*Article* **An Unprecedented Challenge: The North Italian Gastroenterologist Response to COVID-19**

**Gian Eugenio Tontini 1,2,\*, Giovanni Aldinio 1,2, Nicoletta Nandi 1,2, Alessandro Rimondi 1,2, Dario Consonni 3, Massimo Iavarone 4, Paolo Cantù 2, Angelo Sangiovanni 4, Pietro Lampertico 2,4 and Maurizio Vecchi 1,2**


**Abstract:** Background: COVID-19 pandemic has profoundly changed the activities and daily clinical scenarios, subverting organizational requirements of our Gastroenterology Units. AIM: to evaluate the clinical needs and outcomes of the gastroenterological ward metamorphosis during the COVID-19 outbreaks in a high incidence scenario. Methods: we compared the pertinence of gastroenterological hospitalization, modality of access, mortality rate, days of hospitalization, diagnostic and interventional procedures, age, Charlson comorbidity index, and frequency of SARS-CoV-2 infections in patients and healthcare personnel across the first and the second COVID-19 outbreaks in a COVID-free gastroenterological ward in the metropolitan area of Milan, that was hit first and hardest during the first COVID-19 outbreak since March 2020. Results: pertinence of gastroenterological hospitalization decreased both during the first and, to a lesser degree, the second SARS-CoV2 waves as compared to the pre-COVID era (43.6, 85.4, and 96.2%, respectively), as occurred to the admissions from domicile, while age, comorbidities, length of stay and mortality increased. Endoscopic and interventional radiology procedures declined only during the first wave. Hospitalized patients resulted positive to a SARS-CoV-2 nasopharyngeal swab in 10.2% of cases during the first COVID-19 outbreak after a median of 7 days since admission (range 1–15 days) and only 1 out of 318 patients during the second wave (6 days after admission). During the first wave, 19.5% of healthcare workers tested positive for SARS-CoV-2. Conclusions: a sudden metamorphosis of the gastroenterological ward was observed during the first COVID-19 outbreak with a marked reduction in the gastroenterological pertinence at the admission, together with an increase in patients' age and multidisciplinary complexity, hospital stays, and mortality, and a substantial risk of developing a SARS-CoV-2 test positivity. This lesson paved the way for the efficiency of hospital safety protocols and admission management, which contributed to the improved outcomes recorded during the second COVID-19 wave.

**Keywords:** COVID-19; SARS-CoV-2; gastroenterology; hepatology; endoscopy; delivery of healthcare

#### **1. Introduction**

COVID-19 pandemic has profoundly changed the activities and daily clinical scenarios, subverting essential clinical and organizational requirements of all hospital units. As of today, there are only a few studies describing the features and consequences of COVIDrelated re-organization of Gastroenterology departments [1,2], but there are no experiences describing both the changes that occurred in these settings, as well as the consequent adjustments applied and their impact on hospitalized patients and healthcare personnel.

**Citation:** Tontini, G.E.; Aldinio, G.; Nandi, N.; Rimondi, A.; Consonni, D.; Iavarone, M.; Cantù, P.; Sangiovanni, A.; Lampertico, P.; Vecchi, M. An Unprecedented Challenge: The North Italian Gastroenterologist Response to COVID-19. *J. Clin. Med.* **2022**, *11*, 109. https://doi.org/10.3390/ jcm11010109

Academic Editor: Hemant Goyal

Received: 28 October 2021 Accepted: 19 December 2021 Published: 25 December 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

During the firsts SARS-CoV2 outbreak, the Internal Medicine Units and other specialized units were suddenly converted into COVID Units, while other specialized Units, such as Gastroenterology Units and the Nephrology Units, became COVID-free wards with dedicated safety protocols to guarantee adequate inpatients assistance for a broad range of clinical presentations.

We evaluated the clinical needs and outcomes of a COVID-free gastroenterological ward of a hospital in the metropolitan area of Milan that was hit first and hardest during the first COVID-19 outbreak since March 2020 [3], before the availability of the first SARS-CoV-2 vaccinations (27 December 2020 for healthcare workers and only afterward for the general population).

We hypothesized a sudden metamorphosis of the gastroenterological clinical practice towards a situation that resembles an Internal Medicine and a Geriatric Unit in the pre-COVID era, with a marked reduction in the gastroenterological pertinence and elective admissions, together with an increase in hospital stays and mortality.

