The Impact of Initial COVID-19 Episode Inflammation Among Adults on Mortality Within 12 Months Post-hospital Discharge

Authors: Arch G. Mainous III1,2*Benjamin J. Rooks1 and Frank A. Orlando1 May 12, 2022 Frontiers in Medicine

Background: Inflammation in the initial COVID-19 episode may be associated with post-recovery mortality. The goal of this study was to determine the relationship between systemic inflammation in COVID-19 hospitalized adults and mortality after recovery from COVID-19.

Methods: An analysis of electronic health records (EHR) for patients from 1 January, 2020 through 31 December, 2021 was performed for a cohort of COVID-19 positive hospitalized adult patients. 1,207 patients were followed for 12 months post COVID-19 episode at one health system. 12-month risk of mortality associated with inflammation, C-reactive protein (CRP), was assessed in Cox regressions adjusted for age, sex, race and comorbidities. Analyses evaluated whether steroids prescribed upon discharge were associated with later mortality.

Results: Elevated CRP was associated other indicators of severity of the COVID-19 hospitalization including, supplemental oxygen and intravenous dexamethasone. Elevated CRP was associated with an increased mortality risk after recovery from COVID-19. This effect was present for both unadjusted (HR = 1.60; 95% CI 1.18, 2.17) and adjusted analyses (HR = 1.61; 95% CI 1.19, 2.20) when CRP was split into high and low groups at the median. Oral steroid prescriptions at discharge were found to be associated with a lower risk of death post-discharge (adjusted HR = 0.49; 95% CI 0.33, 0.74).

Discussion: Hyperinflammation present with severe COVID-19 is associated with an increased mortality risk after hospital discharge. Although suggestive, treatment with anti-inflammatory medications like steroids upon hospital discharge is associated with a decreased post-acute COVID-19 mortality risk.

Introduction

The impact of coronavirus disease 2019 (COVID-19) has been immense. In terms of directly measured outcomes, as of February, 2022, worldwide more than 5.9 million people have died from directly linked COVID-19 episodes. More than 950,000 direct deaths from COVID-19 have been documented in the United States (1). Some evidence has suggested that some patients with COVID-19 may be at risk for developing health problems after the patient has recovered from the initial episode (24). Common sequelae that have been noted are fatigue, shortness-of-breath, and brain fog. Perhaps more concerningly, in addition to these symptoms, several studies have shown that following recovery from the initial COVID-19 episode, some patients are at risk for severe morbidity and mortality (58). Patients who have recovered from COVID-19 are at increased risk for hospitalization and death within 6–12 months after the initial episode. This morbidity and mortality is typically not listed or considered as a COVID-19 linked hospitalization or death in the medical records and thus are underreported as a post-acute COVID-19 sequelae.

The reason for this phenomenon of severe outcomes as post-acute sequelae of COVID-19 is not well understood. Early in COVID-19 episode, the disease is primarily driven by the replication of SARS-CoV-2. COVID-19 also exhibits a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. The downstream impact of the initial COVID-19 episode is consistently higher in people with more severe acute infection (569). Cytokine storm, hyperinflammation, and multi-organ failure have also been indicated in patients with a severe COVID-19 episode (10). Cerebrospinal fluid samples indicate neuroinflammation during acute COVID-19 episodes (11). Moreover, even 40–60 days post-acute COVID-19 infection there is evidence of a significant remaining inflammatory response in patients (12). Thus, it could be hypothesized that the hyperinflammation that some COVID-19 patients have during the initial COVID-19 episode creates a systemic damage to multiple organ systems (1314). Consequently, that hyperinflammation and the corresponding systemic damage to multiple organ systems may lead to severe post-acute COVID-19 sequelae.

Following from this hyperinflammation, the use of steroids as anti-inflammatory treatments among patients with high inflammation during the initial COVID-19 episode may do more than just help in the initial episode but may act as a buffer to the downstream morbidity and mortality from the initial COVID-19 episode (1415).

The purpose of this study was to examine the relationship between substantial systemic inflammation, as measured by C-reactive protein (CRP), with post-acute COVID-19 sequelae among patients hospitalized with COVID-19. This 12-month mortality risk was examined in a longitudinal cohort of patients who tested positive for COVID-19 as determined by Polymerase Chain Reaction (PCR) testing within a large healthcare system.

Methods

The data for this project comes from a de-identified research databank containing electronic health records (EHR) of patients tested for or diagnosed with COVID-19 in any setting in the University of Florida (UF) Health system. Usage of the databank for research is not considered human subjects research, and IRB review was not required to conduct this study.

Definition of Cohort

The cohort for this study consisted of all adult patients aged 18 and older who were tested for COVID-19 between January 01, 2020 and December 31, 2021 within the UF Health system, in any encounter type (ambulatory, Emergency Department, inpatient, etc.). Although a patient in the cohort could have had a positive test administered in any of these settings, a patient was only included into the cohort if that patient experienced a hospitalization for COVID-19. Since this study included data from the early stages of the pandemic before consistent coding standards for documenting COVID-19 in the EHR had been established, a patient was considered to have been hospitalized for COVID-19 if they experienced any hospitalization within 30 days of a positive test for COVID-19. The databank contained EHR data for all patients in the cohort current through December 31, 2021. COVID-19 diagnosis was validated by PCR. Baseline dates for COVID-19 positive patients were established at the date of their earliest recorded PCR-confirmed positive COVID-19 test. Each patient was only included once in the analysis. For patients with multiple COVID-19 tests, if at least one test gave a positive result, the patient was classified as COVID-19 positive, and the date of their earliest positive COVID-19 test result was used as their baseline date. Patients who did not have a positive COVID-19 test were not included in the analysis. Patients were tested in the context of seeking care for COVID-19; the tests were not part of general screening and surveillance.

Only patients with at least 365 days of follow-up time after their baseline date were retained in the cohort. Patients with more than 365 days of follow-up were censored at 365 days. The cohort was also left censored at the 30-day mark post-hospital discharge to ensure that health care utilization was post-acute and not part of the initial COVID-19 episode of care (e.g., not a readmission).

Inflammation

C-reactive protein (CRP) was used as the measure of inflammation in this study. The UF Health laboratory measured CRP in serum using latex immunoturbidimetry assay. CRP measures were sourced from patient EHR data. The cohort was restricted to only include patients with at least one CRP measurement within their initial COVID-19 episode of care (between the date of their initial positive COVID-19 test and the left-hand censoring date). For patients with multiple measurements of CRP, the maximum value available was used.

Steroids

Intravenous dexamethasone during their initial COVID-19 hospitalization was assessed. Prescriptions for oral steroids (tablets of dexamethasone) that were prescribed either at or post-hospital discharge for their initial COVID-19 episode of care were included into the analysis. Prescriptions were identified using RxNorm codes available in each patient’s EHR.

Severity of Initial COVID-19 Hospitalization

We also measured the severity of the initial episode of COVID-19 hospitalization. This severity should track with the level of inflammation in the initial COVID-19 episode. We used the National Institutes of Health’s “Therapeutic Management of Hospitalized Adults With COVID-19” disease severity levels and definitions (16). The recommendations are based on four ascending levels: hospitalized but does not require supplemental oxygen, hospitalized and requires supplemental oxygen, hospitalized and requires supplemental oxygen through a high-flow device or noninvasive ventilation, hospitalized and requires mechanical ventilation or extracorporeal membrane oxygenation. For this study, because of the general conceptual model of severity moving from no supplemental oxygen to supplemental oxygen to mechanical ventilation, we collapsed the two supplemental non-mechanical ventilation oxygen into one intermediate category of severity.

Outcome Variables

The primary outcome investigated in this study was the 365-day all-cause mortality. Mortality data was sourced both from EHR data and the Social Security Death Index (SSDI), allowing for the assessment of deaths which occurred outside of UF’s healthcare system. When conflicting dates of death were observed between the EHR and SSDI, the date recorded in the patient’s medical record was used. Patients who died within their 365-day follow-up window were censored at the date of their recorded death. The cause of death was not available in the EHR based database and was not routinely and reliably reported in either the SSDI or EHR. We were unable to estimate the cause of death.

Comorbidities

Comorbidities and demographic variables which could potentially confound the association between inflammation represented by CRP and mortality post-acute COVID-19 were collected at baseline for each member of the cohort. Demographic variables included patient age, race, ethnicity, and sex. The Charlson Comorbidity Index was also calculated, accounting for the conditions present for each patient at their baseline. The Charlson Comorbidity Index was designed to be used to predict 1-year mortality and is a widely used measure to account for comorbidities (17).

Analysis

CRP was evaluated using descriptive statistics. We performed a median split of the CRP levels and defined elevated inflammation as a CRP level at or above the median and levels below the median as low inflammation. Additionally, as a way to examine greater separation between high and low inflammation, we segmented CRP levels into tertiles and categorized elevated inflammation as the top tertile and compared it to the first tertile by chi-square tests.

CRP level was also cross classified by severity of COVID-19 hospitalization and associations between the two variables were assessed using one-way ANOVA tests.

Kaplan-Meier curves comparing the survival probabilities of the high and low inflammation groups were created and compared using a log-rank test. Hazard ratios for the risk of death for post-acute COVID-19 complications by COVID-19 status were determined using Cox proportional hazard models. We obtained hazard ratios for mortality based on tertile and median splits of CRP. These analyses were then modified to control for age, sex, race, ethnicity, and the Charlson Comorbidity Index.

Additional analyses stratified by use of steroids were performed to compare the strength of the association between inflammation and death. The proportional hazards assumption was confirmed by inspection of the Schoenfeld residual plots for each variable included in the models and testing of the time-dependent beta coefficients. Analyses were conducted using the survival package in R v4.0.5.

Results

A total of 1,207 patients were included in the final cohort (Table 1). The characteristics of the patients are featured in Table 1. The mean CRP rises with the severity of illness in these COVID-19 inpatients. The mean CRP in the lowest severity (no supplemental oxygen) is 59.4 mg/L (SD = 61.8 mg/L), while the mean CRP in the intermediate severity group (supplemental oxygen) is 126.9 mg/L (SD = 98.6 mg/L), and the mean CRP in the highest severity group (ventilator or ECMO) is 201.2 mg/L (SD = 117.0 mg/L) (p < 0.001). Similarly, since dexamethasone is only recommended for the most severe patients with COVID-19, patients with dexamethasone had higher CRP (158.8 mg/L; SD = 114.9 mg/L) than those not on Dexamethasone (102.8 mg/L; SD = 90/8 mg/L) (p < 0.001).TABLE 1

Table 1. Characteristics of the patients in the cohort.

Figure 1 presents the Kaplan-Meier curves comparing the risk of mortality by inflammation over time. A log-rank test indicated there was a statistically significant difference in survival probabilities between the two groups (p = 0.002).FIGURE 1

Figure 1. All-cause mortality Kaplan-Meier curve comparing individuals with median or greater vs. below median C-reactive protein levels. Log rank test = p.002.

Table 2 shows the relationship between levels of inflammation and mortality post-recovery from COVID-19. In both unadjusted and adjusted analyses, elevated inflammation has a significantly increased risk compared to those with low inflammation in the initial COVID-19 episode. This finding of higher inflammation during the initial COVID-19 hospitalization and increased mortality risk after recovery was similar when CRP was split at the median and when the third tertile of CRP was compared to the first tertile of CRP. The proportional hazards assumption was met when the Schoenfeld plots.TABLE 2

Table 2. All-cause mortality hazard ratios by inflammation and steroid use.

We examined the hypothesized relationship that potentially decreasing inflammation in COVID-19 patients with an initial severe episode may have beneficial downstream effects on post-acute COVID-19 sequelae. Oral steroid prescriptions at discharge among these hospitalized COVID-19 patients were found to be associated with a lower risk of death post-discharge (Table 2).

Discussion

The results of this study reaffirm the importance of post-acute COVID-19 sequelae. This study is the first to show the impact of inflammation in the initial COVID-19 hospitalization episode on downstream mortality after the patient has recovered. This expands our understanding of post-acute COVID-19 sequelae by providing a better concept of why certain patients have post-acute COVID-19 mortality risk.

Previous studies have shown that patients who are hospitalized with COVID-19 have an increased risk of mortality 12 months after recovery (5). Those findings suggest that prevention of COVID-19 hospitalizations is of paramount importance. However, some patients will be hospitalized. The finding that elevated inflammation during the initial hospitalization episode is associated with mortality risk after recovery suggests that it may be worthwhile treating the viral episode but also consider treating the hyperinflammation. The NIH recommendations for care of COVID-19 hospitalized patients recommend steroids only for patients who need supplemental oxygen (16). The finding that the use of steroids prescribed upon discharge from the hospital and the corresponding reduced risk of mortality indicate that treating inflammation after the acute COVID-19 episode may act as a buffer to the downstream mortality risk from the initial COVID-19 episode (1415). Perhaps this requires a reconceptualization of COVID-19 as both an acute disease and potentially a chronic disease because of the lingering risks. Future research is needed to see if ongoing treatment for inflammation in a clinical trial has positive benefits.

There are several strengths and limitations to this study. The strengths of this study include the PCR validated COVID-19 tests at baseline for the cohort. Further, the linked electronic health record allows us to look not only at health care utilization like hospitalizations and both inpatient and outpatient medication but also laboratory tests like CRP levels. The cohort also allows us to have a substantial follow-up time.

In terms of limitations, the first that needs to be considered is that the analysis was based on hospitalized patients seen in one health system with a regional catchment area. Although more than 1200 hospitalized patients with PCR validated COVID-19 diagnoses were included in the analysis, and the cohort was followed for 12 months, the primary independent variable was systemic inflammation which should not be substantially affected by region of the country. Second, the data are observational. Thus, the analyses related to steroids and downstream mortality require a clinical trial to confirm these suggestive findings. Third, we did not have death certificates available to us to compute cause of death. The Social Security Death Index in partnership with the EHR allows us to be confident that the patient died and so we have a strong measure of all-cause mortality but we were unable to determine specific causes of death within this database. Fourth, although there are a variety of other markers of inflammation (e.g., D dimer, IL 6), CRP is one of the most robust measures of systemic inflammation. Moreover, it is much more widely used and was the most prevalent marker among the patients in the study.

In conclusion, hyperinflammation present with severe COVID-19 is associated with an increased mortality risk after hospital discharge. Although suggestive, treatment with anti-inflammatory medications like steroids upon hospital discharge is associated with a decreased post-acute COVID-19 mortality risk. This suggests that treating inflammation may also benefit other post-acute sequelae like long COVID. A reconceptualization of COVID-19 as both an acute and chronic condition may be useful.

References

1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available online at: https://coronavirus.jhu.edu/map.html (accessed February 28, 2022).

Google Scholar

2. Bell ML, Catalfamo CJ, Farland LV, Ernst KC, Jacobs ET, Klimentidis YC, et al. Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT. PLoS ONE. (2021) 16:e0254347. doi: 10.1371/journal.pone.0254347

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. (2020) 81:e4–6. doi: 10.1016/j.jinf.2020.08.029

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Alkodaymi MS, Omrani OA, Fawzy NA, Shaar BA, Almamlouk R, Riaz M, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect. (2022). doi: 10.1016/j.cmi.2022.01.014. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Mainous AG 3rd, Rooks BJ, Wu V, Orlando FA. COVID-19 post-acute sequelae among adults: 12 month mortality risk. Front Med. (2021) 8:778434. doi: 10.3389/fmed.2021.778434

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Mainous AG 3rd, Rooks BJ, Orlando FA. Risk of New Hospitalization Post-COVID-19 Infection for Non-COVID-19 Conditions. J Am Board Fam Med. (2021) 34:907–13. doi: 10.3122/jabfm.2021.05.210170

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Bhaskaran K, Rentsch CT, Hickman G, Hulme WJ, Schultze A, Curtis HJ, et al. Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: a cohort study using linked primary care, secondary care, and death registration data in the OpenSAFELY platform. PLoS Med. (2022) 19:e1003871. doi: 10.1371/journal.pmed.1003871

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature. (2021) 594:259–64. doi: 10.1038/s41586-021-03553-9

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Xie Y, Bowe B, Al-Aly Z. Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status. Nat Commun. (2021) 12:6571. doi: 10.1038/s41467-021-26513-3

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Wong RSY. Inflammation in COVID-19: from pathogenesis to treatment. Int J Clin Exp Pathol. (2021) 14:831–44.

Google Scholar

11. Spudich S, Nath A. Nervous system consequences of COVID-19. Science. (2022) 375:267–9. doi: 10.1126/science.abm2052

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Doykov I, Hällqvist J, Gilmour KC, Grandjean L, Mills K, Heywood WE. ‘The long tail of Covid-19’ – The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients. F1000Res. (2020) 9:1349. doi: 10.12688/f1000research.27287.1

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Theoharides TC. Could SARS-CoV-2 spike protein be responsible for long-COVID syndrome? Mol Neurobiol. (2022) 59:1850–61. doi: 10.1007/s12035-021-02696-0

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Cron RQ, Caricchio R, Chatham WW. Calming the cytokine storm in COVID-19. Nat Med. (2021) 27:1674–5. doi: 10.1038/s41591-021-01500-9

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Keller MJ, Kitsis EA, Arora S, Chen JT, Agarwal S, Ross MJ, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med. (2020) 15:489–93. doi: 10.12788/jhm.3497

PubMed Abstract | CrossRef Full Text | Google Scholar

16. National Institutes of Health. Therapeutic Management of Hospitalized Adults With COVID-19. (2021). https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-adults–therapeutic-management/ (accessed February 28, 2022).

Google Scholar

17. Charlson ME, Carrozzino D, Guidi J, Patierno C. Charlson comorbidity index: a critical review of clinimetric properties. Psychother Psychosom. (2022) 91:8–35. doi: 10.1159/000521288

PubMed Abstract | CrossRef Full Text | Google Scholar

Acute Mesenteric Ischemia in COVID-19 Patients

Authors: Dragos Serban 1,2,*† , Laura Carina Tribus 3,4,†, Geta Vancea 1,5,† , Anca Pantea Stoian, Ana Maria Dascalu 1,* Andra Iulia Suceveanu 6Ciprian Tanasescu 7,8, Andreea Cristina Costea 9 Mihail Silviu Tudosie 1, Corneliu Tudor 2, Gabriel Andrei Gangura 1,10, Lucian Duta 2 and Daniel Ovidiu Costea 6,11,

Abstract:

Acute mesenteric ischemia is a rare but extremely severe complication of SARS-CoV-2 infection. The present review aims to document the clinical, laboratory, and imaging findings, management, and outcomes of acute intestinal ischemia in COVID-19 patients. A comprehensive search was performed on PubMed and Web of Science with the terms “COVID-19” and “bowel ischemia” OR “intestinal ischemia” OR “mesenteric ischemia” OR “mesenteric thrombosis”. After duplication removal, a total of 36 articles were included, reporting data on a total of 89 patients, 63 being hospitalized at the moment of onset. Elevated D-dimers, leukocytosis, and C reactive protein (CRP) were present in most reported cases, and a contrast-enhanced CT exam confirms the vascular thromboembolism and offers important information about the bowel viability. There are distinct features of bowel ischemia in non-hospitalized vs. hospitalized COVID-19 patients, suggesting different pathological pathways. In ICU patients, the most frequently affected was the large bowel alone (56%) or in association with the small bowel (24%), with microvascular thrombosis. Surgery was necessary in 95.4% of cases. In the non-hospitalized group, the small bowel was involved in 80%, with splanchnic veins or arteries thromboembolism, and a favorable response to conservative anticoagulant therapy was reported in 38.4%. Mortality was 54.4% in the hospitalized group and 21.7% in the non-hospitalized group (p < 0.0001). Age over 60 years (p = 0.043) and the need for surgery (p = 0.019) were associated with the worst outcome. Understanding the mechanisms involved and risk factors may help adjust the thromboprophylaxis and fluid management in COVID-19 patients.

