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. 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COVID-19 Can Infect and Harm Digestive Organs

Authors: E.J. Mundell

 The coronavirus isn’t just attacking the lungs: New research shows it’s causing harm to the gastrointestinal tract, especially in more advanced cases of COVID-19.

A variety of imaging scans performed on hospitalized COVID-19 patients showed bowel abnormalities, according to a study published online May 11 in Radiology. Many of the effects were severe and linked with clots and impairment of blood flow.

“Some findings were typical of bowel ischemia, or dying bowel, and in those who had surgery we saw small vessel clots beside areas of dead bowel,” said study lead author Dr. Rajesh Bhayana, who works in the department of radiology at Massachusetts General Hospital in Boston.

“Patients in the ICU can have bowel ischemia for other reasons, but we know COVID-19 can lead to clotting and small vessel injury, so bowel might also be affected by this,” Bhayana explained in a journal news release.

One expert unconnected to the new study said the findings aren’t surprising.

“Our emerging understanding of COVID-19 has found the disease to have multisystem involvement including the nervous, cardiac, vascular [excess clotting] and finally the digestive systems, among others,” said Dr. Sherif Andrawes. He directs endoscopy in the division of gastroenterology and hematology at Staten Island University in New York City.

“It seems that this disease is intricate, in the sense that it can involve multiorgan systems, rather than being a disease of the respiratory system solely,” Andrawes said.

In fact, a study published online May 13 in the journal Science Immunology has found evidence that SARS-CoV-2, the virus behind COVID-19, can infect the human digestive system.

Researchers led by Siyuan Ding of Washington University School of Medicine in St. Louis, said their findings “highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.”

That seems to be borne out by the Boston study.

That research included 412 COVID-19 patients who were hospitalized between March 27 and April 10. They averaged 57 years of age, and 134 of them underwent abdominal imaging, including 137 radiographs, 44 ultrasounds, 42 CT scans, and one MRI.

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.

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Abdominal Pain and Diffuse Colitis Following COVID-19 Infection: Report of a Case

Authors: Rouzbeh ShadidiAsilaSetarehMahmoodiaAmirZamaniaAzadehHakakzadehbcElenaJamalid

International Journal of Surgery Case Reports Volume 8, November 2021, 106473

Highlights

Patients with COVID-19 sometimes presents with GI symptoms in addition to respiratory symptoms.•

Detecting RNA of SARS-CoV-2 in the stool specimen of the patient with COVD-19 has raised the concern of fecal-oral transmission of the virus.•

Invasion of the virus into gastrointestinal tract epithelial cells and GI hyercoagulation state and micro vascular thrombosis might be a cause for diarrhea in among infected patients.

Abstract

Introduction

Although this is often overlooked, the gastrointestinal (GI) involvement of COVID-19 has been introduced. Diarrhea, nausea, vomiting, and abdominal discomfort are among the most common GI symptoms reported. Diffuse Colitis following COVID-19 infection is a rare presentation.

Case presentation

A 52-year-old female presented with intensified abdominal pain following COVID-19 infection to the emergency department. She was diagnosed with peritonitis due to diffuse colitis and perforation of sigmoid colon. The patient was treated with total colectomy with an end ileostomy.

Conclusion

The purpose of this study was to increase awareness among clinicians about the existence of this rare cause of abdominal pain after COVID-19 infection, diffuse colitis. Although uncommon, these presentations can potentially lead to delay in diagnosis among unfamiliar clinicians with GI presentation of COVID-19.

1. Introduction

About 170 million people worldwide have been infected with the SARS-COVID 19 virus in pandemic so far [1]. Although most of previous studies related to COVID-19 focus on respiratory symptoms and complications, the disease has been associated with signs and symptoms of other organs, including the gastrointestinal (GI) system in a number of patients [1]. The information on extra-pulmonary manifestations, however, has been scarce. Involvement of the gastrointestinal (GI) tract and the hepatic system after COVID-19 infection is now being increasingly reported and the first case of COVID-19 in the United States presented with nausea and vomiting in addition to systemic and respiratory symptoms, and later developed abdominal discomfort and diarrhea had been reported [2]. Herein, we reported a case of 52-year-old female presented with intensified abdominal pain following COVID-19 infection who was further diagnosed with peritonitis due to diffuse colitis and perforation of sigmoid. This case report has been presented in line with the SCARE Criteria [3].