#### **2. Material and Methods**

Hospital charts related to hospitalized patients in January and February 2020 were used as a model for the pre-COVID era. Patients admitted between March and April, in September and from October to December 2020 represent, respectively, the first wave, the transition period, and the second wave of COVID-19 pandemic according to the regional epidemiological trends in the general population.

First, we assessed and compared the pertinence of hospitalization within the gastroenterological ward during different periods across the first and the second SARS-CoV2 outbreaks.

Secondly, we evaluated modality of access, mortality, days of hospitalization, gastroenterological diagnostic and operative procedures, age, Charlson comorbidity index (CCI), and frequency of SARS-CoV-2 infections in patients and healthcare personnel within the gastroenterological ward based on a molecular test performed on a nasopharyngeal swab. This monocentric retrospective cohort study was performed in the gastroenterological ward of a tertiary referral university hospital located in the city center of Milan (Italy), which encompasses a Gastroenterology and Endoscopy Unit and a Gastroenterology and Hepatology Unit.

Safety measures adopted in the gastroenterological ward to face the COVID-19 outbreak and protect both patients and healthcare workers were reported in detail in the Supplementary Methods.

The inclusion criteria were adult age (>18 years old), being hospitalized in the Gastroenterology Units from 1 January 1 2020 to 30 April 2020 and from 1 September 2020 to 31 December 2020.

In the absence of a validated definition in literature, the gastroenterological pertinence of the diagnoses was defined a priori as "any primary or secondary condition that determines a clinically significant dysfunction of the gastrointestinal system."

For each patient, the following data were collected: sex, age, entry and exit dates in the Unit; modality of access (collected as 2 categories: from domicile and others including Emergency Department, other Units, other Hospitals); discharge diagnosis; CCI [4,5], date of the positive nasopharyngeal swab for SARS-CoV-2; endoscopic and other interventional procedures (e.g., trans-arterial chemoembolization, TACE) performed throughout the hospitalization period in our Units.

In June 2020, healthcare workers received a questionnaire assessing their involvement in the Gastroenterological ward from 1 January 2020 to 30 April 2020 to weigh their potential worker exposure to SARS-CoV2 infection during the first wave (i.e., hours per week with direct involvement within the Gastroenterological ward).

Descriptive data were expressed as counts and percentages for categorical variables, as medians and ranges for continuous variables. The chi-squared test was used to analyze dichotomous variables. Univariate log-binomial regression models were used to calculate

prevalence ratios (PR) and 95% confidence intervals (CI) for different periods vs. the pre-COVID period. The Kruskal–Wallis test was applied for the analysis of quantitative variables in the 4 periods. Statistical analyses were performed using Stata 17 (StataCorp., College Station, TX, USA, 2021).

The study was carried out in accordance with the Declaration of Helsinki adopted in 1964, incorporating all later amendments after formal approbation from the local Ethical Committee (Comitato Etico Milano Area 2, 19 May 2020; ID1588). All participants gave informed consent to participate in the study according to the study protocol.

#### **3. Results**

The total number of recruited patients in the study periods was 699, of which 426 males and 273 females, with a median age of 68 years (range 17 to 98 years) (Table 1). From March to April 2020, 39 out of 381 patients (10.2%) resulted positive to SARS-CoV-2 testing with a molecular nasopharyngeal swab after a median length of stay of 7 days (range 1–200) (Figure 1). From September to December 2020, only 1 out of 318 patients (0.003%) resulted positive to SARS-CoV-2 after 6 days spent in the gastroenterological ward. Notably, most of them (35/40) had at least one molecular nasopharyngeal swab negative for SARS-CoV-2 performed before ward admission (i.e., emergency room or pre-hospital triage), while 4 cases occurred in patients admitted a few days before the adoption of a systematic SARS-CoV-2 pre-hospital triage when the first COVID19 outbreak was already in progress but still largely unexpected. Among the 40 patients who tested positive for SARS-CoV-2, 27 (67.5%) had respiratory symptoms (at least one among cough, dyspnea, and mild respiratory insufficiency) at the time of hospital admission, 7 (17.5%) developed respiratory symptoms during the hospital stay, and 6 (15.0%) had no respiratory symptom. No false positive or false negative tests were found during the first and the second wave.