1. Introduction Acute mesenteric ischemia (AMI) is a major abdominal emergency, characterized by a sudden decrease in the blood flow to the small bowel, resulting in ischemic lesions of the intestinal loops, necrosis, and if left untreated, death by peritonitis and septic shock. In nonCOVID patients, the etiology may be mesenteric arterial embolism (in 50%), mesenteric arterial thrombosis (15–25%), venous thrombosis (5–15%), or less frequent, from nonocclusive causes associated with low blood flow [1]. Several systemic conditions, such as arterial hypertension, atrial fibrillation, atherosclerosis, heart failure, or valve disease are risk factors for AMI. Portal vein thrombosis and mesenteric vein thrombosis can be seen with celiac disease [2], appendicitis [3], pancreatitis [4], and, in particular, liver cirrhosis and hepatocellular cancer [5]. Acute intestinal ischemia is a rare manifestation during COVID-19 disease, but a correct estimation of its incidence is challenging due to sporadic reports, differences in patients’ selection among previously published studies, and also limitations in diagnosis related to the strict COVID-19 regulations for disease control and difficulties in performing imagistic investigations in the patients in intensive care units. COVID-19 is known to cause significant alteration of coagulation, causing thromboembolic acute events, of which the most documented were pulmonary embolism, acute myocardial infarction, and lower limb ischemia [6]. Gastrointestinal features in COVID-19 disease are relatively frequently reported, varying from less than 10% in early studies from China [7,8] to 30–60%, in other reports [9,10]. In an extensive study on 1992 hospitalized patients for COVID-19 pneumonia from 36 centers, Elmunzer et al. [7] found that the most frequent clinical signs reported were mild and self-limited in up to 74% of cases, consisting of diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). However, severe cases were also reported, requiring emergency surgery for acute bowel ischemia or perforation [5,8]. The pathophysiology of the digestive features in COVID-19 patients involves both ischemic and non-ischemic mechanisms. ACE2 receptors are present at the level of the intestinal wall, and enterocytes may be directly infected by SARS-CoV-2. The virus was evidenced in feces and enteral walls in infected subjects [4,11–13]. In a study by Xu et al., rectal swabs were positive in 8 of 10 pediatric patients, even after the nasopharyngeal swabs became negative [14]. However, the significance of fecal elimination of viral ARN is still not fully understood in the transmission chain of the SARS-CoV-2 infection. On the other hand, disturbance of lung-gut axis, prolonged hospitalization in ICU, and the pro coagulation state induced by SARS-CoV-2 endothelial damage was incriminated for bowel ischemia, resulting in intestinal necrosis and perforation [8,9,15]. Early recognition and treatment of gastrointestinal ischemia are extremely important, but it is often challenging in hospitalized COVID-19 patients with severe illness. The present review aims to document the risk factors, clinical, imagistic, and laboratory findings, management, and outcomes of acute intestinal ischemic complications in COVID-19 patients. 2. Materials and Methods A comprehensive search was performed on PubMed and Web of Science with the terms “COVID-19” AND (“bowel ischemia” OR “intestinal ischemia” OR “mesenteric ischemia” OR “mesenteric thrombosis”). All original papers and case reports, in the English language, for which full text could be obtained, published until November 2021, were included in the review. Meeting abstracts, commentaries, and book chapters were excluded. A hand search was performed in the references of the relevant reviews on the topic. 2.1. Data Extraction and Analysis The review is not registered in PROSPERO. A PRISMA flowchart was employed to screen papers for eligibility (Figure 1) and a PRISMA checklist is presented as a Supple- J. Clin. Med. 2022, 11, 200 3 of 22 mentary File S1. A data extraction sheet was independently completed by two researchers, with strict adherence to PRISMA guidelines. J. Clin. Med. 2022, 11, 200 3 2.1. Data Extraction and Analysis The review is not registered in PROSPERO. A PRISMA flowchart was employedscreen papers for eligibility (Figure 1) and a PRISMA checklist is presented as a Supmentary File S1. A data extraction sheet was independently completed by two researchwith strict adherence to PRISMA guidelines. Figure 1. PRISMA 2020 flowchart for the studies included in the review. The relevant data abstracted from these studies are presented in Tables 1–3. COV19 diagnosis was made by PCR assay in all cases. All patients reported with COVIDdisease and mesenteric ischemia were documented in terms of age, sex, comorbidittime from SARS-CoV-2 infection diagnosis, presentation, investigations, treatment, outcome. A statistical analysis of the differences between acute intestinal ischemia in pviously non-hospitalized vs. previously hospitalized patients was performed. The pottial risk factors for an adverse vital prognosis were analyzed using SciStat® softw(www.scistat.com (accessed on 25 November 2021)). Papers that did not provide sufficient data regarding evaluation at admission, domentation of SARS-CoV-2 infection, or treatment were excluded. Patients suffering frother conditions that could potentially complicate intestinal ischemia, such as liver cirrsis, hepatocellular carcinoma, intraabdominal infection (appendicitis, diverticulitis), pcreatitis, and celiac disease were excluded. Any disagreement was solved by discussioFigure 1. PRISMA 2020 flowchart for the studies included in the review. The relevant data abstracted from these studies are presented in Tables 1–3. COVID-19 diagnosis was made by PCR assay in all cases. All patients reported with COVID-19 disease and mesenteric ischemia were documented in terms of age, sex, comorbidities, time from SARS-CoV-2 infection diagnosis, presentation, investigations, treatment, and outcome. A statistical analysis of the differences between acute intestinal ischemia in previously nonhospitalized vs. previously hospitalized patients was performed. The potential risk factors for an adverse vital prognosis were analyzed using SciStat® software (www.scistat.com (accessed on 25 November 2021)). Papers that did not provide sufficient data regarding evaluation at admission, documentation of SARS-CoV-2 infection, or treatment were excluded. Patients suffering from other conditions that could potentially complicate intestinal ischemia, such as liver cirrhosis, hepatocellular carcinoma, intraabdominal infection (appendicitis, diverticulitis), pancreatitis, and celiac disease were excluded. Any disagreement was solved by discussion. J. Clin. Med. 2022, 11, 200 4 of 22 Table 1. Patients with intestinal ischemia in retrospective studies on hospitalized COVID-19 patients. Study No of Patients with Gastrointestinal Ischemia (Total No of COVID-19 Patients in ICU) Sex (M; F) Age (Mean) BMI Time from Admission to Onset (Days) Abdominal CT Signs Intraoperative/Endoscopic Findings Treatment Outcomes Kaafarani HMA [16] 5 (141); 3.8% 1;3 62.5 32.1 51.5 (18–104) days NA Cecum-1—patchy necrosis Cecum_ileon-1 Small bowel-3; yellow discoloration on the antimesenteric side of the small bowel; 1 case + liver necrosis Surgical resection NA Kraft M [17] 4 (190); 2.1% NA NA NA NA NA Bowel ischemia + perforation (2) Bowel ischemia + perforation (1) MAT+massive bowel ischemia (1) Right hemicolectomy (2) Transverse colectomy (1) Conservative, not fit for surgery Recovery (3) Death (1) Yang C [18] 20 (190 in ICU; 582 in total); 10.5% 15:5 69 31.2 26.5 (17–42) Distension Wall thickness Pneumatosis intestinalis Perforation SMA or celiac thrombosis no info Right hemicolectomy 7(35%) Sub/total colectomy12 (60%) Ileocecal resection 1(5%) Recovery (11) Death (9) Hwabejire J [19] 20 13:7 58.7 32.5 13 (1–31) Pneumatosis intestinalis 42% Portal venous gas (33%) Mesenteric vessel patency 92% large bowel ischemia (8) small bowel ischemia (4) both (8) yellow discoloration of the ischemic bowel resection of the ischemic segment abdomen left open + second look (14) Recovery (10) Death (10) O’Shea A [20] 4 (142); 2.8% NA NA NA NA bowel ischemia, portal vein gas, colic pneumatosis NA NA NA Qayed E [21] 2 (878); 0.22% NA NA NA NA NA diffuse colonic ischemia (1) Small + large bowel ischemia and pneumatosis (1) Total colectomy (1) Extensive resection (1) Recovery (1) Death (1) NA: not acknowledged; MAT: mesenteric artery thrombosis; SMA: superior mesenteric artery. J. Clin. Med. 2022, 11, 200 5 of 22 Table 2. Case reports and case series presenting gastrointestinal ischemia in hospitalized COVID-19 patients under anticoagulant medication. Article Sex Age Comorbidities Time from COVID-19 Diagnosis; Time from Admission (Days) ICU; Type of Ventilation Clinical Signs at Presentation Leukocytes (/mm3 ) CRP (mg/L) Lactat mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Azouz E [22] M 56 none 1; 2 (hospitalized for acute ischemic stroke) No info abdominal pain and vomiting No info – – – – – – Multiple arterial thromboembolic complications: AMS, right middle cerebral artery, a free-floating clot in the aortic arch Anticoagulation (no details), endovascular thrombectomy Laparotomy + resection of necrotic small bowel loops No info Al Mahruqi G [23] M 51 none 26; 24 yes, intubated Fever, metabolic acidosis, required inotropes 30,000 – 7 687 – – 2.5 Non-occlusive AMI Hypoperfused small bowel, permeable aorta, SMA, IMA + deep lower limb thrombosis enoxaparin 40 mg/day from admission; surgery refused by family death Ucpinar BA [24] F 82 Atrial fibrillation, hypertension, chronic kidney disease 3; 3 no – 14,800 196 5.1 – – – 1600 SMA thrombosis; distended small bowel, with diffuse submucosal pneumatosis portomesenteric gas fluid resuscitation; continued ceftriaxone, enoxaparin 0.4cc twice daily; not operable due to fulminant evolution Death Karna ST [25] F 61 DM, hypertension 4; 4 Yes, HFNO diffuse abdominal pain with distention 21,400 421.6 1.4 – – 464,000 No thrombosis of the distal SMA with dilated jejunoileal loops and normal enhancing bowel wall. Iv heparin 5000 ui, followed by 1000 ui, Ecospin and clopidogrel Laparotomy after 10 days with segmental enterectomy of the necrotic bowel Death by septic shock and acute renal failure Singh B [26] F 82 Hypertension, T2DM 32; 18 Yes, Ventilator support severe diffuse abdominal distension and tenderness 22,800 308 2.5 136 333 146,000 1.3 SMA—colic arteries thrombosis pneumatosis intestinalis affecting the ascending colon and cecum laparotomy, ischemic colon resection, ileostomy; heparin in therapeutic doses preand post-surgery slow recovery J. Clin. Med. 2022, 11, 200 6 of 22 Table 2. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis; Time from Admission (Days) ICU; Type of Ventilation Clinical Signs at Presentation Leukocytes (/mm3 ) CRP (mg/L) Lactat mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Nakatsutmi K [27] F 67 DM, diabetic nephropathy requiring dialysis, angina, postresection gastric cancer 16; 12 ICU, intubation hemodynamic deterioration, abdominal distension 15,100 32.14 – – – – 26.51 edematous transverse colon; abdominal vessels with sclerotic changes laparotomy, which revealed vascular micro thrombosis of transverse colon—right segment resection of the ischemic colonic segment, ABTHERA management, second look, and closure of the abdomen after 24 h death Dinoto E [28] F 84 DM, hypertension, renal failure 2; 2 no Acute abdominal pain and distension; 18,000 32.47 – – 431 – 6937 SMA origin stenosis and occlusion at 2 cm from the origin, absence of bowel enhancement Endovascular thrombectomy of SMA; surgical transfemoral thrombectomy and distal superficial femoral artery stenting Death due to respiratory failure Kiwango F [29] F 60 DM, hypertension 12; 3 no Sudden onset abdominal pain 7700 – – – – – 23.8 Not performed Not performed due to rapid oxygen desaturation Massive bowel acute ischemia death J. Clin. Med. 2022, 11, 200 7 of 22 Table 3. Case reports and case series presenting gastrointestinal ischemia in non-hospitalized COVID-19 patients. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Sevella, P [30] M 44 none 10 Acute abdominal pain constipation, vomiting 23,400 – – – 1097 360,000 1590 Viable jejunum, ischemic bowel, peritoneal thickening with fat stranding; free fluid in the peritoneal cavity LMWH 60 mg daily Piperacillin 4g/day Tazobactam 500 mg/day Extensive small bowel + right colon resection death Nasseh S [31] M 68 no info First diagnosis epigastric pain and diarrhea for 4 days 17,660 125 – – – – 6876 terminal segment of the ileocolic artery thrombosis; thickening of the right colon wall and the last 30 cm of the small bowl unfractionated heparin laparoscopy -no bowel resection needed recovery Aleman W [32] M 44 none 20 severe abdominopelvic pain 36,870 – – 456.23 – 574,000 263.87 absence of flow at SMV, splenic, portal vein; Small bowel loop dilatation and mesenteric fat edema enoxaparin and pain control medication 6 days, then switched to warfarin 6 months recovery Jeilani M [33] M 68 Alzheimer disease, COPD 9 Sharp abdominal pain +distension 12,440 307 – – – 318,000 897 a central venous filling defect within the portal vein extending to SMV; no bowel wall changes LMWH, 3 months recovery Randhawa J [34] F 62 none First diagnosis right upper quadrant pain and loss of appetite for 14 days Normal limits – – – 346 – – large thrombus involving the SMV, the main portal vein with extension into its branches Fondaparinux 2.5. mg 5 days, then warfarin 4 mg (adjusted by INR), 6 months recovery Cheung S [35] M 55 none 12 (discharged for 7 days) Nausea, vomiting and worsening generalized abdominal pain with guarding 12,446 – 0.68 – – – – low-density clot, 1.6 cm in length, causing high-grade narrowing of the proximal SMA continuous heparin infusion continued 8 h postoperative, Laparotomy with SMA thromboembolectomy and enterectomy (small bowel) recovery J. Clin. Med. 2022, 11, 200 8 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Beccara L [36] M 52 none 22 (5 days after discharge and cessation prophylactic LWMH) vomiting and abdominal pain, tenderness in epigastrium and mesogastrium 30,000 222 – – – – – arterial thrombosis of vessels efferent of the SMA with bowel distension Enterectomy (small bowel) LMWH plus aspirin 100 mg/day at discharge recovery Vulliamy P [37] M 75 none 14 abdominal pain and vomiting for 2 days 18,100 3.2 – – – 497,000 320 intraluminal thrombus was present in the descending thoracic aorta with embolic occlusion of SMA Catheter-directed thrombolysis, enterectomy (small bowel) recovery De Barry O [38] F 79 none First diagnosis Epigastric pain, diarrhea, fever for 8 days, acute dyspnea 12600 125 5.36 – – – – SMV, portal vein, SMA, and jejunal artery thrombosis Distended loops, free fluid anticoagulation Resection of affected colon+ ileum, SMA thrombolysis, thrombectomy death Romero MCV [39] M 73 smoker, DM, hypertension 14 severe abdominal pain, nausea. fecal emesis, peritoneal irritation 18,000 – – – – 120,000 >5000 RX: distention of intestinal loops, inter-loop edema, intestinal pneumatosis enoxaparin (60 mg/0.6 mL), antibiotics (no info) enterectomy, anastomotic fistula, reintervention death Posada Arango [40] M F F 62 22 65 None Appendectomy 7 days before left nephrectomy, 5 3 15 colicative abdominal pain at food intake; unsystematized gastrointestinal symptoms; abdominal pain in the upper hemiabdomen 20,100 – – – – – – – – 1536 – – 534 – – – – – – – – Case 1: thrombus in distal SMA and its branches, intestinal loops dilatation, hydroaerical levels, free fluid thrombosis of SMV Case 2: SMV thrombosis and adiacent fat edema Case 3: thrombi in the left jejunal artery branch with infarction of the corresponding jejunal loops Case 1: Laparotomy: extensive jejunum + ileum ischemia; surgery could not be performed Case 2: Anticoagulation analgesic and antibiotics Case 3: segmental enterectomy Case 1: death Case 2: recovery Case 3: recovery J. Clin. Med. 2022, 11, 200 9 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Pang JHQ [41] M 30 none First diagnosis colicky abdominal pain, vomiting – – – – – – 20 SMV thrombosis with diffuse mural thickening and fat stranding of multiple jejunal loops conservative, anticoagulation with LMWH 1mg/kc, twice daily, 3 months; readmitted and operated for congenital adherence causing small bowel obstruction recovery Lari E [42] M 38 none First diagnosis abdominal pain, nausea, intractable vomiting, and shortness of breath Mild leukocytosis – 2.2 – – – 2100 extensive thrombosis of the portal, splenic, superior, and inferior mesenteric veins + mild bowel ischemia Anticoagulation, resection of the affected bowel loop No info Carmo Filho A [43] M 33 Obesity (BMI: 33), other not reported 7 severe low back pain radiating to the hypogastric region – 58.2 – 1570 – – 879 enlarged inferior mesenteric vein not filled by contrast associated with infiltration of the adjacent adipose planes enoxaparin 5 days, followed by long term oral warfarin recovery Hanif M [44] F 20 none 8 abdominal pain and abdominal distension 15,900 62 – 1435.3 825 633,000 2340 not performed evidence of SMA thrombosis; enterectomy with exteriorization of both ends recovery Amaravathi U [45] M 45 none 5 Acute epigastric and periumbilical pain – Normal value 1.3 324.3 – – 5.3 SMA and SMV thrombus i.v. heparin; Laparotomy with SMA thrombectomy; 48 h Second look: resection of the gangrenous bowel segment No info Al Mahruqi G [23] M 51 none 4 generalized abdominal pain, nausea, vomiting 16,000 – – 619 – – 10 SMA thrombosis and non-enhancing proximal ileal loops consistent with small bowel ischemia unfractionated heparin, thrombectomy + repeated resections of the ischemic bowel at relook (jejunum+ileon+cecum) Case 2: recovery J. Clin. Med. 2022, 11, 200 10 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Goodfellow M [46] F 36 RYGB, depression, asthma 6 epigastric pain, irradiating back, nausea 9650 1.2 0.7 – – – – abrupt cut-off of the SMV in the proximal portion; diffuse infiltration of the mesentery, wall thickening of small bowel IV heparin infusion, followed by 18,000 UI delteparin after 72 h recovery Abeysekera KW [26] M 42 Hepatitis B 14 right hypochondrial pain, progressively increasing for 9 days – – – – – – – enhancement of the entire length of the portal vein and a smaller thrombus in the mid-superior mesenteric vein, mural edema of the distal duodenum, distal small bowel, and descending colon factor Xa inhibitor apixaban 5 mg ×2/day, 6 months – recovery RodriguezNakamura RM [27] M F 45 42 -vitiligo -obesity 14 severe mesogastric pain, nausea, diaphoresis 16,400 18,800 367 239 – – 970 – – – 685,000 – 1450 14,407 Case 1: SMI of thrombotic etiology with partial rechanneling through the middle colic artery, and hypoxic-ischemic changes in the distal ileum and the cecum Case 2: thrombosis of the portal and mesenteric veins and an abdominopelvic collection in the mesentery with gas Case 1: resection with entero-enteral anastomosis; rivaroxaban 10 mg/day, 6 months Case 2: Loop resection, entero-enteral manual anastomosis, partial omentectomy, and cavity wash (fecal peritonitis) Case 1: Recovery Case 2: death Plotz B [47] F 27 SLE with ITP First diagnosis acute onset nausea, vomiting, and non-bloody diarrhea – – – – – – 5446 diffuse small bowel edema enoxaparin, long term apixaban at discharge recovery J. Clin. Med. 2022, 11, 200 11 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Chiu CY [48] F 49 Hypertension, DM, chronic kidney disease 28 diffuse abdominal pain melena and hematemesis – – – – – – 12,444 distended proximal jejunum with mural thickening laparotomy, proximal jejunum resection no info Farina D [49] M 70 no info 3 abdominal pain, nausea 15,300 149 – – – – – acute small bowel hypoperfusion, SMA thromboembolism not operable due to general condition Death SMA: superior mesenteric artery; SMV: superior mesenteric vein; DM: diabetes mellitus; T2DM: type 2 diabetes mellitus; AMI: acute mesenteric ischemia; IMV: inferior mesenteric vein; RYGB: Roux-en-Y gastric bypass (bariatric surgery). J. Clin. Med. 2022, 11, 200 12 of 22 2.2. Risk of Bias The studies analyzed in the present review were comparable in terms of patient selection, methodology, therapeutic approach, and the report of final outcome. However, there were differences in the reported clinical and laboratory data. The sample size was small, most of them being case reports or case series, which may be a significant source of bias. Therefore, studies were compared only qualitatively. 3. Results After duplication removal, a total of 36 articles were included in the review, reporting data on a total of 89 patients. Among these, we identified 6 retrospective studies [16–21], documenting intestinal ischemia in 55 patients admitted to intensive care units (ICU) with COVID-19 pneumonia for whom surgical consult was necessary (Table 1). We also identified 30 case reports or case series [22–51] presenting 34 cases of acute bowel ischemia in patients positive for SARS-CoV-2 infection in different clinical settings. 8 cases were previously hospitalized for COVID-19 pneumonia and under anticoagulant medication (Table 2). In 26 cases, the acute ischemic event appeared as the first symptom of COVID-19 disease, or in mild forms treated at home, or after discharge for COVID -19 pneumonia and cessation of the anticoagulant medication (Table 3). 3.1. Risk Factors of Intestinal Ischemia in COVID-19 Patients Out of a total of 89 patients included in the review, 63 (70.7%) were hospitalized for severe forms of COVID-19 pneumonia at the moment of onset. These patients were receiving anticoagulant medication when reported, consisting of low molecular weight heparin (LMWH) at prophylactic doses. The incidence of acute intestinal ischemia in ICU patients with COVID-19 varied widely between 0.22–10.5% (Table 1). In a study by O’Shea et al. [20], 26% of hospitalized patients for COVID-19 pneumonia who underwent imagistic examination, presented results positive for coagulopathy, and in 22% of these cases, the thromboembolic events were with multiple locations. The mean age was 56.9 years. We observed a significantly lower age in non-hospitalized COVID-19 patients presenting with acute intestinal ischemia when compared to the previously hospitalized group (p < 0.0001). There is a slight male to female predominance (M:F = 1:68). Obesity might be considered a possible risk factor, with a reported mean BMI of 31.2–32.5 in hospitalized patients [16,18,19]. However, this association should be regarded with caution, since obesity is also a risk factor for severe forms of COVID-19. Prolonged stay in intensive care, intubation, and the need for vasopressor medication was associated with increased risk of acute bowel ischemia [8,18,19]. Diabetes mellitus and hypertension were the most frequent comorbidities encountered in case reports (8 in 34 patients, 23%), and 7 out of 8 patients presented both (Table 4). There was no information regarding the comorbidities in the retrospective studies included in the review. 3.2. Clinical Features in COVID-19 Patients with Acute Mesenteric Ischemia Abdominal pain, out of proportion to physical findings, is a hallmark of portomesenteric thrombosis, typically associated with fever and leukocytosis [4]. Abdominal pain was encountered in all cases, either generalized from the beginning, of high intensity, or firstly localized in the epigastrium or the mezogastric area. In cases of portal vein thrombosis, the initial location may be in the right hypochondrium, mimicking biliary colic [26,34]. Fever is less useful in COVID-19 infected patients, taking into consideration that fever is a general sign of infection, and on the other hand, these patients might be already under antipyretic medication. J. Clin. Med. 2022, 11, 200 13 of 22 Table 4. Demographic data of the patients included in the review. Nr. of Patients 89 M 48 (61.5% *) F 30 (38.5% *) NA 11 The first sign of COVID-19 6 (6.7%) Home treated 17 (19.1%) Hospitalized • ICU 63 (70.7%) 58 (92% of hospitalized patients) Discharged 3 (3.3%) Time from diagnosis of COVID-19 infection • Non-Hospitalized • Hospitalized (*when mentioned) 8.7 ± 7.4 (1–28 days) 9.6 ± 8.3 (1–26 days) Time from admission in hospitalized patients 1–104 days Age (mean) • Hospitalized • Non-hospitalized 59.3 ± 12.7 years 62 ± 9.6 years. (p < 0.0001) 52.8 ± 16.4 years. BMI 31.2–32.5 Comorbidities • Hypertension • DM • smokers • Atrial fibrillation • COPD • Cirrhosis • RYGB • Vitiligo • Recent appendicitis • Operated gastric cancer • Alzheimer disease • SLE 8 7 2 1 2 1 1 1 1 1 1 1 *: percentage calculated in known information group; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SLE: systemic lupus erythematosus. Other clinical signs reported were nausea, anorexia, vomiting, and food intolerance [23,31,38,45]. However, these gastrointestinal signs are encountered in 30–40% of patients with SARS-CoV-2 infection. In a study by Kaafarani et al., up to half of the patients with gastrointestinal features presented some degrees of intestinal hypomotility, possibly due to direct viral invasion of the enterocytes and neuro-enteral disturbances [16]. Physical exam evidenced abdominal distension, reduced bowel sounds, and tenderness at palpation. Guarding may be evocative for peritonitis due to compromised vascularization of bowel loops and bacterial translocation or franc perforation [35,39]. A challenging case was presented by Goodfellow et al. [25] in a patient with a recent history of bariatric surgery with Roux en Y gastric bypass, presenting with acute abdominal pain which imposed the differential diagnosis with an internal hernia. Upcinar et al. [24] reported a case of an 82-years female that also associated atrial fibrillation. The patient was anticoagulated with enoxaparin 0.4 cc twice daily before admission and continued the anticoagulant therapy during hospitalization for COVID-19 pneumonia. Bedside echocardiography was performed to exclude atrial thrombus. Although SMA was reported related to COVID-19 pneumonia, atrial fibrillation is a strong risk factor for SMA of non-COVID-19 etiology. J. Clin. Med. 2022, 11, 200 14 of 22 In ICU patients, acute bowel ischemia should be suspected in cases that present acute onset of digestive intolerance and stasis, abdominal distension, and require an increase of vasopressor medication [19]. 3.3. Imagistic and Lab Test Findings D-dimer is a highly sensitive investigation for the prothrombotic state caused by COVID-19 [45] and, when reported, was found to be above the normal values. Leukocytosis and acute phase biomarkers, such as fibrinogen and CRP were elevated, mirroring the intensity of inflammation and sepsis caused by the ischemic bowel. However, there was no significant statistical correlation between either the leukocyte count (p = 0.803) or D-dimers (p = 0.08) and the outcome. Leucocyte count may be within normal values in case of early presentation [34]. Thrombocytosis and thrombocytopenia have been reported in published cases with mesenteric ischemia [30,35,42,46,50]. Lactate levels were reported in 9 cases, with values higher than 2 mmol/L in 5 cases (55%). LDH was determined in 6 cases, and it was found to be elevated in all cases, with a mean value of 594+/−305 U/L. Ferritin is another biomarker of potential value in mesenteric ischemia, that increases due to ischemia-reperfusion cellular damage. In the reviewed studies, serum ferritin was raised in 7 out of 9 reported cases, with values ranging from 456 to 1570 ng/mL. However, ferritin levels were found to be correlated also with the severity of pulmonary lesions in COVID-19 patients [52]. Due to the low number of cases in which lactate, LDH, and ferritin were reported, no statistical association could be performed with the severity of lesions or with adverse outcomes. The location and extent of venous or arterial thrombosis were determined by contrastenhanced abdominal CT, which also provided important information on the viability of the intestinal segment whose vascularity was affected. Radiological findings in the early stages included dilated intestinal loops, thickening of the intestinal wall, mesenteric fat edema, and air-fluid levels. Once the viability of the affected intestinal segment is compromised, a CT exam may evidence pneumatosis as a sign of bacterial proliferation and translocation in the intestinal wall, pneumoperitoneum due to perforation, and free fluid in the abdominal cavity. In cases with an unconfirmed diagnosis of COVID-19, examination of the pulmonary basis during abdominal CT exam can add consistent findings to establish the diagnosis. Venous thrombosis affecting the superior mesenteric vein and or portal vein was encountered in 40.9% of reported cases of non-hospitalized COVID-19 patients, and in only one case in the hospitalized group (Table 5). One explanation may be the beneficial role of thrombotic prophylaxis in preventing venous thrombosis in COVID-19 patients, which is routinely administrated in hospitalized cases, but not reported in cases treated at home with COVID-19 pneumonia. In ICU patients, CT exam showed in most cases permeable mesenteric vessels and diffuse intestinal ischemia affecting the large bowel alone (56%) or in association with the small bowel (24%), suggesting pathogenic mechanisms, direct viral infection, small vessel thrombosis, or “nonocclusive mesenteric ischemia” [16]. 3.4. Management and Outcomes The management of mesenteric ischemia includes gastrointestinal decompression, fluid resuscitation, hemodynamic support, anticoagulation, and broad antibiotics. Once the thromboembolic event was diagnosed, heparin, 5000IU iv, or enoxaparin or LMWH in therapeutic doses was initiated, followed by long-term oral anticoagulation and/or anti-aggregating therapy. Favorable results were obtained in 7 out of 9 cases (77%) of splanchnic veins thrombosis and in 2 of 7 cases (28.5%) with superior mesenteric artery thrombosis. At discharge, anticoagulation therapy was continued either with LMWH, for a period up to 3 months [33,36,41], either, long term warfarin, with INR control [32,34,41] or apixaban 5 mg/day, up to 6 months [26,47]. No readmissions were reported. J. Clin. Med. 2022, 11, 200 15 of 22 Table 5. Comparative features in acute intestinal ischemia encountered in previously hospitalized and previously non-hospitalized COVID-19 patients. Parameter Hospitalized (63) NonHospitalized (26) p * Value Type of mesenteric ischemia: • Arterial • Venous • Mixt (A + V) • Diffuse microthrombosis • Multiple thromboembolic locations • NA 5 (14.7% *) 1 (2.9%) 0 30 (88.2%) 2 (5.8%) 29 10 (38.4%) 11 (42.3%) 2 (7.6%) 3 (11.5%) 1 (3.8%) 0 p < 0.0001 Management: • Anticoagulation therapy only • Endovascular thrombectomy • Laparotomy with ischemic bowel resection • None (fulminant evolution) 0 2 (1 + surgery) (3%) 60 (95.4%) 2 (3%) 10 (38.4%) 2 (+surgery) 15 (57.6%) 1 (3.8%) p < 0.0001 Location of the resected segment: • Colon • Small bowel • Colon+small bowel • NA 35 (56%) 10 (16%) 15 (24%) 6 0 12 (80%) 3 (20%) 0 p < 0.0001 Outcomes: • Recovery • Death • NA 26 (46.4%) 30 (54.4%) 7 17 (79.3%) 5 (21.7%) 3 p = 0.013 * calculated for Chi-squared test. Antibiotic classes should cover anaerobes including F. necrophorum and include a combination of beta-lactam and beta-lactamase inhibitor (e.g., piperacillin-tazobactam), metronidazole, ceftriaxone, clindamycin, and carbapenems [4]. In early diagnosis, during the first 12 h from the onset, vascular surgery may be tempted, avoiding the enteral resection [25,53]. Endovascular management is a minimally invasive approach, allowing quick restoration of blood flow in affected vessels using techniques such as aspiration, thrombectomy, thrombolysis, and angioplasty with or without stenting [40]. Laparotomy with resection of the necrotic bowel should be performed as quickly as possible to avoid perforation and septic shock. In cases in which intestinal viability cannot be established with certainty, a second look laparotomy was performed after 24–48 h [43] or the abdominal cavity was left open, using negative pressure systems such as ABTHERA [51], and successive segmentary enterectomy was performed. Several authors described in acute bowel ischemia encountered in ICU patients with COVID-19, a distinct yellowish color, rather than the typical purple or black color of ischemic bowel, predominantly located at the antimesenteric side or circumferentially with affected areas well delineated from the adjacent healthy areas [18,19]. In these cases, patency of large mesenteric vessels was confirmed, and the histopathological reports J. Clin. Med. 2022, 11, 200 16 of 22 showed endothelitis, inflammation, and microvascular thrombosis in the submucosa or transmural. Despite early surgery, the outcome is severe in these cases, with an overall mortality of 45–50% in reported studies and up to 100% in patients over 65 years of age according to Hwabejira et al. [19]. In COVID-19 patients non hospitalized at the onset of an acute ischemic event, with mild and moderate forms of the disease, the outcome was less severe, with recovery in 77% of cases. We found that age over 60 years and the necessity of surgical treatment are statistically correlated with a poor outcome in the reviewed studies (Table 6). According to the type of mesenteric ischemia, the venous thrombosis was more likely to have a favorable outcome (recovery in 80% of cases), while vascular micro thombosis lead to death in 66% of cases. Table 6. Risk factors for severe outcome. Parameters Outcome: Death p-Value Age • Age < 60 • Age > 60 27.2% 60% 0.0384 * 0.043 ** Surgery • No surgery • surgery 0% 60% 0.019 ** Type of mesenteric ischemia • Arterial • Venous • Micro thrombosis 47% 20% 66% 0.23 ** D dimers Wide variation 0.085 * 0.394 ** Leucocytes Wide variation (9650–37,000/mmc) 0.803 0.385 ** * One-way ANOVA test; ** Chi-squared test (SciStat® software, www.scistat.com (accessed on 25 November 2021)). 4. Discussions Classically, acute mesenteric ischemia is a rare surgical emergency encountered in the elderly with cardiovascular or portal-associated pathology, such as arterial hypertension, atrial fibrillation, atherosclerosis, heart failure, valve disease, and portal hypertension. However, in the current context of the COVID-19 pandemic, mesenteric ischemia should be suspected in any patient presenting in an emergency with acute abdominal pain, regardless of age and associated diseases. Several biomarkers were investigated for the potential diagnostic and prognostic value in acute mesenteric ischemia. Serum lactate is a non-specific biomarker of tissue hypoperfusion and undergoes significant elevation only after advanced mesenteric damage. Several clinical trials found a value higher than 2 mmol/L was significantly associated with increased mortality in non-COVID-patients. However, its diagnostic value is still a subject of debate. There are two detectable isomers, L-lactate, which is a nonspecific biomarker of anaerobic metabolism, and hypoxia and D-lactate, which is produced by the activity of intestinal bacteria. Higher D-lactate levels could be more specific for mesenteric ischemia due to increased bacterial proliferation at the level of the ischemic bowel, but the results obtained in different studies are mostly inconsistent [53,54]. Several clinical studies found that LDH is a useful biomarker for acute mesenteric ischemia, [55,56]. However, interpretation of the results may be difficult in COVID-19 patients, as both lactate and LDH were also found to be independent risk factors of severe forms of COVID-19 [57,58]. The diagnosis of an ischemic bowel should be one of the top differentials in critically ill patients with acute onset of abdominal pain and distension [50,59]. If diagnosed early, the J. Clin. Med. 2022, 11, 200 17 of 22 intestinal ischemia is potentially reversible and can be treated conservatively. Heparin has an anticoagulant, anti-inflammatory, endothelial protective role in COVID-19, which can improve microcirculation and decrease possible ischemic events [25]. The appropriate dose, however, is still a subject of debate with some authors recommending the prophylactic, others the intermediate or therapeutic daily amount [25,60]. We found that surgery is associated with a severe outcome in the reviewed studies. Mucosal ischemia may induce massive viremia from bowel epithelium causing vasoplegic shock after surgery [25]. Moreover, many studies reported poor outcomes in COVID-19 patients that underwent abdominal surgery [61,62]. 4.1. Pathogenic Pathways of Mesenteric Ischemia in COVID-19 Patients The intestinal manifestations encountered in SARS-CoV-2 infection are represented by inflammatory changes (gastroenteritis, colitis), occlusions, ileus, invaginations, and ischemic manifestations. Severe inflammation in the intestine can cause damage to the submucosal vessels, resulting in hypercoagulability in the intestine. Cases of acute cholecystitis, splenic infarction, or acute pancreatitis have also been reported in patients infected with SARS-CoV-2, with microvascular lesions as a pathophysiological mechanism [63]. In the study of O’Shea et al., on 146 COVID-19 hospitalized patients that underwent CT-scan, vascular thrombosis was identified in 26% of cases, the most frequent location being in lungs [20]. Gastrointestinal ischemic lesions were identified in 4 cases, in multiple locations (pulmonary, hepatic, cerebellar parenchymal infarction) in 3 patients. The authors raised awareness about the possibility of underestimation of the incidence of thrombotic events in COVID-19 patients [20]. Several pathophysiological mechanisms have been considered, and they can be grouped into occlusive and non-occlusive causes [64]. The site of the ischemic process, embolism or thrombosis, may be in the micro vascularization, veins, or mesenteric arteries. Acute arterial obstruction of the small intestinal vessels and mesenteric ischemia may appear due to hypercoagulability associated with SARS-CoV-2 infection, mucosal ischemia, viral dissemination, and endothelial cell invasion vis ACE-2 receptors [65,66]. Viral binding to ACE2Receptors leads to significant changes in fluid-coagulation balance: reduction in Ang 2 degradation leads to increased Il6 levels, and the onset of storm cytokines, such as IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, IgG -induced protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-alpha, and tumor necrosis factor α [67], but also in the expression of the tissue inhibitor of plasminogen -1, and a tissue factor, and subsequently triggering the coagulation system through binding to the clotting factor VIIa [68]. Acute embolism in small vessels may be caused by the direct viral invasion, via ACE-2 Receptors, resulting in endothelitis and inflammation, recruiting immune cells, and expressing high levels of pro-inflammatory cytokines, such as Il-6 and TNF-alfa, with consequently apoptosis of the endothelial cells [69]. Capillary viscometry showed hyperviscosity in critically ill COVID-19 patients [70,71]. Platelet activation, platelet–monocyte aggregation formation, and Neutrophil external traps (NETs) released from activated neutrophils, constitute a mixture of nucleic DNA, histones, and nucleosomes [59,72] were documented in severe COVID-19 patients by several studies [70,71,73]. Plotz et al. found a thrombotic vasculopathy with histological evidence for lectin pathway complement activation mirroring viral protein deposition in a patient with COVID19 and SLE, suggesting this might be a potential mechanism in SARS-CoV-2 associated thrombotic disorders [47]. Numerous alterations in fluid-coagulation balance have been reported in patients hospitalized for COVID-19 pneumonia. Increases in fibrinogen, D-dimers, but also coagulation factors V and VIII. The mechanisms of coagulation disorders in COVID-19 are not yet fully elucidated. In a clinical study by Stefely et al. [68] in a group of 102 patients with severe disease, an increase in factor V > 200 IU was identified in 48% of cases, the levels determined being statistically significantly higher than in non-COVID mechanically J. Clin. Med. 2022, 11, 200 18 of 22 ventilated or unventilated patients hospitalized in intensive care. This showed that the increased activity of Factor V cannot be attributed to disease severity or mechanical ventilation. Additionally, an increase in factor X activity was shown, but not correlated with an increase in factor V activity, but with an increase in acute phase reactants, suggesting distinct pathophysiological mechanisms [74]. Giuffre et al. suggest that fecal calcoprotein (FC) may be a biomarker for the severity of gastrointestinal complications, by both ischemic and inflammatory mechanisms [75]. They found particularly elevated levels of FC to be well correlated with D-dimers levels in patients with bowel perforations, and hypothesized that the mechanism may be related to a thrombosis localized to the gut and that FC increase is related to virus-related inflammation and thrombosis-induced ischemia, as shown by gross pathology [76]. Non-occlusive mesenteric ischemia in patients hospitalized in intensive care units for SARS-CoV-2 pneumonia requiring vasopressor medication may be caused vasospastic constriction [19,64,65]. Thrombosis of the mesenteric vessels could be favored by hypercoagulability, relative dehydration, and side effects of corticosteroids. 4.2. Question Still to Be Answered Current recommendations for in-hospital patients with COVID-19 requiring anticoagulation suggest LMWH as first-line treatment has advantages, with higher stability compared to heparin during cytokine storms, and a reduced risk of interaction with antiviral therapy compared to oral anticoagulant medication [77]. Choosing the adequate doses of LMWH in specific cases—prophylactic, intermediate, or therapeutic—is still in debate. Thromboprophylaxis is highly recommended in the absence of contraindications, due to the increased risk of venous thrombosis and arterial thromboembolism associated with SARS-CoV-2 infection, with dose adjustment based on weight and associated risk factors. Besides the anticoagulant role, some authors also reported an anti-inflammatory role of heparin in severe COVID-19 infection [66,78,79]. Heparin is known to decrease inflammation by inhibiting neutrophil activity, expression of inflammatory mediators, and the proliferation of vascular smooth muscle cells [78]. Thromboprophylaxis with enoxaparin could be also recommended to ambulatory patients with mild to moderate forms of COVID-19 if the results of prospective studies show statistically relevant benefits [80]. In addition to anticoagulants, other therapies, such as anti-complement and interleukin (IL)-1 receptor antagonists, need to be explored, and other new agents should be discovered as they emerge from our better understanding of the pathogenetic mechanisms [81]. Several studies showed the important role of Il-1 in endothelial dysfunction, inflammation, and thrombi formation in COVID-19 patients by stimulating the production of Thromboxane A2 (TxA2) and thromboxane B2 (TxB2). These findings may justify the recommendation for an IL-1 receptor antagonist (IL-1Ra) which can prevent hemodynamic changes, septic shock, organ inflammation, and vascular thrombosis in severe forms of COVID-19 patients [80–82]. 5. Conclusions Understanding the pathological pathways and risk factors could help adjust the thromboprophylaxis and fluid management in COVID-19 patients. The superior mesenteric vein thrombosis is the most frequent cause of acute intestinal ischemia in COVID-19 nonhospitalized patients that are not under anticoagulant medication, while non-occlusive mesenteric ischemia and microvascular thrombosis are most frequent in severe cases, hospitalized in intensive care units. COVID-19 patients should be carefully monitored for acute onset of abdominal symptoms. High-intensity pain and abdominal distension, associated with leukocytosis, raised inflammatory biomarkers and elevated D-dimers and are highly suggestive for mesenteric ischemia. The contrast-enhanced CT exam, repeated, if necessary, offers valuable information regarding the location and extent of the acute ischemic event. Early diagnosis and treatment are essential for survival.