2. Case presentation

A 52-year-old female patient with body mass index of 26, a temperature of 37.8 °C, blood pressure of 100/60 mmHg, pulse of 98 beats per minute, respiratory rate of 16 breaths per minute, oxygen saturation of 96 on ambient air and no past history of any diseases was referred to Loghman Hakim Emergency Department for abdominal pain. She mentioned diarrhea and abdominal pain three weeks before being referred to this center. Due to the positive COVID-19 PCR test, she had been admitted for a week and was treated in another center before admission to this center. The patient’s GI symptoms were continued and hence she was referred to this center, two weeks afterwards. She was suffering from progressive colic type abdominal pain and first was admitted to COVID-19 Emergency ward. She mentioned abdominal pain and diarrhea in 3 previous weeks which has aggravated since 3 days ago and was not concurrent with nausea and vomiting. The patient had no previous history of alcohol use and she was not a tobacco user. The patient claimed no relevant genetic disease in herself and her family. She did not take any drugs and her family history of colitis or inflammatory bowel disease was negative. In physical examination, palpation of abdomen was normal but there was a localized tenderness in the left lower quadrant. Immediately fluid resuscitation with normal saline was initiated. Assessing initial laboratory tests, the patient did not have leukocytosis, CRP was 23.6 mg/l and the patient’s electrolytes and renal function tests were normal. No evidence of blood, inflammatory cells or any infectious organism was reported in patient’s stool exam. A plain chest X-ray was obtained from patient which revealed pneumoperitoneum and an abnormal dilated colon (bowel) loop was found in supine and upright abdominal X-ray. Abdominal and pelvic CT scan with oral and IV (intra venous) contrast agent was ordered. Pneumoperitoneum and some amounts of free intraperitoneal air without contrast extravasation and any transitional zone were seen in abdomen CT scan. The patient was transferred to operating room for diagnostic laparoscopy and due to the presence of exudative fluid and fibrin in the pelvis, the patient was candidate for laparotomy by an experienced general surgeon. During abdominal exploration, we encountered patchy necrosis and walled-off perforation in sigmoid colon. Initially sigmoidectomy was performed, but due to synchronous lesion in proximal colon, a decision was made for total colectomy (Fig. 1Fig. 2).

Fig. 1
Fig. 2

The patient underwent total colectomy with end ileostomy with end ileostomy and Hartmann’s pouch. After the recovery period in the 8th day after the surgery, patient was discharged with good general condition. She was advised to gradually increase the distance of walking and not lifting anything heavier than 4.5 kg for the first 6 weeks after your surgery. She was also advised to drink 8-10 glasses of water in a day. In histopathologic examination, diffuse active colitis with extensive mucosal ulceration and necrosis was reported (Fig. 3). There was no evidence of malignancy, vasculitis or chronic inflammatory bowel disease. Intravascular microthrombi at perforation site were detected.