**Figure 1.** Daily incidence of SARS-CoV-2 during the first wave (SARS-CoV-2 molecular nasopharyngeal swab positive tests).



During the first wave, among the 36 physicians that answered the questionnaire, 6 (16.7%) resulted positive to a nasopharyngeal swab and 1 (2.8%) to the serologic tests (Figure 1). No correlation was found between such SARS-CoV-2 testing and the healthcare workers attending the gastroenterological ward activities.

Compared to the pre-COVID era (96.1%), the gastroenterological pertinence of hospitalized patients decreased both during the first (43.6%) and the second (85.4) COVID-19 wave, while it was similar to the pre-COVID era during the transition period (92.9%) (Figure 2, Table 1). The same trend was observed for admissions from domiciles (Supplementary Figure S1, Table 1). Endoscopic and interventional radiology procedures dropped during the first wave, going back to normal levels during the transition period and the second wave (Supplementary Figure S7, Table 1). The median age at the admission raised during the first and the second wave as well (Supplementary Figure S3, Table 2), while the median CCI raised only during the first wave (Supplementary Figure S5, Table 2). Compared to the pre-COVID era, mortality and the median length of stay increased during all the following periods (Supplementary Figures S2 and S6, Tables 1 and 2). For the discharge diagnoses of the deceased patients, see Supplementary Table S1.

**Figure 2.** Proportions of pertinent gastroenterological discharge diagnoses.


**Table 2.** Length of stay and Charlson comorbidity index.

#### **4. Discussion**

This report clearly shows a remarkable metamorphosis of a COVID-free gastroenterological ward in the area with the highest European SARS-CoV-2 incidence during the first COVID-19 outbreak. Hospitalized patients were older, with more comorbidities, and they were mostly affected by Internal and Geriatric disorders. Hospitalizations were longer and characterized by higher mortality compared to the pre-COVID era. Coherently, elective admissions and endoscopic or dedicated interventional radiological procedures decreased, reflecting the cancellation of all deferrable procedures [6–9] and the relocation of most gastroenterological resources (beds, facilities, instrumentations, healthcare personnel) to the prevaricating care needs linked to the pandemic. Another aspect highlighted in our study is the importance and efficacy of regular active surveillance of patients and healthcare personnel with nasopharyngeal swabs and the use of second-level single-use PPE. Indeed, these strategies learned from experience during the first wave, once applied routinely when the second wave began, have led to a significant decrease in the positive cases among patients admitted in our units (in-hospital positive test within day 9) and in the rate of COVID positivity during hospitalization (possible hospital-acquired infection from day 10 to 14, definite hospital-acquired infection from day 15; Supplementary Table S2 and Supplementary Figure S8) along with the decrease in healthcare personnel infection. Notably, when the first SARS-CoV2 wave invested in the metropolitan area of Milan (March 2020), there were no developed isolation protocols nor recommendations on the systematic use of PPE and SARS-CoV2 testing for patients and healthcare personnel with no history of direct contact with confirmed cases regardless of the presence of respiratory symptoms [10]. Consistently, the first measures adopted to face the COVID-19 outbreak in that area (Supplementary methods) were the result of expert consensus based on limited real-life or published evidence and were updated or refined almost day-by-day and with heterogeneity across different hospitals according to the changing availability of human (e.g., intensive care personnel) and instrumental resources (e.g., PPE, respirators, COVIDfree facilities). This reflects the scenario of the sudden and unexpected metamorphosis of any hospital protocols that shocked at any level the clinical practice with remarkable impacts on either hospitalized patients' outcomes, outpatient care continuity, or healthcare personnel daily practice and safety. Moreover, the implementation of preventive measures allowed a satisfactory recovery of elective admissions, endoscopic and interventional radiology procedures during the second wave. This was reflected in the rise of pertinent gastroenterological discharge diagnoses in the transition period and in the second wave compared with the first wave, despite a non-inferior impact of COVID-19 cases on the regional healthcare system [11].

As with all retrospective studies, the present one allows for rapid analysis of the outcomes to find answers for the current scientific needs present in a state of emergency at a global level. One limitation is the possible heterogeneity of data not systematically collected by multiple healthcare professionals. Moreover, considering the unique geographical and temporal setting, no generalization of these results can be made.