J. Clin. Med. 2022, 11, 200 19 of 22 Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11010200/s1, File S1: The PRISMA 2020 statement. Author Contributions: Conceptualization, D.S., L.C.T. and A.M.D.; methodology, A.P.S., C.T. (Corneliu Tudor); software, G.V.; validation, A.I.S., M.S.T., D.S. and L.D.; formal analysis, A.C.C., C.T. (Ciprian Tanasescu); investigation, G.A.G.; data curation, D.O.C.; writing—original draft preparation, L.C.T., A.M.D., G.V., D.O.C., G.A.G., C.T. (Corneliu Tudor); writing—review and editing, L.D., C.T. (Ciprian Tanasescu), A.C.C., D.S., A.P.S., A.I.S., M.S.T.; visualization, G.V. and L.C.T.; supervision, D.S., A.M.D. and D.S. have conducted the screening and selection of studies included in the review All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Bala, M.; Kashuk, J.; Moore, E.E.; Kluger, Y.; Biffl, W.; Gomes, C.A.; Ben-Ishay, O.; Rubinstein, C.; Balogh, Z.J.; Civil, I.; et al. Acute mesenteric ischemia: Guidelines of the World Society of Emergency Surgery. World J. Emerg. Surg. 2017, 12, 38. [CrossRef] 2. Dumic, I.; Martin, S.; Salfiti, N.; Watson, R.; Alempijevic, T. Deep Venous Thrombosis and Bilateral Pulmonary Embolism Revealing Silent Celiac Disease: Case Report and Review of the Literature. Case Rep. Gastrointest. Med. 2017, 2017, 5236918. [CrossRef] [PubMed] 3. Akhrass, F.A.; Abdallah, L.; Berger, S.; Sartawi, R. Gastrointestinal variant of Lemierre’s syndrome complicating ruptured appendicitis. IDCases 2015, 2, 72–76. [CrossRef] 4. Radovanovic, N.; Dumic, I.; Veselinovic, M.; Burger, S.; Milovanovic, T.; Nordstrom, C.W.; Niendorf, E.; Ramanan, P. Fusobacterium necrophorum subsp. necrophorum Liver Abscess with Pylephlebitis: An Abdominal Variant of Lemierre’s Syndrome. Case Rep. Infect. Dis. 2020, 2020, 9237267. [CrossRef] 5. Sogaard, K.K.; Astrup, L.B.; Vilstrup, H.; Gronbaek, H. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol. 2007, 7, 34. [CrossRef] [PubMed] 6. Moradi, H.; Mouzannar, S.; Miratashi Yazdi, S.A. Post COVID-19 splenic infarction with limb ischemia: A case report. Ann. Med. Surg. 2021, 71, 102935. [CrossRef] [PubMed] 7. Elmunzer, B.J.; Spitzer, R.L.; Foster, L.D.; Merchant, A.A.; Howard, E.F.; Patel, V.A.; West, M.K.; Qayed, E.; Nustas, R.; Zakaria, A.; et al. North American Alliance for the Study of Digestive Manifestations of COVID-19. Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019. Clin. Gastroenterol. Hepatol. 2021, 19, 1355–1365.e4. [CrossRef] 8. Guan, W.J.; Ni, Z.Y.; Hu, Y. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [CrossRef] 9. Estevez-Cerda, S.C.; Saldaña-Rodríguez, J.A.; Alam-Gidi, A.G.; Riojas-Garza, A.; Rodarte-Shade, M.; Velazco-de la Garza, J.; Leyva-Alvizo, A.; Gonzalez-Ruvalcaba, R.; Martinez-Resendez, M.F.; Ortiz de Elguea-Lizarraga, J.I. Severe bowel complications in SARS-CoV-2 patients receiving protocolized care. Rev. Gastroenterol. Mex. Engl. Ed. 2021, 86, 378–386. [CrossRef] 10. Redd, W.D.; Zhou, J.C.; Hathorn, K.E. Prevalence and characteristics of gastrointestinal symptoms in patients with SARS-CoV-2 infection in the United States: A multicenter cohort study. Gastroenterology 2020, 159, 765–767.e2. [CrossRef] 11. Hajifathalian, K.; Krisko, T.; Mehta, A. Gastrointestinal and hepatic manifestations of 2019 novel coronavirus disease in a large cohort of infected patients from New York: Clinical implications. Gastroenterology 2020, 159, 1137–1140.e2. [CrossRef] 12. Kotfis, K.; Skonieczna-Zydecka, K. COVID-19: Gastrointestinal symptoms and potential sources of SARS-CoV-2 transmission. ˙ Anaesthesiol. Intensive Ther. 2020, 52, 171–172. [CrossRef] 13. Xiao, F.; Tang, M.; Zheng, X. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020, 158, 1831–1833. [CrossRef] [PubMed] 14. Xu, Y.; Li, X.; Zhu, B.; Liang, H.; Fang, C.; Gong, Y.; Guo, Q.; Sun, X.; Zhao, D.; Shen, J.; et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat. Med. 2020, 26, 502–505. [CrossRef] [PubMed] 15. Ludewig, S.; Jarbouh, R.; Ardelt, M.; Mothes, H.; Rauchfuß, F.; Fahrner, R.; Zanow, J.; Settmacher, U. Bowel Ischemia in ICU Patients: Diagnostic Value of I-FABP Depends on the Interval to the Triggering Event. Gastroenterol. Res. Pract. 2017, 2795176. [CrossRef] 16. Kaafarani, H.; El Moheb, M.; Hwabejire, J.O.; Naar, L.; Christensen, M.A.; Breen, K.; Gaitanidis, A.; Alser, O.; Mashbari, H.; Bankhead-Kendall, B.; et al. Gastrointestinal Complications in Critically Ill Patients With COVID-19. Ann. Surg. 2020, 272, e61–e62. [CrossRef] 17. Kraft, M.; Pellino, G.; Jofra, M.; Sorribas, M.; Solís-Peña, A.; Biondo, S.; Espín-Basany, E. Incidence, features, outcome and impact on health system of de-novo abdominal surgical diseases in patients admitted with COVID-19. Surg. J. R. Coll. Surg. Edinb. Irel. 2021, 19, e53–e58. [CrossRef] 18. Yang, C.; Hakenberg, P.; Weiß, C.; Herrle, F.; Rahbari, N.; Reißfelder, C.; Hardt, J. Colon ischemia in patients with severe COVID-19: A single-center retrospective cohort study of 20 patients. Int. J. Colorectal Dis. 2021, 36, 2769–2773. [CrossRef] J. Clin. Med. 2022, 11, 200 20 of 22 19. Hwabejire, J.O.; Kaafarani, H.M.; Mashbari, H.; Misdraji, J.; Fagenholz, P.J.; Gartland, R.M.; Abraczinskas, D.R.; Mehta, R.S.; Paranjape, C.N.; Eng, G.; et al. Bowel Ischemia in COVID-19 Infection: One-Year Surgical Experience. Am. Surg. 2021, 87, 1893–1900. [CrossRef] [PubMed] 20. O’shea, A.; Parakh, A.; Hedgire, S.; Lee, S.I. Multisystem assessment of the imaging manifestations of coagulopathy in hospitalized patients with coronavirus. Am. J. Roentgenol. 2021, 216, 1088–1098. [CrossRef] [PubMed] 21. Qayed, E.; Deshpande, A.R.; Elmunzer, B.J.; North American Alliance for the Study of Digestive Manifestations of COVID-19. Low Incidence of Severe Gastrointestinal Complications in COVID-19 Patients Admitted to the Intensive Care Unit: A Large, Multicenter Study. Gastroenterology 2021, 160, 1403–1405. [CrossRef] [PubMed] 22. Azouz, E.; Yang, S.; Monnier-Cholley, L.; Arrivé, L. Systemic arterial thrombosis and acute mesenteric ischemia in a patient with COVID-19. Intensive Care Med. 2020, 46, 1464–1465. [CrossRef] [PubMed] 23. Al Mahruqi, G.; Stephen, E.; Abdelhedy, I.; Al Wahaibi, K. Our early experience with mesenteric ischemia in COVID-19 positive patients. Ann. Vasc. Surg. 2021, 73, 129–132. [CrossRef] [PubMed] 24. Ucpinar, B.A.; Sahin, C. Superior Mesenteric Artery Thrombosis in a Patient with COVID-19: A Unique Presentation. J. Coll Physicians Surg. Pak. 2020, 30, 112–114. [CrossRef] 25. Karna, S.T.; Panda, R.; Maurya, A.P.; Kumari, S. Superior Mesenteric Artery Thrombosis in COVID-19 Pneumonia: An Underestimated Diagnosis—First Case Report in Asia. Indian J. Surg. 2020, 82, 1235–1237. [CrossRef] 26. Abeysekera, K.W.; Karteszi, H.; Clark, A.; Gordon, F.H. Spontaneous portomesenteric thrombosis in a non-cirrhotic patient with SARS-CoV-2 infection. BMJ Case Rep. 2020, 13, e238906. [CrossRef] 27. Rodriguez-Nakamura, R.M.; Gonzalez-Calatayud, M.; Martinez Martinez, A.R. Acute mesenteric thrombosis in two patients with COVID-19. Two cases report and literature review. Int. J. Surg. Case Rep. 2020, 76, 409–414. [CrossRef] 28. Dinoto, E.; Ferlito, F.; La Marca, M.A.; Mirabella, D.; Bajardi, G.; Pecoraro, F. Staged acute mesenteric and peripheral ischemia treatment in COVID-19 patient: Case report. Int. J. Surg. Case Rep. 2021, 84, 106105. [CrossRef] 29. Kiwango, F.; Mremi, A.; Masenga, A.; Akrabi, H. Intestinal ischemia in a COVID-19 patient: Case report from Northern Tanzania. J. Surg. Case Rep. 2021, 2021, rjaa537. [CrossRef] 30. Sevella, P.; Rallabhandi, S.; Jahagirdar, V.; Kankanala, S.R.; Ginnaram, A.R.; Rama, K. Acute Mesenteric Ischemia as an Early Complication of COVID-19. Cureus 2021, 13, e18082. [CrossRef] 31. Nasseh, S.; Trabelsi, M.M.; Oueslati, A.; Haloui, N.; Jerraya, H.; Nouira, R. COVID-19 and gastrointestinal symptoms: A case report of a Mesenteric Large vessel obstruction. Clin. Case Rep. 2021, 9, e04235. [CrossRef] [PubMed] 32. Alemán, W.; Cevallos, L.C. Subacute mesenteric venous thrombosis secondary to COVID-19: A late thrombotic complication in a nonsevere patient. Radiol. Case Rep. 2021, 16, 899–902. [CrossRef] [PubMed] 33. Jeilani, M.; Hill, R.; Riad, M.; Abdulaal, Y. Superior mesenteric vein and portal vein thrombosis in a patient with COVID-19: A rare case. BMJ Case Rep. 2021, 14, e244049. [CrossRef] 34. Randhawa, J.; Kaur, J.; Randhawa, H.S.; Kaur, S.; Singh, H. Thrombosis of the Portal Vein and Superior Mesenteric Vein in a Patient With Subclinical COVID-19 Infection. Cureus 2021, 13, e14366. [CrossRef] [PubMed] 35. Cheung, S.; Quiwa, J.C.; Pillai, A.; Onwu, C.; Tharayil, Z.J.; Gupta, R. Superior Mesenteric Artery Thrombosis and Acute Intestinal Ischemia as a Consequence of COVID-19 Infection. Am. J. Case Rep. 2020, 21, e925753. [CrossRef] 36. Beccara, L.A.; Pacioni, C.; Ponton, S.; Francavilla, S.; Cuzzoli, A. Arterial Mesenteric Thrombosis as a Complication of SARS-CoV-2 Infection. Eur. J. Case Rep. Intern. Med. 2020, 7, 001690. [CrossRef] [PubMed] 37. Vulliamy, P.; Jacob, S.; Davenport, R.A. Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19. Br. J. Haematol. 2020, 189, 1053–1054. [CrossRef] 38. De Barry, O.; Mekki, A.; Diffre, C.; Seror, M.; El Hajjam, M.; Carlier, R.Y. Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia. Radiol. Case Rep. 2020, 15, 1054–1057. [CrossRef] 39. Romero, M.D.C.V.; Cárdenas, A.M.; Fuentes, A.B.; Barragán, A.A.S.; Gómez, D.B.S.; Jiménez, M.T. Acute mesenteric arterial thrombosis in severe SARS-Co-2 patient: A case report and literature review. Int. J. Surg. Case Rep. 2021, 86, 106307. [CrossRef] 40. Posada-Arango, A.M.; García-Madrigal, J.; Echeverri-Isaza, S.; Alberto-Castrillón, G.; Martínez, D.; Gómez, A.C.; Pinto, J.A.; Pinillos, L. Thrombosis in abdominal vessels associated with COVID-19 Infection: A report of three cases. Radiol. Case Rep. 2021, 16, 3044–3050. [CrossRef] 41. Pang, J.H.Q.; Tang, J.H.; Eugene-Fan, B. A peculiar case of small bowel stricture in a coronavirus disease 2019 patient with congenital adhesion band and superior mesenteric vein thrombosis. Ann. Vasc. Surg. 2021, 70, 286–289. [CrossRef] 42. Lari, E.; Lari, A.; AlQinai, S. Severe ischemic complications in COVID-19-a case series. Int. J. Surg. Case Rep. 2020, 75, 131–135. [CrossRef] [PubMed] 43. Carmo Filho, A.; Cunha, B.D.S. Inferior mesenteric vein thrombosis and COVID-19. Rev. Soc. Bras. Med. Trop. 2020, 53, e20200412. [CrossRef] 44. Hanif, M.; Ahmad, Z.; Khan, A.W.; Naz, S.; Sundas, F. COVID-19-Induced Mesenteric Thrombosis. Cureus 2021, 13, e12953. [CrossRef] 45. Amaravathi, U.; Balamurugan, N.; Muthu Pillai, V.; Ayyan, S.M. Superior Mesenteric Arterial and Venous Thrombosis in COVID-19. J. Emerg. Med. 2021, 60, e103–e107. [CrossRef] [PubMed] 46. Goodfellow, M.; Courtney, M.; Upadhyay, Y.; Marsh, R.; Mahawar, K. Mesenteric Venous Thrombosis Due to Coronavirus in a Post Roux-en-Y Gastric Bypass Patient: A Case Report. Obes. Surg. 2021, 31, 2308–2310. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 200 21 of 22 47. Plotz, B.; Castillo, R.; Melamed, J.; Magro, C.; Rosenthal, P.; Belmont, H.M. Focal small bowel thrombotic microvascular injury in COVID-19 mediated by the lectin complement pathway masquerading as lupus enteritis. Rheumatology 2021, 60, e61–e63. [CrossRef] 48. Chiu, C.Y.; Sarwal, A.; Mon, A.M.; Tan, Y.E.; Shah, V. Gastrointestinal: COVID-19 related ischemic bowel disease. J. Gastroenterol. Hepatol. 2021, 36, 850. [CrossRef] [PubMed] 49. Farina, D.; Rondi, P.; Botturi, E.; Renzulli, M.; Borghesi, A.; Guelfi, D.; Ravanelli, M. Gastrointestinal: Bowel ischemia in a suspected coronavirus disease (COVID-19) patient. J. Gastroenterol. Hepatol. 2021, 36, 41. [CrossRef] 50. Singh, B.; Mechineni, A.; Kaur, P.; Ajdir, N.; Maroules, M.; Shamoon, F.; Bikkina, M. Acute Intestinal Ischemia in a Patient with COVID-19 Infection. Korean J. Gastroenterol. 2020, 76, 164–166. [CrossRef] 51. Nakatsutsumi, K.; Endo, A.; Okuzawa, H.; Onishi, I.; Koyanagi, A.; Nagaoka, E.; Morishita, K.; Aiboshi, J.; Otomo, Y. Colon perforation as a complication of COVID-19: A case report. Surg. Case Rep. 2021, 7, 175. [CrossRef] 52. Carubbi, F.; Salvati, L.; Alunno, A.; Maggi, F.; Borghi, E.; Mariani, R.; Mai, F.; Paoloni, M.; Ferri, C.; Desideri, G.; et al. Ferritin is associated with the severity of lung involvement but not with worse prognosis in patients with COVID-19: Data from two Italian COVID-19 units. Sci. Rep. 2021, 11, 4863. [CrossRef] 53. Isfordink, C.J.; Dekker, D.; Monkelbaan, J.F. Clinical value of serum lactate measurement in diagnosing acute mesenteric ischaemia. Neth. J. Med. 2018, 76, 60–64. [PubMed] 54. Montagnana, M.; Danese, E.; Lippi, G. Biochemical markers of acute intestinal ischemia: Possibilities and limitations. Ann. Transl. Med. 2018, 6, 341. [CrossRef] 55. Matsumoto, S.; Sekine, K.; Funaoka, H.; Yamazaki MShimizu, M.; Hayashida, K.; Kitano, M. Diagnostic performance of plasma biomarkers in patients with acute intestinal ischaemia. Br. J. Surg. 2014, 101, 232–238. [CrossRef] [PubMed] 56. Soni, N.; Bhutra, S.; Vidyarthi, S.H.; Sharma, V. Role of serum lactic dehydrogenase, glutamic oxaloacetic transaminase, creatine phosphokinase, alkaline phospatase, serum phosphorus in the cases of bowel Ischaemia in acute abdomen. Int. Surg. J. 2017, 4, 1997–2001. [CrossRef] 57. Han, Y.; Zhang, H.; Mu, S.; Wei, W.; Jin, C.; Tong, C.; Song, Z.; Zha, Y.; Xue, Y.; Gu, G. Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: A retrospective and observational study. Aging 2020, 12, 11245–11258. [CrossRef] 58. Carpenè, G.; Onorato, D.; Nocini, R.; Fortunato, G.; Rizk, J.G.; Henry, B.M.; Lippi, G. Blood lactate concentration in COVID-19: A systematic literature review. Clin. Chem. Lab. Med. 2021. advance online publication. [CrossRef] 59. Singh, B.; Kaur, P.; Maroules, M. Splanchnic vein thrombosis in COVID-19: A review of literature. Dig. Liver Dis. 2020, 52, 1407–1409. [CrossRef] 60. Jagielski, M.; Pi ˛atkowski, J.; Jackowski, M. Challenges encountered during the treatment of acute mesenteric ischemia. Gastroenterol. Res. Pract. 2020, 5316849. [CrossRef] [PubMed] 61. Rasslan, R.; Dos Santos, J.P.; Menegozzo, C.; Pezzano, A.; Lunardeli, H.S.; Dos Santos Miranda, J.; Utiyama, E.M.; Damous, S. Outcomes after emergency abdominal surgery in COVID-19 patients at a referral center in Brazil. Updates Surg. 2021, 73, 763–768. [CrossRef] 62. Lei, S.; Jiang, F.; Su, W.; Chen, C.; Chen, J.; Mei, W.; Zhan, L.Y.; Jia, Y.; Zhang, L.; Liu, D.; et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection. EClinicalMedicine 2020, 21, 100331. [CrossRef] 63. Serban, D.; Socea, B.; Badiu, C.D.; Tudor, C.; Balasescu, S.A.; Dumitrescu, D.; Trotea, A.M.; Spataru, R.I.; Vancea, G.; Dascalu, A.M.; et al. Acute surgical abdomen during the COVID 19 pandemic: Clinical and therapeutic challenges. Exp. Ther. Med. 2021, 21, 519. [CrossRef] [PubMed] 64. Patel, S.; Parikh, C.; Verma, D.; Sundararajan, R.; Agrawal, U.; Bheemisetty, N.; Akku, R.; Sánchez-Velazco, D.; Waleed, M.S. Bowel ischaemia in COVID-19: A systematic review. Int. J. Clin. Pract. 2021, 75, e14930. [CrossRef] [PubMed] 65. Yantiss, R.K.; Qin, L.; He, B.; Crawford, C.V.; Seshan, S.; Patel, S.; Wahid, N.; Jessurun, J. Intestinal Abnormalities in Patients With SARS-CoV-2 Infection: Histopathologic Changes Reflect Mechanisms of Disease. Am. J. Surg. Pathol. 2021, 46, 89–96. [CrossRef] [PubMed] 66. McGonagle, D.; Bridgewood, C.; Ramanan, A.V.; Meaney, J.F.M.; Watad, A. COVID-19 vasculitis and novel vasculitis mimics. Lancet Rheumatol. 2021, 3, e224–e233. [CrossRef] 67. Huang, C.; Wang, Y.; Li, X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet 2020, 395, 497–506. [CrossRef] 68. Avila, J.; Long, B.; Holladay, D.; Gottlieb, M. Thrombotic complications of COVID-19. Am. J. Emerg. Med. 2021, 39, 213–218. [CrossRef] 69. Varga, Z.; Flammer, A.J.; Steiger, P.; Haberecker, M.; Andermatt, R.; Zinkernagel, A.S.; Mehra, M.R.; Schuepbach, R.A.; Ruschitzka, F.; Moch, H. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020, 395, 1417–1418. [CrossRef] 70. Maier, C.L.; Truong, A.D.; Auld, S.C.; Polly, D.M.; Tanksley, C.L.; Duncan, A. COVID-19-associated hyperviscosity: A link between inflammation and thrombophilia? Lancet 2020, 395, 1758–1759. [CrossRef] 71. Miyara, S.J.; Becker, L.B.; Guevara, S.; Kirsch, C.; Metz, C.N.; Shoaib, M.; Grodstein, E.; Nair, V.V.; Jandovitz, N.; McCannMolmenti, A.; et al. Pneumatosis Intestinalis in the Setting of COVID-19: A Single Center Case Series From New York. Front. Med. 2021, 8, 638075. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 200 22 of 22 72. Panigada, M.; Bottino, N.; Tagliabue, P.; Grasselli, G.; Novembrino, C.; Chantarangkul, V.; Pesenti, A.; Peyvandi, F.; Tripodi, A. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J. Thromb. Haemost. 2020, 18, 1738–1742. [CrossRef] 73. Hottz, E.D.; Azevedo-Quintanilha, I.G.; Palhinha, L.; Teixeira, L.; Barreto, E.A.; Pão, C.R.; Righy, C.; Franco, S.; Souza, T.M.; Kurtz, P.; et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood J. Am. Soc. Hematol. 2020, 136, 1330–1341. [CrossRef] 74. Stefely, J.A.; Christensen, B.B.; Gogakos, T.; Cone Sullivan, J.K.; Montgomery, G.G.; Barranco, J.P.; Van Cott, E.M. Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am. J. Hematol. 2020, 95, 1522–1530. [CrossRef] 75. Giuffrè, M.; Di Bella, S.; Sambataro, G.; Zerbato, V.; Cavallaro, M.; Occhipinti, A.A.; Palermo, A.; Crescenti, A.; Monica, F.; Luzzati, R.; et al. COVID-19-Induced Thrombosis in Patients without Gastrointestinal Symptoms and Elevated Fecal Calprotectin: Hypothesis Regarding Mechanism of Intestinal Damage Associated with COVID-19. Trop. Med. Infect. Dis. 2020, 5, 147. [CrossRef] [PubMed] 76. Giuffrè, M.; Vetrugno, L.; Di Bella, S.; Moretti, R.; Berretti, D.; Crocè, L.S. Calprotectin and SARS-CoV-2: A Brief-Report of the Current Literature. Healthcare 2021, 9, 956. [CrossRef] [PubMed] 77. Buso, G.; Becchetti, C.; Berzigotti, A. Acute splanchnic vein thrombosis in patients with COVID-19: A systematic review. Dig. Liver Dis. 2021, 53, 937–949. [CrossRef] 78. Thachil, J. The versatile heparin in COVID-19. J. Thromb. Haemost. 2020, 18, 1020–1022. [CrossRef] 79. Poterucha, T.J.; Libby, P.; Goldhaber, S.Z. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb. Haemost. 2017, 117, 437–444. [CrossRef] 80. Wang, M.K.; Yue, H.Y.; Cai, J.; Zhai, Y.J.; Peng, J.H.; Hui, J.F.; Hou, D.Y.; Li, W.P.; Yang, J.S. COVID-19 and the digestive system: A comprehensive review. World J. Clin. Cases 2021, 9, 3796–3813. [CrossRef] 81. Manolis, A.S.; Manolis, T.A.; Manolis, A.A.; Papatheou, D.; Melita, H. COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management. J. Cardiovasc. Pharmacol. Ther. 2021, 26, 12–24. [CrossRef] [PubMed] 82. Conti, P.; Caraffa, A.; Gallenga, C.E.; Ross, R.; Kritas, S.K.; Frydas, I.; Younes, A.; Di Emidio, P.; Ronconi, G.; Toniato, E. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: Inhibitory effect of the IL-1 receptor antagonist (IL-1Ra). J. Biol. Regul. Homeost. Agents 2020, 34, 1623–1627. [CrossRef] [PubMed]