Fig. 3

3. Discussion

In this case report our patient had no known past medical history and had no other risk factor for pan-colitis except her recent history of viral infection (Covid-19).With the advent of the Covid-19 pandemic, respiratory symptoms such as cough and shortness of breath have been reported to be the most common manifestation of the disease which are concurrent with fever. Over time, GI symptoms such as abdominal pain, diarrhea, nausea and vomiting became apparent among patients infected with coronavirus. Identification of COVID-19 virus in the feces of patients with recently emphasis on the hypothesis of oral-fecal transmission confirms involvement of the GI tract among infected patients [5]. Studies have suggested different causes for diarrhea in COVID-19 patients [6][7]. Among these etiologies are invasion of the virus into gastrointestinal tract epithelial cells and GI hyercoagulation state and micro vascular thrombosis [6]. Also, it has been shown that the RNA of this virus has been detected in the cytoplasm of GI epithelial cells which suggests invasion of virus into gastrointestinal cells [8]. Another cause of diarrhea among these patients is diarrhea following usage of antiviral drugs. Disruption of normal microbial flora of GI tract following the use of antibiotics might be another cause of diarrhea in these patients. Prolonged hypoxia and O2 saturation drop could also be another cause of GI damage in these patients because it can lead to tissue hypoxia, necrosis and damage to GI mucosal cells, followed by ulceration, mucosal bleeding, diarrhea and malabsorption [6][8]. Another hypothesis is that problems related to bowel movement are due to dysfunction of the autonomic nerves because of the tendency of the virus to invade the nerve and hence neural damage [[1][2][3][4][5][6][7][8][9]]. In our patient sigmoid perforation occurred as the consequence of diffuse dilatation of the colon without mechanical obstruction, severe necrosis of the mucosa and diffuse colitis resulted in sigmoid perforation.

4. Conclusions

Although the pathophysiology of COVID-19 virus invasion into gastrointestinal tract epithelial cells has been shown previously, GI hyercoagulation state and micro vascular thrombosis is still unknown. It is important to be vigilant about the rare COVID-19 manifestations among infected patients to prevent serious complications with early precise diagnosis.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Sources of fundings

There was no funding source for this study.

Ethical approval

Ethical approval not required.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Research registration

N/A.

Guarantor

Dr. Amir Zamani.

Author contribution

All authors made a major contribution in preparing this manuscript.

Declaration of competing interest

The author(s) declare no potential conflicts of interests with respect to the research, authorship, and/or publication of this article.

References

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Gastrointestinal perforation secondary to COVID-19

Authors: Case reports and literature review Reem J. Al Argan, MBBS, SB-Med, SF-Endo, FACE, ECNU,Safi G. Alqatari, MBBS, MRCPI, MMedSc, CFP (Rheum), Abir H. Al Said, MBBS, SB-Med, CFP (Pulmo.), Raed M. Alsulaiman, MBBS, SB-Med, Abdulsalam Noor, MBBS, SB-Med, ArBIM, SF-Nephro, Lameyaa A. Al Sheekh, MD, SB-med, and Feda’a H. Al Beladi, MD

Introduction:

Corona virus disease-2019 (COVID-19) presents primarily with respiratory symptoms. However, extra respiratory manifestations are being frequently recognized including gastrointestinal involvement. The most common gastrointestinal symptoms are nausea, vomiting, diarrhea and abdominal pain. Gastrointestinal perforation in association with COVID-19 is rarely reported in the literature.

Patient concerns and diagnosis:

In this series, we are reporting 3 cases with different presentations of gastrointestinal perforation in the setting of COVID-19. Two patients were admitted with critical COVID-19 pneumonia, both required intensive care, intubation and mechanical ventilation. The first one was an elderly gentleman who had difficult weaning from mechanical ventilation and required tracheostomy. During his stay in intensive care unit, he developed Candidemia without clear source. After transfer to the ward, he developed lower gastrointestinal bleeding and found by imaging to have sealed perforated cecal mass with radiological signs of peritonitis. The second one was an obese young gentleman who was found incidentally to have air under diaphragm. Computed tomography showed severe pneumoperitoneum with cecal and gastric wall perforation. The third case was an elderly gentleman who presented with severe COVID-19 pneumonia along with symptoms and signs of acute abdomen who was confirmed by imaging to have sigmoid diverticulitis with perforation and abscess collection.

Interventions:

The first 2 cases were treated conservatively. The third one was treated surgically.

Outcome:

Our cases had a variable hospital course but fortunately all were discharged in a good clinical condition.