#### **5. Conclusions**

Overall, our study suggests that active surveillance with repeated SARS-CoV-2 testing and the systematic adoption of second-level single-use PPE when visiting patients are effective measures to control the spread of the virus in a hospital setting. In addition, our experience clearly demonstrates the nonobvious ability to maintain a balance between the need for beds to hospitalize COVID-19 patients and the necessity of continuing practicing medicine during the pandemic to avoid the effects that postponing the activities left behind would have on specific frail populations (e.g., those affected by cancer, cardiovascular, or other chronic conditions).

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/jcm11010109/s1, Figure S1: Modalities of access. Figure S2: Length of stay in the Gastroenterological Unit. Figure S3: Age at the admission. Figure S4: Gender distribution. Figure S5: Charlson comorbidity index. Figure S6: Mortality. Figure S7: Patients attending at least one diagnostic procedure. Figure S8: Days from admission to diagnosis of SARS-CoV-2 infection. Figure S9: Days from the admission in the Gastroenterological Unit to the diagnosis of COVID-19 shown for each case. Table S1: Discharge diagnoses of deceased patients. Table S2: Days from the admission to the Unit to the diagnosis of COVID-19 during the first wave.

**Author Contributions:** G.E.T.: study concept, interpretation of data, drafting of the manuscript, critical revision of the manuscript, study supervision; G.A.: study concept, acquisition of data, interpretation of data, drafting of the manuscript, critical revision of the manuscript, statistical analysis; N.N. and A.R.: acquisition of data, interpretation of data, critical revision of the manuscript; D.C.: statistical analysis, interpretation of data, critical revision of the manuscript; P.C., M.I., A.S. and P.L.: interpretation of data, critical revision of the manuscript; M.V.: study concept, interpretation of data, drafting of the manuscript, critical revision of the manuscript, study supervision. All authors have read and agreed to the published version of the manuscript.

**Funding:** This spontaneous search has received no funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Milano Area 2 (protocol code 1588; date of approval 19 May 2020).

**Informed Consent Statement:** All participants gave informed consent to participate in the study according to the study protocol.

**Conflicts of Interest:** The authors declare that there is no conflict of interest.

#### **References**


### *Review* **Acute Mesenteric Ischemia in COVID-19 Patients**

**Dragos Serban 1,2,\*,†, Laura Carina Tribus 3,4,†, Geta Vancea 1,5,†, Anca Pantea Stoian 1, Ana Maria Dascalu 1,\*,†, Andra Iulia Suceveanu 6, Ciprian Tanasescu 7,8, Andreea Cristina Costea 9, Mihail Silviu Tudosie 1, Corneliu Tudor 2, Gabriel Andrei Gangura 1,10, Lucian Duta <sup>2</sup> 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.

**Keywords:** acute mesenteric ischemia; COVID-19; thromboemboembolism; SARS-CoV-2; endothelitis; cytokines; hypercoagulability

#### **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

**Citation:** Serban, D.; Tribus, L.C.; Vancea, G.; Stoian, A.P.; Dascalu, A.M.; Suceveanu, A.I.; Tanasescu, C.; Costea, A.C.; Tudosie, M.S.; Tudor, C.; et al. Acute Mesenteric Ischemia in COVID-19 Patients. *J. Clin. Med.* **2022**, *11*, 200. https://doi.org/10.3390/ jcm11010200

Academic Editor: Hiroki Tanabe

Received: 9 December 2021 Accepted: 27 December 2021 Published: 30 December 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

intestinal loops, necrosis, and if left untreated, death by peritonitis and septic shock. In non-COVID 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 Supplementary File S1. A data extraction sheet was independently completed by two researchers, with 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. 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.


**Table1.**PatientswithintestinalischemiainretrospectivestudiesonhospitalizedCOVID-19patients.


derness

and cecum

37

**Table 2.** *Cont.*



**3.**Casereportsandcaseseriespresentinggastrointestinalischemiainnon-hospitalizedCOVID-19




40



**Table 3.** *Cont.*







RYGB: Roux-en-Y gastric bypass (bariatric surgery).

#### *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.


**Table 4.** Demographic data of the patients included in the review.

\*: 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.

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.


**Table 5.** Comparative features in acute intestinal ischemia encountered in previously hospitalized and previously non-hospitalized COVID-19 patients.

\* 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

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.


\* 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 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 COVID-19 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

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.

**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**