Review of Mesenteric Ischemia in COVID-19 Patients

Authors: Amit GuptaOshin SharmaKandhala SrikanthRahul MishraAmoli Tandon & Deepak Rajput  Indian Journal of Surgery (2022) Published: 

Abstract

The new coronavirus (COVID-19) infection, first detected in Wuhan, China in 2019 has become a pandemic that has spread to nearly every country in the world. Through October 11, 2021, more than 23 billion confirmed cases and 4.8 million fatalities were reported globally. The bulk of individuals afflicted in India during the first wave were elderly persons. The second wave, however, resulted in more severe diseases and mortality in even younger age groups due to mutations in the wild virus. Symptoms may range from being asymptomatic to fatal acute respiratory distress syndrome (ARDS). In addition to respiratory symptoms, patients may present with gastrointestinal symptoms such as stomach pain, vomiting, loose stools, or mesenteric vein thrombosis. The frequency of patients presenting with thromboembolic symptoms has recently increased. According to certain studies, the prevalence of venous thromboembolism among hospitalized patients ranges from 9 to 25%. It was also shown that the incidence is significantly greater among critically sick patients, with a prevalence of 21–31%. Although the exact origin of thromboembolism is unknown, it is considered to be produced by several altered pathways that manifest as pulmonary embolism, myocardial infarction, stroke, limb gangrene, and acute mesenteric ischemia. Acute mesenteric ischemia (AMI) is becoming an increasingly prevalent cause of acute surgical abdomen in both intensive care unit (ICU) and emergency room (ER) patients. Mesenteric ischemia should be evaluated in situations with unexplained stomach discomfort. In suspected situations, appropriate imaging techniques and early intervention, either non-surgical or surgical, are necessary to avert mortality. The purpose of this article is to look at the data on acute mesenteric ischemia in people infected with COVID-19.

Introduction

Aside from the respiratory system, the gastrointestinal system is the most common site of SARS-COV-2 infection. This might be because enterocyte and vascular endothelial membranes have large amounts of angiotensin-converting enzyme receptor 2, a membrane integral protein. As a result, the COVID virus induces direct enterocyte invasion as well as indirect endothelial injury-induced thrombosis/intestinal ischemia in the bowel [1]. ICU patients are more prone than non-ICU patients to suffer acute mesenteric ischemia. This might be because, in addition to the direct viral activity on vascular endothelium, ICU patients have extra persistent pro-inflammatory effects. Cases have been observed even among individuals who have recovered from infection [2]. A rising number of cases of acute mesenteric ischemia in COVID-19 patients have been reported in the literature since the outbreak of this pandemic (list of reported cases are summarized in the Table 1). AMI risk was shown to be increased with age, male sex, and comorbidities such as hypertension, obesity, and diabetes mellitus. Because of delayed clinical manifestation, AMI-related mortality is quite significant, with 60–80% [3].Table 1 Summary of the cases reported on mesenteric ischemia in COVID-19 patientsFull size table

Case summary

A 55 years old man with no known comorbidity presented to the emergency department of our institute with severe pain abdomen and multiple episodes of vomiting. He reported the recent recovery from the non-complicated COVID-related illness. He did not report any intake of anticoagulants. On clinical examination, abdomen was unremarkable. X-ray chest, x-ray erect abdomen, and ultrasound abdomen were unremarkable. Mesenteric ischemia was suspected and the patient was subjected to CT angiography abdomen, which revealed thrombus at the origin of the superior mesenteric artery and impending gangrene of the small bowel (Fig. 1). Emergency laparotomy was done and intraoperatively found the gangrenous bowel involving the distal jejunum and almost the entire ileum sparing the terminal ileum (Fig. 2). Resection of the gangrenous small bowel and end jejunostomy was done. Later, he was given ICU care, but unfortunately, the patient succumbed to multi-organ dysfunction syndrome.

figure 1
Fig. 1
figure 2
Fig. 2

Pathophysiology

Although the specific etiology of hypercoagulable state and subsequent mesenteric ischemia in COVID-19 patients is unknown, these thromboembolic events can be related to alterations in all three Virchow triad characteristics (vascular endothelial injury, hypercoagulability, and stasis). A variety of variables complicate the etiology of thrombus development, one of which is vascular endothelial injury. Capillary permeability, hemostasis, and fibrinolysis are all maintained by the vascular endothelium (Fig. 3). Direct invasion causes endothelial cells to be damaged and lysed, resulting in an imbalance between pro and anticoagulant states [4]. Furthermore, vascular endothelial cells displayed morphological changes such as cellular expansion, retraction, and intercellular connection breakage [5]. The elevated levels of pro-inflammatory markers, von Willebrand factor, tissue factor, fibrinogen, and circulating microvesicles in the COVID-19 patients explain their hypercoagulability [6]. Antiphospholipid antibodies are elevated in some situations [7]. Patients who are critically ill, on limited oxygen support, and mechanical breathing are less mobilized, which increases the risk of deep venous thrombosis [3].

figure 3
Fig. 3

These mesenteric vascular thromboses cause acute hypoxia in the intestinal wall, which stimulates the renin-angiotensin system, causing mesenteric vasospasm and an elevated risk of hypoxic injury. SARS-COV binds to ACE 2 receptors in intestinal cells, causing cell lysis [8]. As a result, both hypoxia and direct invasion can trigger intestinal cell death. The loss of this epithelial barrier function in the gut promotes increased contact with enteric bacteria/endotoxins and viral particle penetration into the circulation [5]. The hypoxia continues, resulting in transmural infarction, perforation, and peritonitis. In one example of mesenteric ischemia induced by invasive mucormycosis, the presence of fungal components in the mesenteric microcirculation was documented [2]. See the flow chart summarizing the pathophysiology of mesenteric ischemia in covid-19 infection.

Clinical Presentation

Patients with mesenteric ischemia may exhibit a range of symptoms, from nonspecific complaints to peritonitis-like symptoms. Most of the patients developed symptoms a few days after being discharged successfully with proper symptomatic inpatient care. Although the respiratory symptoms predominate mesenteric ischemia presents with nonspecific abdominal symptoms such as loose stools, abdominal pain, nausea, vomiting, abdominal distension, and bleeding per rectum may occur in addition to the usual clinical presentation with respiratory features [6]. When opposed to arterial thrombosis, venous thrombosis has a delayed onset of symptoms. At first, sudden onset pain in the abdomen may be the sole symptom, and it may develop after 5–14 days. Abdominal clinical examination is nonyielding in the majority of cases. Abdominal signs would not develop unless the bowel gangrene or bowel perforation with peritonitis occurs [9].

Investigations

Blood investigations

Despite extensive study on the subject of acute mesenteric ischemia, the associated biomarkers were shown to be neither sensitive nor selective [10]. Elevated lactic acid levels and fibrin degradation products like D-dimer have low specificity and remain elevated in severe COVID-19 without AMI. However, biomarkers associated with hypercoagulable conditions aid in the initiation of preventive treatment and, to a lesser extent, in the management of COVID-related thrombotic events. Increased biomarkers of inflammation and infection include leukopenia (due to corticosteroid usage) and other signs such as C-reactive protein, procalcitonin, and IL-6. D-dimer, ferritin, prothrombin time, and lactate dehydrogenase are additional significant markers. The severity of increased lactate dehydrogenase and ferritin levels is associated with high mortality[8].