Conclusion:

Our aim from this series is to highlight this fatal complication to clinicians in order to enrich our understanding of this pandemic and as a result improve patients’ outcome.

Keywords: acute abdomen, acute diverticulitis, cecal mass, corona virus disease-2019, gastrointestinal perforation. 

Introduction

Corona virus disease-2019 (COVID-19) had been declared pandemic in March 2020.[1] It presents most commonly with fever in more than 80% of cases followed by respiratory symptoms which could progress to adult respiratory distress syndrome in critical cases.[2] However, extra respiratory manifestations are being frequently recognized in association with COVID-19.[3] The gastrointestinal (GI) manifestations have been reported in descriptive studies from China.[2] The most frequently reported GI symptoms are nausea, vomiting, diarrhoea, and abdominal pain.[2,4,5] However, it is rarely reported for COVID-19 to present with GI perforation. To the date of writing this report, there have been only 13 reported of GI perforation in association with COVID-19.

In this series, we are reporting 3 cases who developed GI perforation in association with COVID-19. The first 2 cases developed this fatal complication after presenting with critical COVID-19 pneumonia which required intensive care unit (ICU) admission and mechanical ventilation. The third case presented with severe COVID-19 pneumonia and was diagnosed to have GI perforation at the time of presentation. The first 2 cases were managed conservatively, and the third case was managed surgically. All of the 3 cases recovered and were discharged in good condition. We are reporting this series in order to highlight this rare but fatal complication of COVID-19. This will enhance awareness of clinicians to such complication where early diagnosis and management is crucial in order to improve the patients’ outcome.

2. Case reports

2.1. The patients provided informed consent for publication of their cases

2.1.1. First case

A 70-year old male patient known to have type 2 diabetes mellitus (T2DM), presented to our emergency department (ED) on 1st of June 2020 complaining of 3-day history of dry cough and fever. On examination: Vital signs were remarkable for tachypnea with respiratory rate (RR): 28/min and desaturation with oxygen saturation (O2 sat):81% on room air (RA) but maintained >94% on 15 litres of oxygen via a non-rebreather mask. Nasopharyngeal swab tested positive for SARS-CoV-2 polymerase chain reaction (PCR). Chest X-ray (CXR) showed bilateral lower lung fields air apace opacities (Fig. ​(Fig.1A)1A) consistent with COVID-19 pneumonia. Laboratory investigations were remarkable for high Lactate dehydrogenase (LDH), inflammatory markers, D-dimer and markedly elevated Ferritin (Table ​(Table1).1). He was started on Methylprednisolone 40 mg IV BID, Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, and Enoxaparin. After 5 days of hospital admission, he deteriorated and could not maintain saturation on non-rebreather mask, so he was shifted to ICU, intubated and mechanically ventilated. Ceftriaxone was upgraded to Meropenem in addition to same previous therapy. COVID-19 therapy was stopped after completing 10 days, but he was continued on steroids. Figure 1

The chest X-ray (CXR) of the 3 cases at the time of presentation. (A): CXR of the 1st case showing bilateral lower lung fields air apace opacities. (B): CXR of the 2nd case showing bilateral scattered air space consolidative patches throughout the lung fields predominantly over peripheral and basal lungs. (C): CXR of the 3rd case showing bilateral middle and lower zones peripheral ground glass opacities.

Table 1

The laboratory investigations of the 3 cases on presentation.

