (OR 1.001, 95% CI 1.000−1.003, p = 0.018), CRP (OR 1.010, 95% CI 1.002−1.017, p = 0.012), invasive mechanical ventilation (MV) (OR 7.667, 95% CI 2.118−27.755, p = 0.002), a predominant pattern of pulmonary consolidation (OR 21.714, 95% CI 4.799−98.261, p < 0.001), and high TSS (OR 2.082, 95% CI 1.579−2.745, p < 0.001). The optimum cut-off value of TSS used to predict in-hospital mortality was 8.5 with a sensitivity of 86.7% and a specificity of 87.5%. There was excellent interobserver agreement (ICC > 0.9) between the two independent radiologists in their quantitative assessment of pulmonary changes using TSS. Conclusions: In-hospital mortality is high in COVID-19 patients with ARI/CKD, especially for those with ARI. High serum bilirubin, a predominant pattern of pulmonary consolidation, and TSS are the most significant predictors of mortality in these patients. Patients with a higher TSS may require more intensive hospital care. TSS is a reliable and helpful auxiliary tool for risk stratification among COVID-19 patients with ARI/CKD.

The association between autonomic dysfunction and long-COVID syndrome is established. However, the prevalence and patterns of symptoms of dysautonomia in long-COVID syndrome in a large population are lacking.

To evaluate the prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome.

We administered the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire to a sample of post-COVID-19 patients who were referred to post-COVID clinic in Assiut University Hospitals, Egypt for symptoms concerning for long-COVID syndrome. Participants were asked to complete the COMPASS-31 questionnaire referring to the period of more than 4 weeks after acute COVID-19.

We included 320 patients (35.92 ± 11.92 years, 73% females). The median COMPASS-31 score was 26.29 (0-76.73). The most affected domains of dysautonomia were gastrointestinal, secretomotor, and orthostatic intolerance with 91.6%, 76.4%, and 73.6%, respectively. There was a positive correlation between COMPASS-31 score and long-COVID duration (p < 0.001) and a positive correlation between orthostatic intolerance domain score and post-COVID duration (p < 0.001). There was a positive correlation between orthostatic intolerance domain score and age of participants (p = 0.004). Two hundred forty-seven patients (76.7%) had a high score of COMPASS-31 >16.4. Patients with COMPASS-31 >16.4 had a longer duration of long-COVID syndrome than those with score <16.4 (46.2 vs. 26.8 weeks, p < 0.001).

Symptoms of dysautonomia are common in long-COVID syndrome. The most common COMPASS-31 affected domains of dysautonomia are gastrointestinal, secretomotor, and orthostatic intolerance. There is a positive correlation between orthostatic intolerance domain score and patients' age.

Gastrointestinal symptoms have been reported in patients with COVID-19. Several clinical investigations suggested that gastrointestinal symptoms were associated with disease severity of COVID-19. However, the relevance of gastrointestinal symptoms and mortality of COVID-19 remains largely unknown. We aim to investigate the relationship between gastrointestinal symptoms and COVID-19 mortality.

We searched the PubMed, Embase, Web of science and Cochrane for studies published between Dec 1, 2019 and May 1, 2021, that had data on gastrointestinal symptoms in COVID-19 patients. Additional literatures were obtained by screening the citations of included studies and recent reviews. Only studies that reported the mortality of COVID-19 patients with/without gastrointestinal symptoms were included. Raw data were pooled to calculate OR (Odds Ratio). The mortality was compared between patients with and without gastrointestinal symptoms, as well as between patients with and without individual symptoms (diarrhea, nausea/vomiting, abdominal pain).

Fifty-three literatures with 55,245 COVID-19 patients (4955 non-survivors and 50,290 survivors) were included. The presence of GI symptoms was not associated with the mortality of COVID-19 patients (OR=0.88; 95% CI 0.71-1.09; P=0.23). As for individual symptoms, diarrhea (OR=1.01; 95% CI 0.72-1.41; P=0.96), nausea/vomiting (OR=1.16; 95% CI 0.78-1.71; P=0.46) and abdominal pain (OR=1.55; 95% CI 0.68-3.54; P=0.3) also showed non-relevance with the death of COVID-19 patients.

Gastrointestinal symptoms are not associated with higher mortality of COVID-19 patients. The prognostic value of gastrointestinal symptoms in COVID-19 requires further investigation.