Radiological imaging

In the emergency room, an X-ray of the abdomen and an ultrasound are helpful for early examinations. X-ray of the erect abdomen helps in initial assessment in cases presented with features of obstruction or perforation. Ultrasound in the early phase may show SMA occlusion and bowel spasm or ultrasound findings in the early stages of acute mesenteric ischemia may appear normal [11]. In the intermediate phase, USG is not useful because of the presence of a large amount of gas-filled intestinal loops. In the late phase, USG may reveal fluid-filled lumen, bowel wall thinning, evidence of extra-luminal fluid, decreased or absent peristalsis. Therefore, USG may be helpful in the diagnosis of advanced bowel obstruction, gangrene, and perforation with peritoneal collection [12]. Ultrasonography revealed some other important features with distended and sludge-filled gall bladder with bile stasis. Portal venous gas also can be detected on ultrasonography which can be better characterized with the help of computed tomography [13].

Computed tomography

The gold standard investigation is CT angiography. CT observations commonly encountered in acute mesenteric ischemia secondary to COVID-19 includes thrombus in the aorta/SMA/portal circulation, augmentation of the bowel wall, thickness of the bowel wall with distention(> 3 cm), edema, and stranding of the mesentery, pneumatosis intestinalis or portal venous gas suggesting bowel wall ischemia, and non-enhancing thick bowel wall seen in bowel infarction, bowel perforation secondary to bowel infarction may present discontinuity of bowel wall with localized air collection. One should remember that pneumatosis intestinalis may also occur due to mechanical ventilation. Pneumoperitoneum occurs when there is severe intestinal necrosis and perforation. There were additional reports of nonspecific features such as a dilated gut with a fluid-filled lumen, distended gallbladder with bile stasis, features of solid organ ischemia, and pancreatitis [14]. MRI, despite its accessibility, has drawbacks such as a longer acquisition time and lower resolution than CT angiography [12].

Management

A summary of cases of acute mesenteric ischemia has been tabulated (Table 1). Management of acute mesenteric ischemia in COVID-19 includes the following:

  • Supportive measures: Crystalloid rehydration and empirical antibacterial treatment should begin before angiography or any surgical resection. Comorbidity management, hemodynamic support in unstable patients, and electrolyte balance correction are all critical components of patient care [10].
  • Anticoagulation: There is insufficient data in 19 patients to warrant thromboprophylaxis. According to the Tang et al. study, low-dose heparin prophylaxis decreased thrombotic events and mortality in those with D-dimer levels over 3 mg/ml. Despite the increased risk of bleeding, mesenteric ischemia should be treated with intraoperative and postoperative anticoagulation [15].
  • Revascularisation: Revascularization with catheter-directed thrombolysis and thrombectomy by percutaneous/surgical intervention can be explored in instances where there is no indication of significant intestinal ischemia. Catheter-directed thrombolysis with unfractionated heparin and recombinant tissue plasminogen activators can accomplish this. Because of the increased risk of re-thrombosis, vascular clearance is not indicated in instances of superior mesenteric vein thrombus [15].
  • Resection of the gangrenous bowel: Depending on clinical suspicion, a CT angiography examination of mesenteric vasculature and bowel health can be performed, and an emergency exploration call should be placed. Intraoperatively, if the patient is normotensive, has no sepsis or peritonitis, and the remaining bowel viability is unquestionable, the gangrenous bowel is to be removed, and the remaining bowel can be considered for re-anastomosis. In unfavorable circumstances, a stoma should be created following gangrenous bowel resection [11]. The margin dissection in venous thrombosis should be broader than in arterial thrombosis. To assure the bowel’s survivability, abdominal closure should be temporary, and a relook laparotomy should be done 48 h later. Histopathological examination of the resected intestine may indicate patchy or widespread necrotic changes from mucosa to transmural thickness. In the submucosal vasculature, fibrin-containing microthrombi with perivascular neutrophilic infiltration is observed.
  • Management of short bowel syndrome: The therapy varies depending on the length of colon left after excision of infarcted bowel caused by mesenteric ischemia.
  • Medical- In severe diarrhea, fluid and electrolyte loss must be replaced. TPN for feeding and histamine-2 receptor antagonists or PPIs for stomach acid secretion reduction. Loperamide and diphenoxylate are anti-motility medicines that delay small intestine transit whereas Octreotide reduces the volume of gastrointestinal secretions.
  • Non-transplant surgical therapy- Done to improve the absorption capacity of the remaining intestine by restoring intestinal continuity. Increased nutrient and fluid absorption is the goal. Segmental reversal of the small bowel, fabrication of small intestinal valves, and electrical pacing of the small bowel are all procedures used to delay intestinal transit. Longitudinal intestinal lengthening and tailoring technique (LILT) and serial transverse arthroplasty process are two intestinal lengthening procedures (STEP).
  • Intestinal transplantation- Life-threatening problems such as liver failure, thrombosis of major central veins, frequent episodes of severe dehydration, and catheter-related sepsis are reasons for intestinal transplantation [16].

Prognosis

Acute mesenteric ischemia has a poor prognosis, and life is reliant on prompt diagnosis and treatment. If detected within 24 h, the likelihood of survival is 50%, but it declines to 30% beyond that [17].In operated cases, COVID infection acts as an independent risk factor and is responsible for higher mortality [18].

Conclusion

SARS-COV-2 infection even though initially thought to be respiratory infection; later cases detected presenting with multisystem involvement. The presentation may vary from asymptomatic or mildly symptomatic to severe respiratory distress syndrome or thromboembolic phenomenon requiring ICU care. The exact mechanism of thromboembolism is not established. However, the increasing number of acute mesenteric ischemia is quite alarming. The treating physician should be overcautious in patients presenting with abdominal symptoms either currently affected or recovered from COVID-related illness. In high-risk patients, early start of prophylactic anticoagulation may be beneficial. Earlier intervention is known acute mesenteric ischemia cases with operative or minimally invasive procedures may give higher survival benefits. It mandates more research to determine the causes of thromboembolism, as well as preventive and therapeutic anticoagulation in these individuals.

References

  1. Jin B, Singh R, Ha SE, Zogg H, Park PJ, Ro S (2021) Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19. World J Gastroenterol. Baishideng Publishing Group Co 27:2341–52CAS Article Google Scholar 
  2. Jain M, Tyagi R, Tyagi R, Jain G (2021) Post-COVID-19 gastrointestinal invasive mucormycosis. Indian J Surg 22:1–3
  3. Kerawala AA, Das B, Solangi A (2021) Mesenteric ischemia in COVID-19 patients: a review of current literature. World J Clin Cases 9(18):4700–4708Article Google Scholar 
  4. Kichloo A, Dettloff K, Aljadah M, Albosta M, Jamal S, Singh J et al (2020) COVID-19 and hypercoagulability: a review. Clin Appl Thromb 26
  5. Parry AH, Wani AH, Yaseen M (2020) Acute mesenteric ischemia in severe Coronavirus-19 (COVID-19): possible mechanisms and diagnostic pathway. Acad Radiol 27(8):1190Article Google Scholar 
  6. Cheung S, Quiwa JC, Pillai A, Onwu C, Tharayil ZJ, Gupta R (2020) Superior mesenteric artery thrombosis and acute intestinal ischemia as a consequence of COVID-19 infection. Am J Case Rep 21:1–3Google Scholar 
  7. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W et al (2020) Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 382(17):e38Article Google Scholar 
  8. Al Mahruqi G, Stephen E, Abdelhedy I, Al WK (2021) Our early experience with mesenteric ischemia in COVID-19 positive patients. Ann Vasc Surg 73:129–132Article Google Scholar 
  9. Karna ST, Panda R, Maurya AP, Kumari S (2020) Superior mesenteric artery thrombosis in COVID-19 Pneumonia: an underestimated diagnosis—first case report in Asia. Indian J Surg 82(6):1235–1237Article Google Scholar 
  10. Singh B, Kaur P (2021) COVID-19 and acute mesenteric ischemia: a review of literature. Hematol Transfus Cell Ther 43(1):112–116Article Google Scholar 
  11. Janež J, Klen J (2021) Multidisciplinary diagnostic and therapeutic approach to acute mesenteric ischaemia: a case report with literature review. SAGE Open Med Case Rep 9:2050313X2110048Article Google Scholar 
  12. Mc W (2010) Acute mesenteric ischemia: diagnostic approach and surgical treatment. Semin Vasc Surg 23(1):9–20Article Google Scholar 
  13. Bhayana R, Som A, Li MD, Carey DE, Anderson MA, Blake MA et al (2020) Abdominal imaging findings in COVID-19: Preliminary observations. Radiology 297(1):E207–E215
  14. Keshavarz P, Rafiee F, Kavandi H, Goudarzi S, Heidari F, Gholamrezanezhad A (2021) Ischemic gastrointestinal complications of COVID-19: a systematic review on imaging presentation. Clin Imaging 73:86–95Article Google Scholar 
  15. Bergqvist D, Svensson PJ (2010) Treatment of mesenteric vein thrombosis. Semin Vasc Surg 23(1):65–68Article Google Scholar 
  16. Seetharam P, Rodrigues G (2011) Short bowel syndrome: a review of management options. Saudi J Gastroenterol 17(4):229–235Article Google Scholar 
  17. Krothapalli N, Jacob J (2021) A rare case of acute mesenteric ischemia in the setting of COVID-19 infection. Cureus 13(3):0–4Google Scholar 
  18. Haffner MR, Le HV, Saiz AM, Han G, Fine J, Wolinsky P et al (2021) Postoperative In-hospital morbidity and mortality of patients with COVID-19 infection compared with patients without COVID-19 infection. JAMA Netw Open 4(4):10–13Article Google Scholar 
  19. Ucpinar BA, Sahin C (2020) Superior mesenteric artery thrombosis in a patient with COVID-19: a unique presentation. J Coll Physicians Surg Pak 30(10):S112–S114Google Scholar 
  20. Khesrani LS, Chana k, Sadar FZ, Dahdouh A, Ladjadj Y, Bouguermouh D (2020) Intestinal ischemia secondary to Covid-19. J Pediatr Surg Case Rep 61:101604Article Google Scholar 
  21. Norsa L, Valle C, Morotti D, Bonaffini PA, Indriolo A, Sonzogni A (2020) Intestinal ischemia in the COVID-19 era. Dig Liver Dis 52(10):1090–1091CAS Article Google Scholar 
  22. Rodriguez-Nakamura RM, Gonzalez-Calatayud M, Martinez Martinez AR (2020) Acute mesenteric thrombosis in two patients with COVID-19. Two cases report and literature review. Int J Surg Case Rep 76:409–14Article Google Scholar 
  23. VartanogluAktokmakyan T, Tokocin M, Meric S, Celebi F (2021) Is mesenteric ischemia in COVID-19 patients a surprise? Surg Innov 28(2):236–238Article Google Scholar 
  24. Levolger S, Bokkers RPH, Wille J, Kropman RHJ, de Vries JPPM (2020) Arterial thrombotic complications in COVID-19 patients. J Vasc Surg Cases Innov Tech 6(3):454–459Article Google Scholar 
  25. Thuluva SK, Zhu H, Tan MML, Gupta S, Yeong KY, Wah STC et al (2020) A 29-year-old male construction worker from india who presented with left-sided abdominal pain due to isolated superior mesenteric vein thrombosis associated with SARS-CoV-2 infection. Am J Case Rep 21:1–5Article Google Scholar 
  26. Lari E, Lari A, AlQinai S, Abdulrasoul M, AlSafran S, Ameer A et al (2020) Severe ischemic complications in Covid-19—a case series. Int J Surg Case Rep 75(June):131–135Article Google Scholar 
  27. Singh B, Mechineni A, Kaur P, Ajdir N, Maroules M, Shamoon F et al (2020) Acute intestinal ischemia in a patient with COVID-19 infection. Korean J Gastroenterol 76(3):164–166Article Google Scholar 
  28. De Roquetaillade C, Chousterman BG, Tomasoni D, Zeitouni M, Houdart E (2020) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19. The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. (January)
  29. Sehhat S, Talebzadeh H, Hakamifard A, Melali H, Shabib S, Rahmati A et al (2020) Acute mesenteric ischemia in a patient with COVID-19: a case report. Arch Iran Med 23(9):639–643Article Google Scholar 
  30. Beccara LA, Pacioni C, Ponton S, Francavilla S, Cuzzoli A (2020) Arterial mesenteric thrombosis as a complication of SARS-CoV-2 infection. Eur J Case Rep Intern Med 7(5).
  31. Ignat M, Philouze G, Aussenac-belle L (2020) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. (Jan)
  32. Farina D, Rondi P, Botturi E, Renzulli M, Borghesi A, Guelfi D et al (2021) Gastrointestinal: bowel ischemia in a suspected coronavirus disease (COVID-19) patient. J Gastroenterol Hepatol 36(1):41CAS Article Google Scholar 
  33. Azouz E, Yang S, Monnier-Cholley L, Arrivé L (2020) Systemic arterial thrombosis and acute mesenteric ischemia in a patient with COVID-19. Intensive Care Med 46(7):1464–1465CAS Article Google Scholar 
  34. Vulliamy P, Jacob S, Davenport RA (2020) Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19. Br J Haematol 189(6):1053–1054CAS Article Google Scholar 
  35. Bianco F, Ranieri AJ, Paterniti G, Pata F, Gallo G (2020) Acute intestinal ischemia in a patient with COVID-19. Tech Coloproctol 24(11):1217–1218CAS Article Google Scholar 
  36. Filho A do C, Cunha B da S (2020) Case report – inferior mesenteric vein thrombosis and COVID-19. 2020060282
  37. Mitchell JM, Rakheja D, Gopal P (2021) SARS-CoV-2-related hypercoagulable state leading to ischemic enteritis secondary to superior mesenteric artery thrombosis. Clin Gastroenterol Hepatol 19(11):e111CAS Article Google Scholar 
  38. English W, Banerjee S (2020) Coagulopathy and mesenteric ischaemia in severe SARS-CoV-2 infection. ANZ J Surg 90(9):1826Article Google Scholar 
  39. de Barry O, Mekki A, Diffre C, Seror M, El Hajjam M, Carlier RY (2020) Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia. Radiol Case Rep 15(7):1054–1057Article Google Scholar 
  40. Kraft M, Pellino G, Jofra M, Sorribas M, Solís-Peña A, Biondo S, Espín-Basany E (2021) Incidence, features, outcome and impact on health system of de-novo abdominal surgical diseases in patients admitted with COVID-19. Surg J R Coll Surg Edinb Irel 19:e53–e58Google Scholar 
  41. Besutti G, Bonacini R, Iotti V, Marini G, Riva N, Dolci G et al (2020) Abdominal visceral infarction in 3 patients with COVID-19. Emerg Infect Dis 26(8):1926–1928CAS Article Google Scholar 
  42. Kielty J, Duggan WP, O’Dwyer M (2020) Extensive pneumatosis intestinalis and portal venous gas mimicking mesenteric ischaemia in a patient with SARS-CoV-2. Ann R Coll Surg Engl 102(6):E145–E147CAS Article Google Scholar 
  43. Pang JHQ, Tang JH, Eugene-Fan B (2021) A peculiar case of small bowel stricture in a coronavirus disease 2019 patient with congenital adhesion band and superior mesenteric vein thrombosis. Ann Vasc Surg 70:286–289Article Google Scholar 
  44. Osilli D, Pavlovica J, Mane R, Ibrahim M, Bouhelal A, Jacob S (2020) Case reports: mild COVID-19 infection and acute arterial thrombosis. J Surg Case Rep (9):1–3

Consequences of COVID-19 for the Pancreas

Authors: Urszula Abramczyk,1,*Maciej Nowaczyński,2Adam Słomczyński,2Piotr Wojnicz,2Piotr Zatyka,2 and Aleksandra Kuzan1 Int J Mol Sci. 2022 Jan; 23(2): 864.Published online 2022 Jan 13. doi: 10.3390/ijms23020864

Abstract

Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the pancreas either. This review presents a summary of the molecular mechanisms involved in the development of pancreatic dysfunction during the course of COVID-19, the comparison of the effects of non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic function, and a summary of how drugs used in COVID-19 treatment may affect this organ. It appears that diabetes is not only a condition that predisposes a patient to suffer from more severe COVID-19, but it may also develop as a consequence of infection with this virus. Some SARS-CoV-2 inpatients experience acute pancreatitis due to direct infection of the tissue with the virus or due to systemic multiple organ dysfunction syndrome (MODS) accompanied by elevated levels of amylase and lipase. There are also reports that reveal a relationship between the development and treatment of pancreatic cancer and SARS-CoV-2 infection. It has been postulated that evaluation of pancreatic function should be increased in post-COVID-19 patients, both adults and children.

1. Effects of Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-Related Coronavirus (MERS-CoV) on the Pancreas

Coronaviruses are enveloped, single- and positive-stranded RNA viruses that infect birds and mammals. In humans, coronaviruses cause respiratory tract infection, usually the common cold, but they can also cause severe respiratory illness including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), caused by severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), respectively [1]. Coronaviruses tend to cause epidemics and even pandemics. The first coronavirus pandemic was the SARS outbreak in 2002–2003 [2]. With the experience gained during the SARS pandemic, it was possible to more quickly identify subsequent outbreaks of the MERS epidemic in 2012 [3]. The pathomechanism of both viruses is very similar—they even both use transmembrane protease serine 2 (TMPRSS2), except SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as its receptor, whereas MERS uses dipeptidyl peptidase-4 (DPP4) [4,5]. Moreover, there is a difference in terms of the severity and frequency of symptoms, which was observed in MERS patients as more frequent hospitalization in the intensive care unit (ICU) compared to SARS patients [2] (Table 1). Diabetes was one of the significant and independent predictors for developing severe SARS-CoV and MERS-CoV [6,7,8]. In MERS, no viral antigen was detected in any tissue other than pneumocytes [7], despite multiple organ dysfunction syndrome in critically ill patients. In SARS-CoV, the presence of the virus was detected not only in respiratory epithelial cells, but also in small intestinal and colonic epithelial cells, in which it also revealed replication features [9]. It is known that the ACE2 receptor is also present in tissues such as the heart, kidney, and pancreas [8,9]. According to some authors, the presence of the receptor is sufficient for tissue entry and pathogenic activity, although other researchers do not support this thesis [9,10]. Yang et al. were some of the first researchers who hypothesized that SARS coronavirus enters islets using ACE2 as its receptor and damages islets causing acute diabetes [8]. Yang’s study revealed that SARS-CoV had a much higher affinity for pancreatic islet cells than for pancreatic exocrine cells, which was consistent with the hyperglycemia observed in some patients and rarely reported acute pancreatitis (AP) [8]. Furthermore, insulin-dependent diabetes mellitus (IDDM) and high fasting blood glucose values were observed in some inpatients [8]. A 3-year follow-up revealed that both abnormalities were transient, which may be indicative of only temporary damage to the pancreatic islets [8]. However, another reason (different from that given by Young et al.) for high fasting blood glucose value in patients may result from increased stress hormones release. Cortisol, catecholamines, growth hormone, and glucagon, which are released during infection, fever, and trauma, can lead to hyperglycemia to the same degree as SARS-CoV can [11]. No information was found in the literature about a direct impact of the MERS virus on the pancreas or on glycemia during or after infection. This may be due to an insufficiently detailed analysis of the available data during previous studies that oscillated primarily, for laboratory tests, between complete blood count (CBC), lactate dehydrogenase (LDH), urea, and creatinine analysis. A summary of SARS-CoV, MERS, and SARS-CoV-2 is shown in Table 1.Table 1. The summary of characteristics of SARS and MERS coronaviruses. Dipeptidyl peptidase-4 (DPP4), transmembrane protease serine 2 (TMPRSS2), hospitalization in the intensive care unit (ICU), and cathepsin L (CTSL).

Table

In 2019, a new coronavirus named SARS-CoV-2 was identified, causing COVID-19. This virus has many characteristics that are analogous to SARS-CoV, for example, ACE2 is also used as its receptor [12]. Patients with diabetes are among those with the most severe forms of COVID-19 and related mortality; insights from recent experience can guide future management [17], particularly for the consequences on the pancreas. As the COVID-19 pandemic has been ongoing for nearly two years, this study aims to collect data concerning the impact of SARS-CoV-2 on the pancreas and analyze them to estimate the future health consequences of COVID-19 in populations.

2. Pancreatic Damage during Diabetes Mellitus and COVID-19

Pancreas tissue damage may cause to the lack of control over normal blood glucose levels in the body. Type 1 diabetes (T1D) is caused by insulin deficiency due to βcell dysfunction of immunologic or idiopathic cause. In contrast, β pancreatic cells in type 2 diabetes (T2D) become depleted over time due to compensatory insulin secretion caused by insulin resistance. There is also type 3 diabetes (T3D), which is described as diabetes associated with the development of Alzheimer’s disease [18]. It should not be confused with type 3c (pancreatogenic) diabetes, which relates to the exocrine and digestive functions of the pancreas. The issue concerning the impairing effect of hyperglycemia (glucotoxicity) on the secretory function of the islets of Langerhans has also been increasingly raised. In addition to endocrine dysfunction, some diabetic patients may also develop moderate exocrine pancreatic insufficiency (EPI), in which pancreatic enzyme secretion is impaired. EPI can be observed in almost all patients with type 3c (pancreatogenic) diabetes (secondary to pancreatic pathology), whereas the prevalence of this dysfunction in patients with T1D or T2D is 40% and 27%, respectively [19].With the ongoing SARS-CoV-2 pandemic, patients with reduced normal pancreatic function are at high risk for COVID-19 requiring hospitalization. In particular, elevated blood glucose levels in patient with and without diabetes makes them at high risk of mortality [20]. Hyperglycemia impairs the immune response (e.g., by reducing the activity of macrophages and polymorphonuclear leukocytes), which in addition influences the excessive cytokine response, and thus has a strong proinflammatory effect.The receptors for ACE2, which are also present in the pancreas, are a target of SARS-CoV-2 in the body, which may result in acute failure of both the islets of Langerhans and exocrine cells [15]. Infection-induced, transient β cell dysfunction may cause an uncontrolled hyperglycemic state, especially in patients whose pancreas is already affected by diabetes mellitus. Persistent hyperglycemia usually predisposes to severe COVID-19 and to viral infection complicated by secondary infections. The aforementioned risk can be found in T1D, T2D, and gestational diabetes mellitus (GDM). In T2D patients, the much more frequent coexistence of other risk factors such as atherosclerosis, hypertension, and obesity should be taken into consideration, which usually implies a worse prognosis for the course of COVID-19 [21,22]. In GDM, SARS-CoV-2 infection not only increases the risk of more severe course of the disease in a patient, but may also result in diabetic fetopathy or, in more advanced pregnancies, increase the risk of future pathologies involving glucose metabolism (such as T2D) in a child [23].