TestFirst caseSecond caseThird caseNormal range
Complete Blood Count
 White Blood cells6.44.25.7(4.0–11.0) K/uI
 Hemoglobin15.112.113.4(11.6–14.5) g/dL
 Platelets147232283(140–450) K/uI
Renal Profile
 Blood urea nitrogen101411(8.4–21) mg/dL
 Creatinine0.920.820.82(0.6–1.3) mg/dL
Liver Profile
 Total Bilirubin0.50.51.0(0.2–1.2) mg/dL
 Direct Bilirubin0.30.20.3(0.1–0.5) mg/dL
 Alanine Transferase (ALT)265241(7–55) U/L
 Aspartate transferase (AST)425052(5–34) U/L
 Alkaline phosphatase (ALP)745574(40–150) U/L
 Gamma-glutamyl transpeptidase (GGTP)532139(12–64) U/L
 Lactate dehydrogenase (LDH)434442617(81–234) U/L
Inflammatory Markers
 Erythrocyte Sedimentation rate (ESR)63101490–10 mm/h
 C-Reactive Protein (CRP)7.9218.3210.780–5 mg/dL
Others
 Ferritin1114.72565.86654.87(21.81–274.66) ng/mL
 D-Dimer0.60.411.66<=0.5 ug/mL

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Multiple trials of weaning from mechanical ventilation failed. So, tracheostomy was carried out on 20th day of ICU admission and then he was successfully extubated. During his stay in ICU, urine analysis was persistently positive for urinary tract infection secondary to Candida Abican. So, he was started on Caspofungin. At that time, blood culture was negative. After 4 days of Caspofungin, urine analysis and culture became negative. On 32nd day of hospital admission, he was stable clinically, requiring 40% FiO2 through tracheostomy mask, so he was transferred to COVID-19 isolation ward. Meropenem was stopped after 20 days of treatment. Steroid was tapered after transfer to the ward till it was discontinued after 28 days of therapy.

After 14 days of treatment with Caspofungin, follow up C-reactive protein was persistently high. Thus, full septic workup was requested and revealed Candida Albican bacteremia. At that time, urine analysis and culture were negative, Caspofungin was continued for additional 14 days. However, Candidemia persisted, so he was shifted to Anidulafungin for another 14 days. Patient at that time did not have any GI symptoms or signs. For work up of Candidemia, echocardiogram could not be done due to the hospital policy of isolation rooms. Bed side ophthalmology examination was unremarkable.

On 44th day of hospital admission, he developed fresh bleeding per rectum. Hemodynamics were stable. The bleeding resulted in acute drop of 2 g/dL of hemoglobin over 24 hours. He denied abdominal pain, abdominal examination was negative for signs of peritonitis and per rectum examination was unremarkable. Therefore, computed tomography (CT) scan of the abdomen with contrast was carried out. It showed a well-defined mass within the posterior wall of the cecum measuring 3.1 × 3.2 cm associated with discontinuous enhancement and extra-luminal air foci suggestive of complicated perforated sealed cecal mass. This is in addition to radiological findings of peritonitis (Fig. ​(Fig.22A).Figure 2

The contrast enhanced computed tomography (CT) of the abdomen of the 3 cases. (A): CT scan abdomen of the 1st case (Coronal image) showing a well-defined rounded heterogeneous enhanced soft tissue mass lesion within the posterior wall of the cecum measuring (3.1 × 3.2 cm) in anteroposterior and transverse diameter associated with discontinuous enhancement of posterior cecum wall and extra-luminal air foci suggestive of complicated perforated sealed cecum mass. This is in addition to adjacent fat stranding with free fluid as well as enhancement of peritoneal reflection suggestive of peritonitis. (B &C): CT scan abdomen of the 2nd case (Axial & Coronal images). (2B): Axial image showing moderate to severe pneumoperitoneum with air seen more tracking along the ascending colon suggestive of a wall defect in the anterior aspect of the cecum. (2C): Coronal image showing a second defect in the stomach wall. (D): CT scan abdomen of the 3rd case (Coronal image) showing severe sigmoid diverticulosis with circumferential bowel wall thickening compatible with acute diverticulitis, small amount of free air compatible with bowel perforation likely arising from the sigmoid colon and a well-defined 3.3 × 1.5 cm abscess collection adjacent to the sigmoid colon.