Although COVID-19 was first recognised as an acute respiratory illness, extra-pulmonary manifestations are increasingly being recognised. Acute gastrointestinal side effects have been well reported with COVID-19 infection and are estimated to affect around 17% of patients. With COVID-19 still being a relatively new illness, the chronic gastrointestinal symptoms are less well characterised. Post-infectious irritable bowel syndrome (IBS) can occur following bacterial and viral infections, and with ACE-2 receptors being shown to be present in the gastrointestinal tract and SARS-Cov-2 RNA being present in stool, SARS-CoV-2 is now appreciated as an enteric pathogen. In our study, we survey acute and chronic gastrointestinal symptoms after COVID-19 infection. We have conducted one of the few UK studies on gastrointestinal symptoms, with the longest follow-up duration of 6 months. We have found that gastrointestinal symptoms are common at 6 months, affecting 43.8% of our patients. Further research is needed to explore whether this represents a new post-COVID-19 IBS, which has not previous been described in the literature, including its clinical course and response to any potential medical therapies.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a pandemic worldwide. Although COVID-19 mainly affects the respiratory system, gastrointestinal (GI) manifestations have been frequently reported in such cases, even as initial symptoms. There have been several studies on different GI manifestations in patients with mild and severe disease or in remission. In this review article we summarized different GI manifestations of COVID-19 at various disease stages and the possible mechanisms based on published literatures, as well as the significance of GI manifestations in systemic inflammatory injury.

The gastrointestinal tract is the body's largest interface between the host and the external environment. People infected with SARS-CoV-2 are at higher risk of microbiome alterations and severe diseases. Recent evidence has suggested that the pathophysiological and molecular mechanisms associated with gastrointestinal complicity in SARS-CoV-2 infection could be explained by the role of angiotensin-converting enzyme-2 (ACE2) cell receptors. These receptors are overexpressed in the gut lining, leading to a high intestinal permeability to foreign pathogens. It is believed that SARS-CoV-2 has a lesser likelihood of causing liver infection because of the diminished expression of ACE2 in liver cells. Interestingly, an interconnection between the lungs, brain, and gastrointestinal tract during severe COVID-19 has been mentioned. We hope that this review on the molecular mechanisms related to the gastrointestinal disorders as well as neurological and hepatic manifestations experienced by COVID-19 patients will help scientists to find a convenient solution for this and other pandemic events.

Background: Patients with coronavirus disease 2019 (COVID-19) can present with gastrointestinal (GI) symptoms. However, the prevalence of GI symptoms and their association with outcomes remain controversial in COVID-19 patients. Methods: All COVID-19 patients consecutively admitted to the Wuhan Huoshenshan hospital from February 2020 to April 2020 were collected. Disease severity and outcomes were compared between COVID-19 patients with and without GI symptoms. Logistic regression analyses were performed to evaluate the association of GI symptoms with the composite endpoint and death in COVID-19 patients. A composite endpoint was defined as transfer to intensive care unit, requirement of mechanical ventilation, and death. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Overall, 2,552 COVID-19 patients were included. The prevalence of GI symptoms was 21.0% (537/2,552). Diarrhea (8.9%, 226/2,552) was the most common GI symptom. Patients with GI symptoms had significantly higher proportions of severe COVID-19 and worse outcomes than those without. Univariate logistic regression analyses demonstrated that GI symptoms were significantly associated with the composite endpoint (OR = 2.426, 95% CI = 1.608-3.661; P < 0.001) and death (OR = 2.137, 95% CI = 1.209-3.778; P = 0.009). After adjusting for age, sex, and severe/critical COVID-19, GI symptoms were still independently associated with the composite endpoint (OR = 2.029, 95% CI = 1.294-3.182; P = 0.002), but not death (OR = 1.726, 95% CI = 0.946-3.150; P = 0.075). According to the type of GI symptoms, GI bleeding was an independent predictor of the composite endpoint (OR = 8.416, 95% CI = 3.465-20.438, P < 0.001) and death (OR = 6.640, 95% CI = 2.567-17.179, P < 0.001), but not other GI symptoms (i.e., diarrhea, abdominal discomfort, nausea and/or vomiting, constipation, acid reflux and/or heartburn, or abdominal pain). Conclusion: GI symptoms are common in COVID-19 patients and may be associated with their worse outcomes. Notably, such a negative impact of GI symptoms on the outcomes should be attributed to GI bleeding.

Assessment of the prevalence and prognostic value of gastroenterological manifestations in patients with COVID-19.

A single-center retrospective cohort study was carried out. Only cases with laboratory confirmed detection of SARS-CoV-2 virus RNA using polymerase chain reaction in oro-/nasopharyngeal smear samples were subject to analysis. Patients with documented (according to anamnestic data and/or according to examination data during hospitalization) organic pathology of the gastrointestinal tract (GIT) and/or hepatobiliary system, malignant neoplasms of any localization, as well as pregnant patients were excluded from the general register of retrospective data. The final cohort was divided into two groups depending on the presence of gastrointestinal symptoms: COVID-19 with gastrointestinal symptoms (cases) and COVID-19 without gastrointestinal symptoms (control).