3. Pancreatic Damage in Patients without Pre-Existing Diabetes Infected with SARS-CoV-2

It has been postulated that, either by direct invasion of pancreatic cells by the virus or by indirect mechanisms described below, SARS-CoV-2 has a destructive effect on the pancreas and can lead to insulin deficiency and development of T1D [24].If the hypothesis that SARS-CoV-2 infection causes hyperglycemia is true, increased statistics of new T1D cases should be observed. Indeed, there are publications that describe such a phenomenon. For instance, Unsworth et al. and Kamrath et al. describe an increase in new-onset T1D in children during the COVID-19 pandemic [16,25]. Although pancreatic β cell damage induced transient hyperglycemia in SARS-CoV, it is still unclear whether β cell damage is transient or permanent in SARS-CoV-2 [22]. This information appears to be of great importance because COVID-19 in children is frequently considered “harmless”. Therefore, it is reasonable to sensitize parents to the fact that the consequences of COVID-19 may be potentially dangerous for their children.Below you will find the proposed molecular mechanisms that may participate in pancreatic damage that causes carbohydrate metabolism disorders.

4. Etiology Associated with ACE2, TMPRSS2, and Na+/H+ Exchanger

As previously mentioned, SARS-CoV infection of host cells is facilitated by ACE2, but also by the transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL) [13].ACE2 is an enzyme that is expressed to varying degrees in most cells of the human body [14,26,27]. This enzyme catalyzes the conversion of angiotensin II to angiotensin 1–7, taking part in the maintenance of body homeostasis by influencing the regulation of blood pressure and water–electrolyte balance through the renin–angiotensin–aldosterone (RAA) system [28]. Moreover, ACE2/angiotensin (1–7) stimulates insulin secretion, reduces insulin resistance, and increases pancreatic βcell survival [27,28].In addition to the key role it plays in maintaining body homeostasis, ACE2 is now also the best-studied target for SARS-CoV-2 S glycoprotein, enabling infection of host cells [27,29]. ACE2 in the pancreas is expressed mainly within the pericytes of pancreatic microvessels and to a lesser extent on the surface of the islets of Langerhans, including pancreatic β cells [30]. SARS-CoV-2 shows 10–20 times more activity against ACE2 than SARS-CoV, which significantly increases the infectivity of SARS-CoV-2 [31,32]. Furthermore, studies indicate that SARS-CoV may also downregulate ACE2 expression in cells. This causes an imbalance between ACE and ACE2, consequently leading to blood pressure disorders and systemic inflammation [27,33,34]. Due to the 79% genetic similarity between SARS-CoV and SARS-CoV-2 [35], it is speculated that ACE2 expression may also be downregulated during SARS-CoV-2 infection, causing i.a. MODS observed in COVID-19 [27].During cell infection by SARS-CoV-2, in addition to the role played by ACE2, it is also appropriate to consider the significant pathogenic role of TMPRSS2 that is necessary for the preparation of S glycoprotein by its cleavage, thereby enabling fusion of the virus with the host cell [36,37]. The S1 and S2 domains can be distinguished in the SARS-CoV-2 S glycoprotein. The S1 domain is involved in binding to the ACE2 receptor and then TMPRSS2 intersects with the S protein, including at the boundary of the S1 and S2 domains and within the S2 domain, which enables the virus–cell fusion [38,39]. According to studies, TMPRSS2 expression is significantly increased in obese patients, which may contribute to the poorer prognosis that is observed during COVID-19 in this patient group [40]. Moreover, obese patients are frequently already burdened with problems such as insulin resistance at baseline, while the presence of ACE2 and TMPRSS2 within the pancreas as a binding site for SARS-CoV-2 may exacerbate insulin resistance causing problems in terms of diabetes management in COVID-19 patients.There are also other mechanisms by which COVID-19 may affect the development of hyperglycemia. It is reported that the virus may also affect the glucose regulation through the Na+/H+ exchanger and lactate pathways. The mechanism is that angiotensin II, which accumulates during infection, contributes to insulin resistance and—by activating the Na+/H+ exchanger in the pancreas—it leads to hypoxia and extracellular acidification, which, through the accumulation of calcium and sodium ions in the cells and the production of reactive oxygen species, damages pancreatic tissue [41]. Simultaneously, the concentration of lactate increases, which in COVID-19 infection is intensively released, among other things, from adipose tissue, and then monocarboxylate transporters transport lactate and H+ ion inward in the cell, which increases Na+/H+ exchanger activation, further disrupting pancreatic homeostasis [41].

5. The Etiology Associated with a Systemic Proinflammatory Environment, Immune System Aggression, and Production of Novel Autoantigens

A broad spectrum of proinflammatory cytokines, such as IL-2, IL-6, IL-7, IL-8, interferon-γ, and Tumor Necrosis Factor α (TNF-α), is released during, in particular severe, COVID-19 infection [42,43,44]. Based on current studies, it is reasonable to suspect that these cytokines are released in response to the binding of the virus to ACE2 receptors that are also located in the pancreas [9,42]. The cause of pancreatic damage during COVID-19 is the cytokine storm that plays a key role in this case, because in both acute pancreatitis (AP) and severe COVID-19, elevated levels of the aforementioned interleukins are associated with the severity of these both disease entities. Particular attention should be paid to IL-6, because it is suspected to play a key role in the pathogenesis of AP as well as acute respiratory distress syndrome (ARDS) that is the most common and most severe clinical manifestation of COVID-19. In COVID-19-induced ARDS, IL-6 levels are correlated with disease-related mortality [45,46,47]. At the same time, high IL-6 levels correlate with an increased risk of developing severe pancreatitis [48,49].The production of neutralizing antibodies is also an important response of the body in the course of COVID-19 [50,51,52]. It has been observed that early seroconversion and very high antibody titers occur in patients with severe SARS-CoV-2 infection [53,54]. The available literature details a mechanism called antibody-dependent enhancement (ADE), which is associated with a pathological response of the immune system [53]. ADE exploits the existence of FcRS receptors located on various cells of the immune system, for example, macrophages and B lymphocytes [53]. This relationship may lead to a likely bypass of the classical viral infection pathway by ACE2, and virus–antibody complexes may stimulate macrophages to overproduce cytokines including significant IL-6 [53,55].Molecular mimicry may be also one of potential causes of pancreatic cell damage [56]. There are similarities in the protein structure of the virus and β-pancreatic cells, which may induce cross-reactivity and lead to autoimmunity [56]. Furthermore, viral infection may also lead to increased cytokine secretion by surrounding dendritic cells and activation of naive T cells in genetically predisposed individuals [56].

6. Pancreatitis in COVID-19

Although the impact of the discussed coronavirus-induced disease on exocrine function is not fully understood, available literature is not able to unambiguously determine whether the tissue damage leading to AP occurs as a result of direct SARS-CoV-2 infection [57] or as a result of systemic MODS with increased levels of amylase and lipase [42]. Liu et al.’s study involving 121 COVID-19 patients with a mean age of 57 years and a variable course of infection proved above-normal levels of amylase and lipase in 1–2% of patients with moderate COVID-19 infection and in 17% of patients with severe COVID-19 infection. This may support the hypothesis that SARS-CoV-2-induced disease has a destructive effect not only on the endocrine portion of this gland, but also on the exocrine one [15].However, elevated levels of pancreatic enzymes in question do not have to mean the destruction of pancreatic cells—after all, such a situation may occur during kidney failure or diarrhea in the course of COVID-19. Furthermore, there remains the question of the effect of drugs administered during SARS-CoV-2 infection on changes in pancreatic function [42], discussed further in this article.According to the International Association of Pancreatology (IAP) and the American Pancreatic Association (APA), the diagnosis of AP is based on meeting two out of three of the following criteria: clinical (epigastric pain), laboratory (serum amylase or lipase > 3 × upper limit of normal), and/or imaging criteria (computed tomography, magnetic resonance imaging, ultrasound) [58]. Pancreatic lipase is considered as a potential marker of SARS-CoV-2 severity with concomitant AP. In Hemant Goyal et al.’s study, as many as 11.7% out of 756 COVID-19 patients had hyperlipidemia and they were three times more likely to have severe COVID-19 [59]. Those with higher lipase levels—17% out of 83 patients—required hospitalization [60]. However, it is difficult to distinguish whether these patients required hospitalization for severe systemic COVID-19 infection or for pancreatitis in the course of COVID-19 infection.AP in the course of COVID-19 was analyzed in different age groups; however, some studies only involve children [61]. Compared to pancreatic islet cells, cells of the exocrine pancreatic ducts are more abundant in ACE2 and TMPRSS2 that are necessary for the virus to penetrate the cell [62]. Infection of these cells may be one of the causes of AP [63]. Infections, both bacterial and viral, are one of the causes of AP. The definitive mechanism of how viral infections affect pancreatic cells is not known; however, a study by Maria K Smatti et al. found that there is infection of pancreatic islet cells and replication of the virus within them, ultimately resulting in autoimmune reactions that eventually affect both diabetes and AP in a negative way [64]. For non-SARS-CoV-2 patients, the etiology of AP is known and confirmed in most cases, although 69% of those undergoing infection do not have definite etiology of AP while meeting the AP-Atlanta criteria for diagnosis [65].Hegyi et al. show the mechanism of MODS formation during COVID-19 infection and AP [66]. This is lipotoxicity, involving an interstitial increase in pancreatic lipase levels, which leads to the breakdown of triacylglycerols contained in adipose tissue cells and the release of unsaturated fatty acids. These in turn exert a toxic effect on mitochondria causing the release of cytokines, which results in a cytokine storm.There is also a hypothesis, which claims that AP can develop because of blood circulatory centralization resulting from uncontrolled cytokine storm created by SARS-CoV-2 infection [67]. There exist reports that say that pancreatic ischemia may be the cause of different degrees of acute pancreatitis [68,69]. This statement can be supported by the reports that state that pancreatic blood reperfusion inhibits the development of AP and accelerate pancreas recovery [70].Another mechanism of developing AP during COVID-19 may be a coagulation cascade activation caused by active inflammatory process due to SARS-CoV-2 infection [71]. The ongoing inflammatory process causes not only hemostasis imbalance for blood clotting, but it also leads to intensification of coagulation by removing epithelial cell protein C receptor (EPCR) from epithelial by the means of inflammatory mediators and thrombin [71]. This means that both processes intensify each other. Simultaneously, it was proved that COVID-19 predisposes patients to venous thromboembolism resulting from excessive inflammation, platelet activation, and endothelial dysfunction [72]. It is also important to notice that AP is inherently connected with a coagulation cascade activation, increased fibrinolysis and, hence, higher level of D-dimers [73]. Acute pancreatitis severity may depend on hemostasis imbalance; local coagulation results in mild AP whereas, in more severe AP cases, the imbalance may lead to development of disseminated intravascular coagulation (DIC) [74]. These observations have been supported by the results of experimental studies showing that the inhibition of coagulation reduces the development of AP [75,76,77] and exhibits therapeutic effect in this disease [78,79]. Additionally it is worth noticing that infection-related hyperglycemia has powerful inflammation-promoting effects on the organism (especially when organism is under stress), thus increasing the number of inflammatory mediators [74]. Unfortunately, it is impossible to decide which process is dominant in causing AP in COVID-19 patients: local inflammation caused by SARS-CoV-2 or systemic hemostasis imbalance.Clinical reports on low molecular weight heparin (LMWH) treatment in AP seem to emphasize a more significant role of hemostasis imbalance in causing AP [74,80,81]. Heparin is extremely significant in the treatment of COVID19 patients due to its properties, mainly its similarity to heparan sulphate, which appears in a respiratory tract, its interactions with SARS-CoV-2 S protein, leading to viral adhesion inhibiting to the cell membrane [82], and its anti-inflammatory effects. Thanks to these properties, heparin may not only show its therapeutic effect as the anticoagulant, but also its protective role in acute pancreatitis or respiratory inflammations [83,84,85].

7. Drugs Used against SARS-CoV-2 Infection (Glucocorticoids, Lopinavir, Ritonavir, Remedesivir, Interferon-β1 (IFN-β1), and Azithromycin) Induce Pancreatic β Cell Damage

Statistical analyses revealed a significantly higher incidence of AP with the concomitant systemic use of glucocorticosteroids (GCS) [86]. In one study analyzing the development of drug-induced AP, dexamethasone, was classified as type IB—there was one case report in which administration of this drug-induced AP occurred; however, other causes of pancreatitis such as alcohol consumption could not be excluded [87]. Other GCS such as hydrocortisone, prednisone, and prednisolone were used in patients with mild to moderate AP; however, they cannot be classified into any group because they are frequently used together with other drugs that cause AP [86,87]. However, it has been determined that GCS independently increase the risk of AP, and patients with residual AP risk factors during GCS treatment should be more monitored for the development of AP [23]. Javier A. Cienfuegos et al. additionally observed that one of mechanisms of AP formation in COVID-19 patients may be GCS administered at the time of admission to the ICU with severe respiratory failure [88]. Because GCS were used in severe COVID-19 cases, it is difficult to say what true reason for AP was—either a severe course of COVID-19 or GCS application or both.GCS are used in the treatment of many diseases due to their immunosuppressive and anti-inflammatory nature. They induce diabetes in previously healthy patients as well as significantly exacerbate diabetes in diabetic patients [89,90]. Diabetes develops in these patients likely due to pancreatic β cell dysfunction, decreased insulin secretion, and increased insulin resistance in other tissues, which may depend on the timing and the dose of GCS used [89,91]. Long-acting or intermediate-acting insulin alone or combined with short-acting insulin should be used during the treatment [90]. At the same time, no advantage was found over the use of oral hypoglycemics [92]. Certainly, patients after long-term GCS therapy will need further observation for diabetes.Lopinavir/ritonavir was classified in the previously mentioned study as a type IV drug—medications reported with little information [87]. Both drugs are included in the group of antiretrovirals that act as protease inhibitors, and they are primarily used for HIV infection. Although Lopinavir is an active drug, it is not used alone. There have been reports about the occurrence of AP during the use of protease inhibitors in question, which is also described in the Summary of Product Characteristics (SmPC) of products approved by Committee for Medicinal Products for Human Use (CHMP). It has been proved that the use of lopinavir/ritonavir causes hyperglycemia [93,94].Remdesivir is an adenosine analogue with antiviral activity. There are single reports about the occurrence of pancreatitis as a result of the use of the aforementioned medication [95,96]. At the same time, it should be noted that other nucleoside-derivative drugs may cause pancreatitis [97].The current state of knowledge does not clearly indicate the therapeutic benefit of interferon-β in the treatment of COVID-19 patients [98,99]. To date, only single cases suggesting induction of pancreatitis by interferon-β have been reported. Based on this, Badalov et al. classified interferon into type III [87].There are few reports about the development of AP due to the use of azithromycin [100]. In the previously mentioned study by Badalov et al., two macrolide antibiotics were classified as type II and III. Unfortunately, there are no direct data concerning azithromycin. Interestingly, there were cases of patients with concomitant symptoms of AP and viral pneumonia caused by SARS-CoV-2 who were treated with azithromycin, which resulted in complete resolution of symptoms for both conditions [96,101]. Based on available data, the risk of azithromycin-induced AP is low.There is no clear evidence that azithromycin affects blood glucose levels in humans. However, it is known for its prokinetic effects, which may be helpful in patients who suffer from diabetic gastroparesis [102]). The incidence of hypo- and hyperglycemic episodes was not proved to be significant for azithromycin [103]; however, the risk of dysglycemia is emphasized [94]. In the SmPC, where azithromycin is the main ingredient, it is not possible to establish a causal relationship between the occurrence of pancreatitis and taking medications (Zithromax) based on the available data. In contrast, glycemic disturbances were not indicated as side effects (Zithromax) [104].Hydroxychloroquine has been extensively promoted for COVID-19 due to its anti-inflammatory and antiviral action; yet, the use of this agent in diabetes deserves particular attention for its documented hypoglycemic action, and its benefit on COVID-19 is controversial, although there is large usage [105].Table 2 shows a comparison of the side effects of medications in question.Table 2. Side effects of medications used in SARS-CoV-2 infection in the area of pancreatic effects and hyperglycemia.

Table

8. COVID-19, Pancreas, and Glycation

In T2D diabetics, oxidative stress leading to pancreatic damage may be stimulated by, among other things, the intense glycation that accompanies hyperglycemia [24]. Glycation is a non-enzymatic process involving reducing sugar and amino groups of proteins, which contributes to the formation of advanced glycation end products (AGEs). These products have significantly altered biochemical properties relative to the substrates, including proteins that have altered conformation, increased rigidity, resistance to proteolysis, etc. [106,107].Part of the pathomechanism involved in facilitating coronavirus infection in diabetics may be due to glycation of ACE2 and SARS-CoV-2 spike protein [108,109].An interesting hypothesis is that COVID-19 has a worse prognosis in patients with intense glycation, and thus high tissue AGE content. Glycated hemoglobin (HbA1c) is a commonly used diagnostic tool that estimates intensity of glycation. The parameter is not only a marker of long-term persistent hyperglycemia, but an active participant in immune processes, as HbA1c levels are associated with NK cell activity [110].Zhang et al.’s retrospective cohort study concerning COVID-19 patients revealed that glycated hemoglobin correlates negatively with saturation (SaO2) and positively with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen (Fbg). It was concluded that determination of HbA1c levels may be helpful in assessing inflammation, hypercoagulability, and prognosis of COVID-19 patients [111].According to the meta-analysis by Chen et al. (2020), Hba1c levels were slightly higher in patients with severe COVID-19 compared to patients with mild COVID-19; however, this correlation was not statistically significant. However, it is of great importance to note that only two studies analyzing HbA1c in COVID-19 patients were included in this analysis because only these studies were available in May 2020 [112].Glycation plays its physiological effects not only directly by changing the properties of various proteins, but also indirectly through various receptors. RAGE is the most common receptor for AGEs. Binding of RAGE to its ligands activates a proinflammatory response primarily by mitogen-activated protein kinase (MAPK) and nuclear factor κβ (NFκβ) pathways. This interaction was proved to be significant in the pathogenesis of cancer, diabetes mellitus, and other inflammatory disorders [113]. RAGE was found to be expressed in the pancreas, and S100P-derived RAGE antagonistic peptide (RAP) reduces pancreatic tumor growth and metastasis [113]. The implications of this fact may also apply to the etiology and treatment of COVID-19. It has been postulated that targeting RAGE by various antagonists of this receptor may inhibit damage to various organs including the pancreas [114].

9. COVID-19 vs. Pancreatic Cancer

Immunosuppression as a treatment effect, elevated cytokine levels, altered expression of receptors for SARS-CoV-2, and a prothrombotic state in patients with various types of cancer may exacerbate the effects of COVID-19 [115].Focusing on pancreatic cancer, it can be observed that the pathomechanism of both diseases—COVID-19 and tumorigenesis in the pancreas—overlap in several molecular mechanisms. As mentioned above, SARS-CoV-2 infection of host cells is facilitated by ACE-2, TMPRSS2, and CTSL. Cathepsin L is upregulated in a wide variety of cancers, including pancreatic adenocarcinoma [13]. TMPRSS2 upregulation in pancreatic cancers is moderate, whereas ACE-2 is overexpressed in some cancers, including pancreatic carcinomas [115]. Interestingly, ACE2 upregulation seems to be associated with favorable survival in pancreatic cancer [116], and it is known that SARS-CoV-2 reduces ACE2 expression [22]. Furthermore, the above-mentioned RAGE may also participate in both pancreatic cancer development and SARS-CoV-2 infection. RAGE facilitates neutrophil extracellular trap (NET) formation in pancreatic cancer [117]. In conclusion, pancreatic cancer predisposes to an increased risk of COVID-19 and its more severe course, and coronavirus infection may contribute to pancreatic cancer.It also seems important how the COVID-19 epidemic has affected the treatment of patients with pancreatic cancer of SARS-CoV-2-independent etiology. According to the study by Pergolini et al., care of patients with pancreatic cancer can be disrupted or delayed, particularly in the context of treatment selection, postoperative course, and outpatient care [118].A separate issue is how patients after pancreatoduodenectomy respond to SARS-CoV-2 infection. A case series reported by Bacalbasa reveal that patients who develop SARS-CoV-2 infection postoperatively require re-admission in the ICU and a longer hospital stay; however, these infections are not fatal [119]. Although the analysis was performed on single cases, it is concluded that these results are an argument to perform elective oncological surgeries [119].There are also reports that chemotherapy in pancreatic cancer patients who become ill between treatment series can be successfully completed after a complete cure of the infection [120]. Guidelines for, e.g., prioritization and treatment regimens regarding pancreatic cancer treatment in the era of the pandemic, are developed and described, for example, by Catanese et al. or Jones et al. [121,122].

10. Conclusions

Evidence shows that SARS-CoV-2 infection contributes to damage within the pancreas. The mechanisms that are involved in this include but are not limited to direct cytopathic effect of SARS-CoV-2 replication and systemic and local inflammatory response [123]. At the current state of knowledge, it is certain that the virus attacks the endocrine portion of the pancreas as well as, to a much lesser extent, the exocrine portion. It has been shown that a bidirectional relationship between COVID-19 and diabetes exists; indeed, diabetes is associated with COVID-19 severity and mortality but, at the same time, patients with COVID-19 have shown new onset of diabetes [124]. SARS-CoV-2 virus infection not only directly affects glycemic levels, but also exacerbates already existing hyperglycemia through its negative impact on the functional competence of the islets of Langerhans. It cannot be excluded that the real cause of exocrine dysfunction of this gland is the negative effect of the drugs used for treatment of the infection. As the pandemic progresses, special attention should be given to the evaluation of chronic and acute pancreatic diseases, including pancreatic cancer, so that faster diagnosis enables faster implementation of treatment.

Author Contributions

Conceptualization, A.K.; investigation, U.A., M.N., A.S., P.W., P.Z. and A.K.; resources, U.A., M.N., A.S., P.W., P.Z. and A.K.; writing—original draft preparation, U.A., M.N., A.S., P.W., P.Z. and A.K.; visualization, U.A.; supervision, A.K. All authors have read and agreed to the published version of the manuscript.