In consideration of his stable clinical status, absent signs of peritonitis clinically and being a sealed perforation, he was managed conservatively. So, Meropenem was resumed and Clindamycin was started. 2 days later, bleeding stopped, and he stayed stable clinically without clinical signs of peritonitis. Feeding through nasogastric tube was introduced gradually as tolerated. Antibiotics were continued for a total of 8 days. Trial of weaning from oxygen was attempted gradually which he tolerated till he was maintained on RA. After closure of tracheostomy, on 70th day of hospital admission, the patient was discharged in a good condition with a plan of follow up of cecal mass progression. However, the patient did not follow up in outpatient clinics after discharge.

2.1.2. Second case

A 37-year old male patient, morbidly obese, negative past history, presented to our ED on 11th June 2020. He reported 3-day history of shortness of breath. Vital signs were remarkable for Temperature (Temp.): 38.5 C, pulse rate (PR): 111/min, RR: 30/min and O2 sat: 80% on RA. Laboratory investigations showed high LDH, inflammatory markers and Ferritin (Table ​(Table1).1). He had positive SARS-CoV-2 PCR and CXR showed bilateral air space consolidative patches scattered throughout the lung predominantly over peripheral and basal lungs (Fig. ​(Fig.1B).1B). He was admitted to COVID-19 isolation ward as a case of COVID-19 pneumonia and started on: Triple therapy in the form of: Interferon B1, Lopinavir/Ritonavir and Ribavirin, in addition to Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, Dexamethasone 6 mg IV OD and Enoxaparin.

On the 3rd day of admission, his condition deteriorated so, he was shifted to ICU and intubated because of respiratory failure. He was maintained on same treatment for COVID-19. On 2nd day postintubation, clinically he was vitally stable without active clinical GI signs but a routine follow-up CXR showed air under the diaphragm. Therefore, abdomen CT scan with contrast was carried out and showed moderate to severe pneumoperitoneum with air tracking along the ascending colon suggestive of wall defect at the cecum, in addition to another defect noted in the stomach wall (Fig. ​(Fig.2B2B & 2C). Ceftriaxone was upgraded to Piperacillin-Tazobactam and Caspofungin was added to cover for possibility of peritonitis. Again, the patient was managed conservatively, since he was asymptomatic. He remained vitally stable without signs of peritonitis. Enteral feeding was started gradually 3 days later and on the 10th day of hospital admission, he was extubated and shifted to COVID-19 isolation ward. COVID-19 therapy was continued for 12 days.

He tolerated feeding very well. Gradual weaning of oxygen supplementation was carried out till it was discontinued. After 14 days of antibiotics, a follow up CT scan of abdomen showed interval resolution of previously seen pneumoperitoneum. He was discharged on 30th day of hospitalization in a good condition.

2.1.3. Third case

A 74-year old male patient known case of T2DM presented to our ED on 17th July 2020. He gave 3-day history of dry cough, shortness of breath and generalized colicky abdominal pain. No other pulmonary or GI symptoms. He had negative past surgical history. Vital signs were remarkable for Temp: 38.4 C, PR: 105/min, RR: 22/min and O2 sat: 90% on RA, required 3 L/min O2 through nasal cannula. Chest examination was remarkable for reduced breath sound intensity bilaterally without added sounds. Abdomen was distended with generalized tenderness and guarding. Blood tests were remarkable for high LDH, inflammatory markers, Ferritin and D-dimer (Table ​(Table1).1). PCR for SARS-COV-2 was positive and CXR showed bilateral peripheral ground glass opacities at middle and lower lung lobes (Fig. ​(Fig.1C).1C). Due to the presence of abdominal pain along with signs of acute abdomen on examination, a CT scan of the abdomen was done. It showed severe sigmoid diverticulosis with radiological findings of acute diverticulitis, free air compatible with bowel perforation likely at the sigmoid colon with 3.3 cm adjacent abscess collection (Fig. ​(Fig.22D).