The final sample consisted of 3764 patients, including 2108 (56%) women and 1656 (44%) men. The average age of the subjects included in the analysis was 58.0 years (95% confidence interval CI 48.663.0). In the study cohort, gastroenterological manifestations (alone or in combination) were recorded in 885 (23.51%) patients. Calculation of the odds ratio (OR) of unfavorable and lethal outcomes between the analyzed groups showed that the presence of gastroenterological symptoms significantly increases the chances of lethal outcome in a cohort of elderly and senile patients (OR 1.6817, 95% CI 1.03352.7364; p=0.0364), determines a higher risk of hospitalization or transfer to the intensive care unit (OR 1.2959, 95% CI 1.05471.5922; p=0.0136), development of acute respiratory distress syndrome (OR 1.5952, 95% CI 1.31641.9329; p0.0001), as well as the need for mechanical ventilation (OR 1.2849, 95% CI 1.0771.5329; p=0.0054).

The present study has demonstrated that gastroenterological symptoms are detected in about one in four patients infected with the SARS-CoV-2 virus and multiply the risk of adverse and life-threatening complications of COVID-19.

The pandemic of COVID19 which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first described in China as an unexplained pneumonia transmitted by respiratory droplets. Gastrointestinal (GI) and liver injury associated with SARS-CoV-2 infection were reported as an early or sole disease manifestation, mainly outside China. The exact mechanism and incidence of GI and liver involvement are not well elucidated.

We conducted a PubMed search for all articles written in the English language about SARS-CoV-2 affecting the GI and liver. Following data extraction, 590 articles were selected. In addition to respiratory droplets, SARS-CoV-2 may reach the GI system through the fecal-oral route, saliva, and swallowing of nasopharyngeal fluids, while breastmilk and blood transmission were not implicated. Moreover, GI infection may act as a septic focus for viral persistence and transmission to the liver, appendix, and brain. In addition to the direct viral cytopathic effect, the mechanism of injury is multifactorial and is related to genetic and demographic variations. The most frequently reported GI symptoms are diarrhea, nausea, vomiting, abdominal pain, and bleeding. However, liver infection is generally discovered during laboratory testing or a post-mortem. Radiological imaging is the gold standard in diagnosing COVID-19 patients and contributes to understanding the mechanism of extra-thoracic involvement. Medications should be prescribed with caution, especially in chronic GI and liver patients.

GI manifestations are common in COVID-19 patients. Special care should be paid for high-risk patients, older males, and those with background liver disease.

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.

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.

The COVID-19 pandemic has infected millions worldwide, leaving a global burden for long-term care of COVID-19 survivors. It is thus imperative to study post-COVID (i.e., short-term) and long-COVID (i.e., long-term) effects, specifically as local and systemic pathophysiological outcomes of other coronavirus-related diseases (such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS)) were well-cataloged. We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain-Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures.

COVID-19 clinical presentation is heterogeneous, ranging from asymptomatic to severe cases. While there are a number of early publications relating to risk factors for COVID-19 infection, low sample size and heterogeneity in study design impacted consolidation of early findings. There is a pressing need to identify the factors which predispose patients to severe cases of COVID-19. For rapid and widespread risk stratification, these factors should be easily obtainable, inexpensive, and avoid invasive clinical procedures. The aim of our study is to fill this knowledge gap by systematically mapping all the available evidence on the association of various clinical, demographic, and lifestyle variables with the risk of specific adverse outcomes in patients with COVID-19.

The systematic review was conducted using standardized methodology, searching two electronic databases (PubMed and SCOPUS) for relevant literature published between 1st January 2020 and 9th July 2020. Included studies reported characteristics of patients with COVID-19 while reporting outcomes relating to disease severity. In the case of sufficient comparable data, meta-analyses were conducted to estimate risk of each variable.

Seventy-six studies were identified, with a total of 17,860,001 patients across 14 countries. The studies were highly heterogeneous in terms of the sample under study, outcomes, and risk measures reported. A large number of risk factors were presented for COVID-19. Commonly reported variables for adverse outcome from COVID-19 comprised patient characteristics, including age >75 (OR: 2.65, 95% CI: 1.81-3.90), male sex (OR: 2.05, 95% CI: 1.39-3.04) and severe obesity (OR: 2.57, 95% CI: 1.31-5.05). Active cancer (OR: 1.46, 95% CI: 1.04-2.04) was associated with increased risk of severe outcome. A number of common symptoms and vital measures (respiratory rate and SpO2) also suggested elevated risk profiles.

Based on the findings of this study, a range of easily assessed parameters are valuable to predict elevated risk of severe illness and mortality as a result of COVID-19, including patient characteristics and detailed comorbidities, alongside the novel inclusion of real-time symptoms and vital measurements.