References

  1. Zhang, S.F.; Tuo, J.L.; Huang, X.B.; Zhu, X.; Zhang, D.M.; Zhou, K.; Yuan, L.; Luo, H.J.; Zheng, B.J.; Yuen, K.Y.; et al. Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010–2015 in Guangzhou. PLoS ONE 201813, e0191789. [Google Scholar] [CrossRef]
  2. De Wit, E.; Van Doremalen, N.; Falzarano, D.; Munster, V.J. SARS and MERS: Recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 201614, 523–534. [Google Scholar] [CrossRef]
  3. Zaki, A.M.; van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.M.E.; Fouchier, R.A.M. Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. N. Engl. J. Med. 2012367, 1814–1820. [Google Scholar] [CrossRef] [PubMed]
  4. Song, Z.; Xu, Y.; Bao, L.; Zhang, L.; Yu, P.; Qu, Y.; Zhu, H.; Zhao, W.; Han, Y.; Qin, C. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 201911, 59. [Google Scholar] [CrossRef]
  5. Shirato, K.; Kawase, M.; Matsuyama, S. Middle East Respiratory Syndrome Coronavirus Infection Mediated by the Transmembrane Serine Protease TMPRSS2. J. Virol. 201387, 12552. [Google Scholar] [CrossRef]
  6. Azhar, E.I.; Hui, D.S.C.; Memish, Z.A.; Drosten, C.; Zumla, A. The Middle East Respiratory Syndrome (MERS). Infect. Dis. Clin. N. Am. 202033, 891–905. [Google Scholar] [CrossRef]
  7. Arabi, Y.M.; Balkhy, H.H.; Hayden, F.G.; Bouchama, A.; Luke, T.; Baillie, J.K.; Al-Omari, A.; Hajeer, A.H.; Senga, M.; Denison, M.R.; et al. Middle East Respiratory Syndrome. N. Engl. J. Med. 2017376, 584–594. [Google Scholar] [CrossRef]
  8. Yang, J.K.; Lin, S.S.; Ji, X.J.; Guo, L.M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 201047, 193–199. [Google Scholar] [CrossRef] [PubMed]
  9. Leung, W.K.; To, K.; Chan, P.K.; Chan, H.L.; Wu, A.K.; Lee, N.; Yuen, K.Y.; Sung, J.J. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology 2003125, 1011–1017. [Google Scholar] [CrossRef]
  10. Shi, X.; Gong, E.; Gao, D.; Zhang, B.; Zheng, J.; Gao, Z.; Zhong, Y.; Zou, W.; Wu, B.; Fang, W.; et al. Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases. Am. J. Gastroenterol. 2005100, 169–176. [Google Scholar] [CrossRef]
  11. Buczkowska, E.O. Alterations of blood glucose homeostasis during septic or injury stress-hyperglycemia. Wiad Lek. 200255, 731–744. [Google Scholar] [PubMed]
  12. Zippi, M.; Hong, W.; Traversa, G.; Maccioni, F.; De Biase, D.; Gallo, C.; Fiorino, S. Involvement of the exocrine pancreas during COVID-19 infection and possible pathogenetic hypothesis: A concise review. Infez. Med. 202028, 507–515. [Google Scholar]
  13. Katopodis, P.; Anikin, V.; Randeva, H.S.; Spandidos, D.A.; Chatha, K.; Kyrou, I.; Karteris, E. Pan-cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS‑CoV‑2 infection leading to COVID-19. Int. J. Oncol. 202057, 533–539. [Google Scholar] [CrossRef] [PubMed]
  14. Zou, X.; Chen, K.; Zou, J.; Han, P.; Hao, J.; Han, Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med. 202014, 185–192. [Google Scholar] [CrossRef] [PubMed]
  15. Liu, F.; Long, X.; Zhang, B.; Zhang, W.; Chen, X.; Zhang, Z. ACE2 Expression in Pancreas May Cause Pancreatic Damage after SARS-CoV-2 Infection. Clin. Gastroenterol. Hepatol. 202018, 2128–2130. [Google Scholar] [CrossRef]
  16. Unsworth, R.; Wallace, S.; Oliver, N.S.; Yeung, S.; Kshirsagar, A.; Naidu, H.; Kwong, R.M.W.; Kumar, P.; Logan, K.M. New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K. Diabetes Care 202043, e170–e171. [Google Scholar] [CrossRef] [PubMed]
  17. Stoian, A.P.; Banerjee, Y.; Rizvi, A.A.; Rizzo, M. Diabetes and the COVID-19 Pandemic: How Insights from Recent Experience Might Guide Future Management. Metab. Syndr. Relat. Disord. 202018, 173–175. [Google Scholar] [CrossRef]
  18. Nguyen, T.T.; Ta, Q.T.H.; Nguyen, T.K.O.; Nguyen, T.T.D.; Giau, V. Van Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int. J. Mol. Sci. 202021, 3165. [Google Scholar] [CrossRef]
  19. Pezzilli, R.; Andriulli, A.; Bassi, C.; Balzano, G.; Cantore, M.; Fave, G.D.; Falconi, M.; Group, L.F. the E.P.I. collaborative (EPIc) Exocrine pancreatic insufficiency in adults: A shared position statement of the Italian association for the study of the pancreas. World J. Gastroenterol. 201319, 7930–7946. [Google Scholar] [CrossRef]
  20. Abramczyk, U.; Kuzan, A. What Every Diabetologist Should Know about SARS-CoV-2: State of Knowledge at the Beginning of 2021. J. Clin. Med. 202110, 1022. [Google Scholar] [CrossRef]
  21. Apicella, M.; Campopiano, M.C.; Mantuano, M.; Mazoni, L.; Coppelli, A.; Del Prato, S. COVID-19 in people with diabetes: Understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 20209, 782–792. [Google Scholar] [CrossRef]
  22. Boddu, S.K.; Aurangabadkar, G.; Kuchay, M.S. New onset diabetes, type 1 diabetes and COVID-19. Diabetes Metab. Syndr. 202014, 2211–2217. [Google Scholar] [CrossRef] [PubMed]
  23. Sadr-Azodi, O.; Mattsson, F.; Bexlius, T.S.; Lindblad, M.; Lagergren, J.; Ljung, R. Association of oral glucocorticoid use with an increased risk of acute pancreatitis: A population-based nested case-control study. JAMA Intern. Med. 2013173, 444–449. [Google Scholar] [CrossRef]
  24. Hayden, M.R. An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms. Cells 20209, 2475. [Google Scholar] [CrossRef]
  25. Kamrath, C.; Mönkemöller, K.; Biester, T.; Rohrer, T.R.; Warncke, K.; Hammersen, J.; Holl, R.W. Ketoacidosis in Children and Adolescents with Newly Diagnosed Type 1 Diabetes During the COVID-19 Pandemic in Germany. JAMA 2020324, 801–804. [Google Scholar] [CrossRef] [PubMed]
  26. Hamming, I.; Timens, W.; Bulthuis, M.; Lely, A.; Navis, G.; Goor, H. van Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004203, 631–637. [Google Scholar] [CrossRef]
  27. Ni, W.; Yang, X.; Yang, D.; Bao, J.; Li, R.; Xiao, Y.; Hou, C.; Wang, H.; Liu, J.; Yang, D.; et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit. Care 202024, 422. [Google Scholar] [CrossRef] [PubMed]
  28. Santos, R.A.S.; Sampaio, W.O.; Alzamora, A.C.; Motta-Santos, D.; Alenina, N.; Bader, M.; Campagnole-Santos, M.J. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7). Physiol. Rev. 201898, 505–553. [Google Scholar] [CrossRef]
  29. Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003426, 450–454. [Google Scholar] [CrossRef] [PubMed]
  30. Fignani, D.; Licata, G.; Brusco, N.; Nigi, L.; Grieco, G.E.; Marselli, L.; Overbergh, L.; Gysemans, C.; Colli, M.L.; Marchetti, P.; et al. SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature. Front. Endocrinol. 202011, 596898. [Google Scholar] [CrossRef] [PubMed]
  31. Wrapp, D.; Wang, N.; Corbett, K.S.; Goldsmith, J.A.; Hsieh, C.-L.; Abiona, O.; Graham, B.S.; McLellan, J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020367, 1260–1263. [Google Scholar] [CrossRef]
  32. Glowacka, I.; Bertram, S.; Herzog, P.; Pfefferle, S.; Steffen, I.; Muench, M.O.; Simmons, G.; Hofmann, H.; Kuri, T.; Weber, F.; et al. Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63. J. Virol. 201084, 1198–1205. [Google Scholar] [CrossRef] [PubMed]
  33. Haga, S.; Yamamoto, N.; Nakai-Murakami, C.; Osawa, Y.; Tokunaga, K.; Sata, T.; Yamamoto, N.; Sasazuki, T.; Ishizaka, Y. Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry. Proc. Natl. Acad. Sci. USA 2008105, 7809–7814. [Google Scholar] [CrossRef] [PubMed]
  34. Oudit, G.Y.; Kassiri, Z.; Jiang, C.; Liu, P.P.; Poutanen, S.M.; Penninger, J.M.; Butany, J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur. J. Clin. Investig. 200939, 618–625. [Google Scholar] [CrossRef] [PubMed]
  35. Muniangi-Muhitu, H.; Akalestou, E.; Salem, V.; Misra, S.; Oliver, N.S.; Rutter, G.A. COVID-19 and Diabetes: A Complex Bidirectional Relationship. Front. Endocrinol. 202011, 758. [Google Scholar] [CrossRef]
  36. Baughn, L.B.; Sharma, N.; Elhaik, E.; Sekulic, A.; Bryce, A.H.; Fonseca, R. Targeting TMPRSS2 in SARS-CoV-2 Infection. Mayo Clin. Proc. 202095, 1989–1999. [Google Scholar] [CrossRef] [PubMed]
  37. Matsuyama, S.; Nao, N.; Shirato, K.; Kawase, M.; Saito, S.; Takayama, I.; Nagata, N.; Sekizuka, T.; Katoh, H.; Kato, F.; et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc. Natl. Acad. Sci. USA 2020117, 7001–7003. [Google Scholar] [CrossRef]
  38. Thunders, M.; Delahunt, B. Gene of the month: TMPRSS2 (transmembrane serine protease 2). J. Clin. Pathol. 202073, 773–776. [Google Scholar] [CrossRef]
  39. Shen, L.W.; Mao, H.J.; Wu, Y.L.; Tanaka, Y.; Zhang, W. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 2017142, 1–10. [Google Scholar] [CrossRef]
  40. Taneera, J.; El-Huneidi, W.; Hamad, M.; Mohammed, A.K.; Elaraby, E.; Hachim, M.Y. Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors. Biology 20209, 215. [Google Scholar] [CrossRef]
  41. Cure, E.; Cure, M.C. COVID-19 may affect the endocrine pancreas by activating Na+/H+ exchanger 2 and increasing lactate levels. J. Endocrinol. Investig. 202043, 1167–1168. [Google Scholar] [CrossRef]
  42. Zippi, M.; Fiorino, S.; Occhigrossi, G.; Hong, W. Hypertransaminasemia in the course of infection with SARS-CoV-2: Incidence and pathogenetic hypothesis. World J. Clin. Cases 20208, 1385–1390. [Google Scholar] [CrossRef]
  43. Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.T.; Katze, M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 201276, 16–32. [Google Scholar] [CrossRef]
  44. Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020395, 1033–1034. [Google Scholar] [CrossRef]
  45. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020395, 1054–1062. [Google Scholar] [CrossRef]
  46. Hojyo, S.; Uchida, M.; Tanaka, K.; Hasebe, R.; Tanaka, Y.; Murakami, M.; Hirano, T. How COVID-19 induces cytokine storm with high mortality. Inflamm. Regen. 202040, 37. [Google Scholar] [CrossRef]
  47. Liu, B.; Li, M.; Zhou, Z.; Guan, X.; Xiang, Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J. Autoimmun. 2020111, 102452. [Google Scholar] [CrossRef] [PubMed]
  48. Rao, S.A.; Kunte, A.R. Interleukin-6: An Early Predictive Marker for Severity of Acute Pancreatitis. Indian J. Crit. Care Med. 201721, 424–428. [Google Scholar] [CrossRef] [PubMed]
  49. Sathyanarayan, G.; Garg, P.K.; Prasad, H.; Tandon, R.K. Elevated level of interleukin-6 predicts organ failure and severe disease in patients with acute pancreatitis. J. Gastroenterol. Hepatol. 200722, 550–554. [Google Scholar] [CrossRef]
  50. Cao, Y.; Liu, X.; Xiong, L.; Cai, K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis. J. Med. Virol. 202092, 1449–1459. [Google Scholar] [CrossRef]
  51. Assis, R.R.; de Jain, A.; Nakajima, R.; Jasinskas, A.; Felgner, J.; Obiero, J.M.; Norris, P.J.; Stone, M.; Simmons, G.; Bagri, A.; et al. Analysis of SARS-CoV-2 antibodies in COVID-19 convalescent blood using a coronavirus antigen microarray. Nat. Commun. 202112, 6. [Google Scholar] [CrossRef]
  52. Zhao, J.; Yuan, Q.; Wang, H.; Liu, W.; Liao, X.; Su, Y.; Wang, X.; Yuan, J.; Li, T.; Li, J.; et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin. Infect. Dis. 202071, 2027–2034. [Google Scholar] [CrossRef]
  53. Iwasaki, A.; Yang, Y. The potential danger of suboptimal antibody responses in COVID-19. Nat. Rev. Immunol. 202020, 339–341. [Google Scholar] [CrossRef]
  54. Lee, N.; Chan, P.K.S.; Ip, M.; Wong, E.; Ho, J.; Ho, C.; Cockram, C.S.; Hui, D.S. Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome. J. Clin. Virol. 200635, 179–184. [Google Scholar] [CrossRef]
  55. Yasui, F.; Kai, C.; Kitabatake, M.; Inoue, S.; Yoneda, M.; Yokochi, S.; Kase, R.; Sekiguchi, S.; Morita, K.; Hishima, T.; et al. Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV. J. Immunol. 2008181, 6337–6348. [Google Scholar] [CrossRef]
  56. Caruso, P.; Longo, M.; Esposito, K.; Maiorino, M.I. Type 1 diabetes triggered by COVID19 pandemic: A potential outbreak? Diabetes Res. Clin. Pract. 2020164, 108219. [Google Scholar] [CrossRef]
  57. de-Madaria, E.; Capurso, G. COVID-19 and acute pancreatitis: Examining the causality. Nat. Rev. Gastroenterol. Hepatol. 202118, 3–4. [Google Scholar] [CrossRef] [PubMed]
  58. Group, W.; Apa, I.A.P.; Pancreatitis, A. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 201313, e1–e15. [Google Scholar] [CrossRef]
  59. Goyal, H.; Sachdeva, S.; Perisetti, A.; Mann, R.; Inamdar, S.; Tharian, B. Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander? Gastroenterology 2021160, 946–948. [Google Scholar] [CrossRef] [PubMed]
  60. Barlass, U.; Wiliams, B.; Dhana, K.; Adnan, D.; Khan, S.R.; Mahdavinia, M.; Bishehsari, F. Marked elevation of lipase in COVID-19 Disease: A cohort study. Clin. Transl. Gastroenterol. 202011, e00215. [Google Scholar] [CrossRef] [PubMed]
  61. Suchman, K.; Raphael, K.L.; Liu, Y.; Wee, D.; Trindade, A.J. Acute pancreatitis in children hospitalized with COVID-19. Pancreatology 202121, 31–33. [Google Scholar] [CrossRef]
  62. Müller, J.A.; Groß, R.; Conzelmann, C.; Krüger, J.; Merle, U.; Steinhart, J.; Weil, T.; Koepke, L.; Bozzo, C.P.; Read, C.; et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat. Metab. 20213, 149–165. [Google Scholar] [CrossRef] [PubMed]
  63. Correia de Sá, T.; Soares, C.; Rocha, M. Acute pancreatitis and COVID-19: A literature review. World J. Gastrointest. Surg. 202113, 574–584. [Google Scholar] [CrossRef] [PubMed]
  64. Smatti, M.K.; Cyprian, F.S.; Nasrallah, G.K.; Al Thani, A.A.; Almishal, R.O.; Yassine, H.M. Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses 201911, 762. [Google Scholar] [CrossRef] [PubMed]
  65. Inamdar, S.; Benias, P.C.; Liu, Y.; Sejpal, D.V.; Satapathy, S.K.; Trindade, A.J.; Northwell COVID-19 Research Consortium. Prevalence, Risk Factors, and Outcomes of Hospitalized Patients with Coronavirus Disease 2019 Presenting as Acute Pancreatitis. Gastroenterology 2020159, 2226–2228.e2. [Google Scholar] [CrossRef] [PubMed]
  66. Hegyi, P.; Szakács, Z.; Sahin-Tóth, M. Lipotoxicity and Cytokine Storm in Severe Acute Pancreatitis and COVID-19. Gastroenterology 2020159, 824–827. [Google Scholar] [CrossRef] [PubMed]
  67. Hu, B.; Huang, S.; Lianghong, Y. Lianghong The cytokine storm and COVID-19. J. Med. Virol. 202193, 250–256. [Google Scholar] [CrossRef] [PubMed]
  68. Gullo, L.; Cavicchi, L.; Tomassetti, P.; Spagnolo, C.; Freyrie, A.; D’addato, M. Effects of Ischemia on the Human Pancreas. Gastroenterology 1996111, 1033–1038. [Google Scholar] [CrossRef]
  69. Lonardo, A.; Grisendi, A.; Bonilauri, S.; Rambaldi, M.; Selmi, I.; Tondelli, E. Ischaemic necrotizing pancreatitis after cardiac surgery. A case report and review of the literature. Ital. J. Gastroenterol. Hepatol. 199931, 872–875. [Google Scholar] [PubMed]
  70. Warzecha, Z.; Dembiński, A.; Ceranowicz, P.; Konturek, P.C.; Stachura, J.; Konturek, S.J.; Niemiec, J. Protective effect of calcitonin gene-related peptide against caerulein-induced pancreatitis in rats. J. Physiol. Pharmacol. 199748, 775–787. [Google Scholar]
  71. Esmon, C.T. Crosstalk between inflammation and thrombosis. Maturitas 200861, 122–131. [Google Scholar] [CrossRef]
  72. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 NovelCoronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020323, 1061–1069. [Google Scholar] [CrossRef] [PubMed]
  73. Lasson, Å.; Ohlsson, K. Consumptive coagulopathy, fibrinolysis and protease-antiprotease interactions during acute human pancreatitis. Thromb. Res. 198641, 167–183. [Google Scholar] [CrossRef]
  74. Du, J.D.; Zheng, X.; Huang, Z.Q.; Cai, S.W.; Tan, J.W.; Li, Z.L.; Yao, Y.M.; Jiao, H.B.; Yin, H.N.; Zhu, Z.M. Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis. Exp. Ther. Med. 20148, 141–146. [Google Scholar] [CrossRef] [PubMed]
  75. Maduzia, D.; Ceranowicz, P.; Cieszkowski, J.; Gałazka, K.; Kusnierz-Cabala, B.; Warzecha, Z. Pretreatment with Warfarin Attenuates the Development of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats. Molecules 202025, 2493. [Google Scholar] [CrossRef]
  76. Warzecha, Z.; Sendur, P.; Ceranowicz, P.; Dembinski, M.; Cieszkowski, J.; Kusnierz-Cabala, B.; Tomaszewska, R.; Dembinski, A. Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis. J. Physiol. Pharmacol. 201566, 731–740. [Google Scholar] [PubMed]
  77. Warzecha, Z.; Sendur, P.; Ceranowicz, P.; Dembiński, M.; Cieszkowski, J.; Kuśnierz-Cabala, B.; Olszanecki, R.; Tomaszewska, R.; Ambroży, T.; Dembiński, A. Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis. Int. J. Mol. Sci. 20167, 1709. [Google Scholar] [CrossRef] [PubMed]
  78. Maduzia, D.; Ceranowicz, P.; Cieszkowski, J.; Chmura, A.; Galazka, K.; Kusnierz-Cabala, B.; Warzecha, Z. Administration of warfarin accelerates the recovery in ischemia/reperfusion-induced acute pancreatitis. J. Physiol. Pharmacol. 202071, 417–427. [Google Scholar] [CrossRef]
  79. Ceranowicz, P.; Dembinski, A.; Warzecha, Z.; Dembinski, M.; Cieszkowski, J.; Rembiasz, K.; Konturek, S.J.; Kusnierz-Cabala, B.; Tomaszewska, R.; Pawlik, W.W. Protective and therapeutic effect of heparin in acute pancreatitis. J. Physiol. Pharmacol. 200859, 103–125. [Google Scholar]
  80. Xin-Sheng, L.; Fu, Q.; Jie-Qin, L.; Qin-Qiao, F.; Ri-Guang, Z.; Yu-Hang, A.; Kai-Cheng, Z.; Yi-Xiong, L. Low Molecular Weight Heparin in the Treatment of Severe Acute Pancreatitis: A Multiple Centre Prospective Clinical Study. Asian J. Surg. 200932, 89–94. [Google Scholar] [CrossRef]
  81. Tozlu, M.; Kayar, Y.; Ince, A.T.; Baysal, B.; Şenturk, H. Low molecular weight heparin treatment of acute moderate and severe pancreatitis: A randomized, controlled, open-label study. Turk. J. Gastroenterol. 201930, 81–87. [Google Scholar] [CrossRef]
  82. Agarwal, R.N.; Aggarwal, H.; Verma, A.; Tripathi, M.K. A case report of a patient on therapeutic warfarin who died of COVID19 infection with a sudden rise in d-dimer. Biomedicines 20219, 1382. [Google Scholar] [CrossRef]
  83. Di Micco, P.; Imbalzano, E.; Russo, V.; Attena, E.; Mandaliti, V.; Orlando, L.; Lombardi, M.; Micco, G.; Di Camporese, G.; Annunziata, S.; et al. Heparin and SARS-CoV-2: Multiple Pathophysiological Links. Viruses 202113, 2486. [Google Scholar] [CrossRef] [PubMed]
  84. Bukowczan, J.; Warzecha, Z.; Ceranowicz, P.; Kusnierz-Cabala, B.; Tomaszewska, R.; Dembinski, A. Therapeutic effect of ghrelin in the course of ischemia/reperfusion-induced acute pancreatitis. Curr. Pharm. Des. 201521, 2284–2290. [Google Scholar] [CrossRef]
  85. Warzecha, Z.; Dembiñski, A.; Ceranowicz, P.; Konturek, S.J.; Tomaszewska, R.; Stachura, J.; Konturek, P.C. IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis. J. Physiol. Pharmacol. 200354, 575–590. [Google Scholar] [PubMed]
  86. Nango, D.; Hirose, Y.; Goto, M.; Echizen, H. Analysis of the Association of Administration of various glucocorticoids with development of acute pancreatitis using US Food and Drug Administration adverse event reporting system (FAERS). J. Pharm. Healthc. Sci. 20195, 5. [Google Scholar] [CrossRef]
  87. Badalov, N.; Baradarian, R.; Iswara, K.; Li, J.; Steinberg, W.; Tenner, S. Drug-Induced Acute Pancreatitis: An Evidence-Based Review. Clin. Gastroenterol. Hepatol. 20075, 648–661. [Google Scholar] [CrossRef]
  88. Cienfuegos, J.A.; Almeida, A.; Aliseda, D. Pancreatic injury and acute pancreatitis in COVID-19 patients. Rev. Esp. Enferm. Dig. 2021113, 389. [Google Scholar] [CrossRef] [PubMed]
  89. Hwang, J.L.; Weiss, R.E. Steroid-induced diabetes: A clinical and molecular approach to understanding and treatment. Diabetes Metab. Res. Rev. 201430, 96–102. [Google Scholar] [CrossRef]
  90. Radhakutty, A.; Burt, M.G. Management of endocrine disease: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia. Eur. J. Endocrinol. 2018179, R207–R218. [Google Scholar] [CrossRef]
  91. Van Raalte, D.H.; Nofrate, V.; Bunck, M.C.; Van Iersel, T.; Schaap, J.E.; Nässander, U.K.; Heine, R.J.; Mari, A.; Dokter, W.H.A.; Diamant, M. Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men. Eur. J. Endocrinol. 2010162, 729–735. [Google Scholar] [CrossRef] [PubMed]
  92. Klarskov, C.K.; Holm Schultz, H.; Wilbek Fabricius, T.; Persson, F.; Pedersen-Bjergaard, U.; Lommer Kristensen, P. Oral treatment of glucocorticoid-induced diabetes mellitus: A systematic review. Int. J. Clin. Pract. 202074, e13529. [Google Scholar] [CrossRef]
  93. Kaletra 200 mg/50 mg Film-Coated Tablets—Summary of Product Characteristics (SmPC)—(emc). Available online: https://www.medicines.org.uk/emc/product/221/smpc (accessed on 10 January 2022).
  94. Rimesh Pal, S.K.B. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab. Syndr. Clin. Res. Rev. 202014, 513–517. [Google Scholar] [CrossRef]
  95. Khadka, S.; Williams, K.; Solanki, S. Remdesivir-Associated Pancreatitis. Am. J. Ther. 2021. [Google Scholar] [CrossRef]
  96. Ehsan, P.; Haseeb, M.; Khan, Z.; Rehan, A.; Singh, R. Coronavirus Disease 2019 Pneumonia and Acute Pancreatitis in a Young Girl. Cureus 202113, e15374. [Google Scholar] [CrossRef]
  97. Jorgensen, S.C.J.; Kebriaei, R.; Dresser, L.D. Remdesivir: Review of Pharmacology, Pre-Clinical Data, and Emerging Clinical Experience for COVID-19. Pharmacotherapy 202040, 659–671. [Google Scholar] [CrossRef]
  98. Pan, H.; Peto, R.; Henao-Restrepo, A.; Preziosi, M.; Sathiyamoorthy, V.; Abdool Karim, Q.; Alejandria, M.; Hernández García, C.; Kieny, M.; Malekzadeh, R.; et al. Repurposed Antiviral Drugs for COVID19—Interim WHO Solidarity. N. Engl. J. Med. 2021384, 497–511. [Google Scholar] [CrossRef] [PubMed]
  99. Rahmani, H.; Davoudi-Monfared, E.; Nourian, A.; Khalili, H.; Hajizadeh, N.; Jalalabadi, N.Z.; Fazeli, M.R.; Ghazaeian, M.; Yekaninejad, M.S. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int. Immunopharmacol. 202088, 106903. [Google Scholar] [CrossRef] [PubMed]
  100. Gonzalo-Voltas, A.; Fernández-Pérez-Torres, C.U.; Baena-Díez, J.M. Acute pancreatitis in a patient with COVID-19 infection. Med. Clin. 2020155, 183–184. [Google Scholar] [CrossRef] [PubMed]
  101. Díaz Lobato, S.; Carratalá Perales, J.M.; Alonso Íñigo, J.M. Can we use noninvasive respiratory therapies in COVID-19 pandemic? Med. Clin. 2020155, 183. [Google Scholar] [CrossRef] [PubMed]
  102. Sutera, L.; Dominguez, L.J.; Belvedere, M.; Putignano, E.; Vernuccio, L.; Ferlisi, A.; Fazio, G.; Costanza, G.; Barbagallo, M. Azithromycin in an older woman with diabetic gastroparesis. Am. J. Ther. 200815, 85–88. [Google Scholar] [CrossRef]
  103. Aspinall, S.L.; Good, C.B.; Jiang, R.; McCarren, M.; Dong, D.; Cunningham, F.E. Severe dysglycemia with the fluoroquinolones: A class effect? Clin. Infect. Dis. 200949, 402–408. [Google Scholar] [CrossRef] [PubMed]
  104. Zithromax Powder for Oral Suspension—Summary of Product Characteristics (SmPC)—(emc). Available online: https://www.medicines.org.uk/emc/product/3006/smpc#gref (accessed on 10 January 2022).
  105. Stoian, A.P.; Catrinoiu, D.; Rizzo, M.; Ceriello, A. Hydroxychloroquine, COVID-19 and diabetes. Why it is a different story. Diabetes Metab. Res. Rev. 202137, e3379. [Google Scholar] [CrossRef] [PubMed]
  106. Kuzan, A. Toxicity of advanced glycation end products (Review). Biomed. Rep. 202114, 46. [Google Scholar] [CrossRef] [PubMed]
  107. Kuzan, A.; Chwiłkowska, A.; Maksymowicz, K.; Bronowicka-Szydełko, A.; Stach, K.; Pezowicz, C.; Gamian, A. Advanced glycation end products as a source of artifacts in immunoenzymatic methods. Glycoconj. J. 201835, 95–103. [Google Scholar] [CrossRef]
  108. Liao, Y.-H.; Zheng, J.-Q.; Zheng, C.-M.; Lu, K.-C.; Chao, Y.-C. Novel Molecular Evidence Related to COVID-19 in Patients with Diabetes Mellitus. J. Clin. Med. 20209, 3962. [Google Scholar] [CrossRef]
  109. Sartore, G.; Ragazzi, E.; Faccin, L.; Lapolla, A. A role of glycation and methylation for SARS-CoV-2 infection in diabetes? Med. Hypotheses 2020144, 110247. [Google Scholar] [CrossRef]
  110. Kim, J.H.; Park, K.; Lee, S.B.; Kang, S.; Park, J.S.; Ahn, C.W.; Nam, J.S. Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes. J. Diabetes Investig. 201910, 1223–1228. [Google Scholar] [CrossRef]
  111. Zhang, W.; Li, C.; Xu, Y.; He, B.; Hu, M.; Cao, G.; Li, L.; Wu, S.; Wang, X.; Zhang, C.; et al. Hyperglycemia and Correlated High Levels of Inflammation Have a Positive Relationship with the Severity of Coronavirus Disease 2019. Mediat. Inflamm. 20212021, 8812304. [Google Scholar] [CrossRef]
  112. Chen, J.; Wu, C.; Wang, X.; Yu, J.; Sun, Z. The Impact of COVID-19 on Blood Glucose: A Systematic Review and Meta-Analysis. Front. Endocrinol. 202011, 574541. [Google Scholar] [CrossRef]
  113. Arumugam, T.; Ramachandran, V.; Gomez, S.B.; Schmidt, A.M.; Logsdon, C.D. S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis. Clin. Cancer Res. 201218, 4356–4364. [Google Scholar] [CrossRef]
  114. Chiappalupi, S.; Salvadori, L.; Vukasinovic, A.; Donato, R.; Sorci, G.; Riuzzi, F. Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives. Life Sci. 2021272, 119251. [Google Scholar] [CrossRef]
  115. van Dam, P.A.; Huizing, M.; Mestach, G.; Dierckxsens, S.; Tjalma, W.; Trinh, X.B.; Papadimitriou, K.; Altintas, S.; Vermorken, J.; Vulsteke, C.; et al. SARS-CoV-2 and cancer: Are they really partners in crime? Cancer Treat. Rev. 202089, 102068. [Google Scholar] [CrossRef] [PubMed]
  116. Zhang, Z.; Li, L.; Li, M.; Wang, X. The SARS-CoV-2 host cell receptor ACE2 correlates positively with immunotherapy response and is a potential protective factor for cancer progression. Comput. Struct. Biotechnol. J. 202018, 2438–2444. [Google Scholar] [CrossRef] [PubMed]
  117. Boone, B.A.; Orlichenko, L.; Schapiro, N.E.; Loughran, P.; Gianfrate, G.C.; Ellis, J.T.; Singhi, A.D.; Kang, R.; Tang, D.; Lotze, M.T.; et al. The Receptor for Advanced Glycation End Products (RAGE) Enhances Autophagy and Neutrophil Extracellular Traps in Pancreatic Cancer. Cancer Gene Therapy 201522, 326–334. [Google Scholar] [CrossRef]
  118. Pergolini, I.; Demir, I.E.; Stöss, C.; Emmanuel, K.; Rosenberg, R.; Friess, H.; Novotny, A. Effects of COVID-19 Pandemic on the Treatment of Pancreatic Cancer: A Perspective from Central Europe. Dig. Surg. 202138, 158–165. [Google Scholar] [CrossRef] [PubMed]
  119. Bacalbasa, N.; Diaconu, C.; Savu, C.; Savu, C.; Stiru, O.; Balescu, I. The impact of COVID-19 infection on the postoperative outcomes in pancreatic cancer patients. In Vivo 202135, 1307–1311. [Google Scholar] [CrossRef]
  120. Nagai, K.; Kitamura, K.; Hirai, Y.; Nutahara, D.; Nakamura, H.; Taira, J.; Matsue, Y.; Abe, M.; Kikuchi, M.; Itoi, T. Successful and Safe Reinstitution of Chemotherapy for Pancreatic Cancer after COVID-19. Intern. Med. 202160, 231–234. [Google Scholar] [CrossRef] [PubMed]
  121. Catanese, S.; Pentheroudakis, G.; Douillard, J.Y.; Lordick, F. ESMO Management and treatment adapted recommendations in the COVID-19 era: Pancreatic Cancer. ESMO Open 20205, e000804. [Google Scholar] [CrossRef]
  122. Jones, C.M.; Radhakrishna, G.; Aitken, K.; Bridgewater, J.; Corrie, P.; Eatock, M.; Goody, R.; Ghaneh, P.; Good, J.; Grose, D.; et al. Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: The UK consensus position. Br. J. Cancer 2020123, 709–713. [Google Scholar] [CrossRef]
  123. Ugwueze, C.V.; Ezeokpo, B.C.; Nnolim, B.I.; Agim, E.A.; Anikpo, N.C.; Onyekachi, K.E. COVID-19 and Diabetes Mellitus: The Link and Clinical Implications. Dubai Diabetes Endocrinol. J. 202026, 69–77. [Google Scholar] [CrossRef]
  124. Al Mahmeed, W.; Al-Rasadi, K.; Banerjee, Y.; Ceriello, A.; Cosentino, F.; Galia, M.; Goh, S.-Y.; Kempler, P.; Lessan, N.; Papanas, N.; et al. Promoting a Syndemic Approach for Cardiometabolic Disease Management During COVID-19: The CAPISCO International Expert Panel. Front. Cardiovasc. Med. 20218, 787761. [Google Scholar] [CrossRef] [PubMed]
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Comparison between RT-qPCR for SARS-CoV-2 and expanded triage in sputum of symptomatic and asymptomatic COVID-19 subjects in Ecuador

BMC Infectious Diseases volume 21, Article number: 558 (2021) 

Abstract

Background

The quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) effectively detects the SARS-COV-2 virus. SARS-CoV-2 Nevertheless, some critical gaps remain in the identification and monitoring of asymptomatic people.

Methods

This retrospective study included 733 asymptomatic and symptomatic COVID-19 subjects, who were submitted to the RT-qPCR test. The objective was to assess the efficacy of an expanded triage of subjects undergoing the RT-qPCR test for SARS-COV-2 to identify the largest possible number of COVID-19 cases in a hospital setting in Ecuador. SARS-CoV-2 Firstly, the sensitivity and specificity as well as the predictive values of an expanded triage method were calculated. In addition, the Kappa coefficient was also determined to assess the concordance between laboratory test results and the expanded triage.

Results

Of a total of 733 sputum samples; 229 were RT-qPCR-positive (31.2%) and mortality rate reached 1.2%. Overall sensitivity and specificity were 86.0% (95% confidence interval: 81.0–90.0%) and 37.0% (95% confidence interval: 32.0–41.0%) respectively, with a diagnostic accuracy of 52.0% and a Kappa coefficient of 0.73. An association between the positivity of the test and its performance before 10 days was found.

Conclusions

The clinical sensitivity for COVID-19 detection was within acceptable standards, but the specificity still fell below the values of reference. The lack of symptoms did not always mean to have a negative SARS-COV-2 RT-qPCR test. The expanded triage identified a still unnoticed percentage of asymptomatic subjects showing positive results for the SARS-COV-2 RT-qPCR test. The study also revealed a significant relationship between the number of RT-qPCR-positive cases and the performance of the molecular diagnosis within the first 10 days of COVID-19 in the symptomatic group.

For More Information: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06272-8

Analysis of the Study of the Expression of Apoptosis Markers (CD95) and Intercellular Adhesion Markers (CD54) in Healthy Individuals and Patients Who Underwent COVID-19 When Using the Drug Mercureid

Authors: Sergey N Gusev1*, Velichko LN2, Bogdanova AV2, Khramenko NI2, Konovalova NV2 Published Date: 26-08-2021

Abstract

SARS-CoV-2, the pathogen, which is responsible for coronavirus disease 2019 (COVID-19), has caused unprecedented morbidity and mortality worldwide. Scientific and clinical evidence testifies about long-term COVID-19 effects that can affect many organ systems. Cellular damage, overproduction of proinflammatory cytokines and procoagulant abnormalities caused by SARS-CoV-2 infection may lead to these consequences. After suffering from COVID-19, a negative PCR test is only the beginning of a difficult path to full recovery. 61 % of patients will continue to have the signs of post-covid syndrome with the risk of developing serious COVID-19 health complications for a long time. Post-COVID syndrome is an underestimated large-scale problem that can lead to the collapse of the healthcare system in the nearest future.

The treatment and prevention of post-covid syndrome require integrated rather than organ or disease specific approaches and there is an urgent need to conduct a special research to establish the risk factors.

For this purpose, we studied the expression of markers of apoptosis (CD95) and intercellular adhesion (CD54) in healthy individuals and patients who underwent COVID-19, as well as the efficacy of the drug Mercureid for the treatment of post-covid syndrome.

The expression level of the apoptosis marker CD95 in patients who underwent COVID-19 is 1.7-2.5 times higher than the norm and the intercellular adhesion marker CD54 is 2.9-4.4 times higher. This fact indicates a persistent high level of dysfunctional immune response in the short term after recovery. The severity of the expression of the intercellular adhesion molecule (ICAM-1, CD54) shows the involvement of the endothelium of the vascular wall in the inflammatory process as one of the mechanisms of the pathogenesis of post-covid syndrome.

The use of Mercureid made it possible to reduce the overexpression of CD95 in 73.4 % of patients that led to the restoration of the number of CD4+/CD8+ T-cells, which are crucial in the restoration of functionally active antiviral and antitumor immunity of patients. Also, the use of Mercureid led to a normalization of ICAM-1 (CD54) levels in 75.8 % of patients.

The pharmacological properties of the new targeted immunotherapy drug Mercureid provide new therapeutic opportunities for the physician to influence a number of therapeutic targets, such as CD95, ICAM-1 (CD54), to reduce the risk of post-COVID complications.

For More Information: https://athenaeumpub.com/analysis-of-the-study-of-the-expression-of-apoptosis-markers-cd95-and-intercellular-adhesion-markers-cd54-in-healthy-individuals-and-patients-who-underwent-covid-19-when-using-the-drug-mercureid/

Pathological findings in organs and tissues of patients with COVID-19: A systematic review

Authors: Sasha Peiris 1 2Hector Mesa 3Agnes Aysola 4Juan Manivel 5Joao Toledo 1 2Marcio Borges-Sa 6Sylvain Aldighieri 1 2Ludovic Reveiz 2 7

Abstract

Background: Coronavirus disease (COVID-19) is the pandemic caused by SARS-CoV-2 that has caused more than 2.2 million deaths worldwide. We summarize the reported pathologic findings on biopsy and autopsy in patients with severe/fatal COVID-19 and documented the presence and/or effect of SARS-CoV-2 in all organs.

Methods and findings: A systematic search of the PubMed, Embase, MedRxiv, Lilacs and Epistemonikos databases from January to August 2020 for all case reports and case series that reported histopathologic findings of COVID-19 infection at autopsy or tissue biopsy was performed. 603 COVID-19 cases from 75 of 451 screened studies met inclusion criteria. The most common pathologic findings were lungs: diffuse alveolar damage (DAD) (92%) and superimposed acute bronchopneumonia (27%); liver: hepatitis (21%), heart: myocarditis (11.4%). Vasculitis was common only in skin biopsies (25%). Microthrombi were described in the placenta (57.9%), lung (38%), kidney (20%), Central Nervous System (CNS) (18%), and gastrointestinal (GI) tract (2%). Injury of endothelial cells was common in the lung (18%) and heart (4%). Hemodynamic changes such as necrosis due to hypoxia/hypoperfusion, edema and congestion were common in kidney (53%), liver (48%), CNS (31%) and GI tract (18%). SARS-CoV-2 viral particles were demonstrated within organ-specific cells in the trachea, lung, liver, large intestine, kidney, CNS either by electron microscopy, immunofluorescence, or immunohistochemistry. Additional tissues were positive by Polymerase Chain Reaction (PCR) tests only. The included studies were from numerous countries, some were not peer reviewed, and some studies were performed by subspecialists, resulting in variable and inconsistent reporting or over statement of the reported findings.

Conclusions: The main pathologic findings of severe/fatal COVID-19 infection are DAD, changes related to coagulopathy and/or hemodynamic compromise. In addition, according to the observed organ damage myocarditis may be associated with sequelae.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33909679/

Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study

Authors: Brandon Michael Henry1http://orcid.org/0000-0002-1211-8247Isaac Cheruiyot2, Stefanie W Benoit3,4, Fabian Sanchis-Gomar5,6http://orcid.org/0000-0001-9523-9054Giuseppe Lippi7, Justin Benoit8 Correspondence to Dr Brandon Michael Henry, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA;

Abstract

Background The mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis.

Methods Blood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65.

Results A total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively).

Conclusion Necrosis appears to be the main driver of hospitalization, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.

For More Information: https://jcp.bmj.com/content/early/2021/03/30/jclinpath-2020-207242

Characteristics of SARS-CoV-2 and COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail.

Introduction

Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild to severe respiratory infections in humans. In 2002 and 2012, respectively, two highly pathogenic coronaviruses with zoonotic origin, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in humans and caused fatal respiratory illness, making emerging coronaviruses a new public health concern in the twenty-first century1. At the end of 2019, a novel coronavirus designated as SARS-CoV-2 emerged in the city of Wuhan, China, and caused an outbreak of unusual viral pneumonia. Being highly transmissible, this novel coronavirus disease, also known as coronavirus disease 2019 (COVID-19), has spread fast all over the world2,3. It has overwhelmingly surpassed SARS and MERS in terms of both the number of infected people and the spatial range of epidemic areas. The ongoing outbreak of COVID-19 has posed an extraordinary threat to global public health4,5. In this Review, we summarize the current understanding of the nature of SARS-CoV-2 and COVID-19. On the basis of recently published findings, this comprehensive Review covers the basic biology of SARS-CoV-2, including the genetic characteristics, the potential zoonotic origin and its receptor binding. Furthermore, we will discuss the clinical and epidemiological features, diagnosis of and countermeasures against COVID-19.

Emergence and spread

In late December 2019, several health facilities in Wuhan, in Hubei province in China, reported clusters of patients with pneumonia of unknown cause6. Similarly to patients with SARS and MERS, these patients showed symptoms of viral pneumonia, including fever, cough and chest discomfort, and in severe cases dyspnea and bilateral lung infiltration6,7. Among the first 27 documented hospitalized patients, most cases were epidemiologically linked to Huanan Seafood Wholesale Market, a wet market located in downtown Wuhan, which sells not only seafood but also live animals, including poultry and wildlife4,8. According to a retrospective study, the onset of the first known case dates back to 8 December 2019 (ref.9). On 31 December, Wuhan Municipal Health Commission notified the public of a pneumonia outbreak of unidentified cause and informed the World Health Organization (WHO)9 (Fig. 1).

figure1
Fig. 1: Timeline of the key events of the COVID-19 outbreak.

By metagenomic RNA sequencing and virus isolation from bronchoalveolar lavage fluid samples from patients with severe pneumonia, independent teams of Chinese scientists identified that the causative agent of this emerging disease is a betacoronavirus that had never been seen before6,10,11. On 9 January 2020, the result of this etiological identification was publicly announced (Fig. 1). The first genome sequence of the novel coronavirus was published on the Virological website on 10 January, and more nearly complete genome sequences determined by different research institutes were then released via the GISAID database on 12 January7. Later, more patients with no history of exposure to Huanan Seafood Wholesale Market were identified. Several familial clusters of infection were reported, and nosocomial infection also occurred in health-care facilities. All these cases provided clear evidence for human-to-human transmission of the new virus4,12,13,14. As the outbreak coincided with the approach of the lunar New Year, travel between cities before the festival facilitated virus transmission in China. This novel coronavirus pneumonia soon spread to other cities in Hubei province and to other parts of China. Within 1 month, it had spread massively to all 34 provinces of China. The number of confirmed cases suddenly increased, with thousands of new cases diagnosed daily during late January15. On 30 January, the WHO declared the novel coronavirus outbreak a public health emergency of international concern16. On 11 February, the International Committee on Taxonomy of Viruses named the novel coronavirus ‘SARS-CoV-2’, and the WHO named the disease ‘COVID-19’ (ref.17).

The outbreak of COVID-19 in China reached an epidemic peak in February. According to the National Health Commission of China, the total number of cases continued to rise sharply in early February at an average rate of more than 3,000 newly confirmed cases per day. To control COVID-19, China implemented unprecedentedly strict public health measures. The city of Wuhan was shut down on 23 January, and all travel and transportation connecting the city was blocked. In the following couple of weeks, all outdoor activities and gatherings were restricted, and public facilities were closed in most cities as well as in countryside18. Owing to these measures, the daily number of new cases in China started to decrease steadily19.

However, despite the declining trend in China, the international spread of COVID-19 accelerated from late February. Large clusters of infection have been reported from an increasing number of countries18. The high transmission efficiency of SARS-CoV-2 and the abundance of international travel enabled rapid worldwide spread of COVID-19. On 11 March 2020, the WHO officially characterized the global COVID-19 outbreak as a pandemic20. Since March, while COVID-19 in China has become effectively controlled, the case numbers in Europe, the USA and other regions have jumped sharply. According to the COVID-19 dashboard of the Center for System Science and Engineering at Johns Hopkins University, as of 11 August 2020, 216 countries and regions from all six continents had reported more than 20 million cases of COVID-19, and more than 733,000 patients had died21. High mortality occurred especially when health-care resources were overwhelmed. The USA is the country with the largest number of cases so far.

Although genetic evidence suggests that SARS-CoV-2 is a natural virus that likely originated in animals, there is no conclusion yet about when and where the virus first entered humans. As some of the first reported cases in Wuhan had no epidemiological link to the seafood market22, it has been suggested that the market may not be the initial source of human infection with SARS-CoV-2. One study from France detected SARS-CoV-2 by PCR in a stored sample from a patient who had pneumonia at the end of 2019, suggesting SARS-CoV-2 might have spread there much earlier than the generally known starting time of the outbreak in France23. However, this individual early report cannot give a solid answer to the origin of SARS-CoV-2 and contamination, and thus a false positive result cannot be excluded. To address this highly controversial issue, further retrospective investigations involving a larger number of banked samples from patients, animals and environments need to be conducted worldwide with well-validated assays.

For More Information: https://www.nature.com/articles/s41579-020-00459-7

Overweight/obesity as the potentially most important lifestyle factor associated with signs of pneumonia in COVID-19

PLOS
  • Published: November 18, 2020

Abstract

Objective

The occurrence of pneumonia separates severe cases of COVID-19 from the majority of cases with mild disease. However, the factors determining whether or not pneumonia develops remain to be fully uncovered. We therefore explored the associations of several lifestyle factors with signs of pneumonia in COVID-19.

Methods

Between May and July 2020, we conducted an online survey of 201 adults in Germany who had recently gone through COVID-19, predominantly as outpatients. Of these, 165 had a PCR-based diagnosis and 36 had a retrospective diagnosis by antibody testing. The survey covered demographic information, eight lifestyle factors, comorbidities and medication use. We defined the main outcome as the presence vs. the absence of signs of pneumonia, represented by dyspnea, the requirement for oxygen therapy or intubation.

Results

Signs of pneumonia occurred in 39 of the 165 individuals with a PCR-based diagnosis of COVID-19 (23.6%). Among the lifestyle factors examined, only overweight/obesity was associated with signs of pneumonia (odds ratio 2.68 (1.29–5.59) p = 0.008). The observed association remained significant after multivariate adjustment, with BMI as a metric variable, and also after including the antibody-positive individuals into the analysis.

Conclusions

This exploratory study finds an association of overweight/obesity with signs of pneumonia in COVID-19. This finding suggests that a signal proportional to body fat mass, such as the hormone leptin, impairs the body’s ability to clear SARS-CoV-2 before pneumonia develops. This hypothesis concurs with previous work and should be investigated further to possibly reduce the proportion of severe cases of COVID-19.

For More Information: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237799