Therefore, the patient was started on Piperacillin-Tazobactam, Metronidazole in addition to COVID-19 therapy. He underwent emergency exploratory laparotomy. Intra-operatively, pus and fecal peritonitis along with perforation of 0.5 cm at the distal sigmoid colon were found. So, a Hartmann’s procedure was performed. Pathology result of resected sigmoid colon revealed diverticular disease with surrounding fibrosis, moderate mucosal inflammation with mixed acute and chronic inflammatory cells, negative for malignancy.

He had smooth postoperative course. Enteral feeding was started on 3rd day postoperation and he improved clinically. After a total of 10 days of hospitalization, supplemental oxygen and antibiotics were discontinued. He was discharged on 11th day of hospitalization in a good condition.

3. Discussion

The GI manifestations are the most frequently reported extra-pulmonary manifestations of COVID-19[2] with a prevalence of 10% to 50%.[4,5] The most commonly reported GI symptoms are nausea, vomiting, diarrhoea and abdominal pain.[2,4,5] However, there have been case reports of COVID-19 cases presenting with other GI manifestations. Those include acute surgical abdomen,[6] lower GI bleeding[7] and nonbiliary pancreatitis.[8] In fact, the GI manifestations could be the presenting symptoms of COVID-19 as was reported in a case report by Siegel et al where the patient presented with abdominal pain and upon abdominal imaging, the patient was found to have pulmonary manifestations of COVID-19 in the CT scan of the lung bases.[9]

GI perforation is a surgical emergency, carries a significant mortality rate that could reach up to 90% due to peritonitis especially if complicated by multiple organ failure.[10] It can be caused by many reasons. Those include foreign body perforation, extrinsic bowel obstruction like in cases of GI tumors, intrinsic bowel obstruction like in cases of diverticulitis/appendicitis, loss of GI wall integrity such as peptic ulcer and inflammatory bowel disease in addition to GI ischemia and infections.[11] Several infections have been reported to result in GI perforation like Clostridium difficile, Mycobacterium tuberculosis, Cytomegalovirus and others.[1214] COVID-19 have been rarely reported to result in GI perforation. Till the date of writing this report only 13 cases[1523] have been reported in the literature (Table ​(Table2).2). In addition, Meini et al reported a case of pneumatosis intestinalis in association with COVID-19 but without perforation.[25]

Table 2

Summary of the previously published cases of gastrointestinal perforation in association with COVID-19.

First Author [Reference]Age/ SexCo-morbid ConditionsPresenting symptomsSeverity of COVID-19 pneumoniaCOVID-19 TherapySymptoms prompted investigations for GI perforationSite of PerforationTiming of Perforation post admissionManagement of PerforationOutcome
1Gonzalvez Guardiola et al [15]66 Y/ MMetabolic syndromeNot mentionedCriticalMethylprednisoloneTocilizumab Hydroxychloroquine AzithromycinLopinavir/RitonavirAbdominal painIncreased WBC and CRP.CecumNot mentionedRight colectomyNot mentioned
2De Nardi et al [16]53 Y/MHypertension Supra-ventricular tachycardiaFeverCoughDyspneaCriticalAnakinra Lopinavir/Ritonavir Hydroxychloroquine + AntibioticsAbdominal pain Abdominal distentionSigns of PeritonitisCecum11th day of admissionRight colectomy & ileo-transverse anastomosisDischarged Home
3Kangas-Dick et al [17]74 Y/MNegativeFeverDyspneaDry coughCriticalHydroxychloroquine +AntibioticsIncreased Oxygen requirementMarkedly distended abdomenNot specified (CT scan: Not done)5th day of admissionConservativeDied
4Galvez et al [18]59 Y/MStatus post laparoscopic Roux-en-Y gastric bypass surgeryFeverDry coughMyalgiaHeadacheDyspneaModerateMethylprednisolone + COVID-19 protocol (Not specified)Acute abdominal painWorsening dyspneaGastro-jejunal anastomosis5th day of admissionLaparoscopy& Graham Patch RepairDischarged Home
5Poggiali et al [19]54 Y/ F§HypertensionFeverDry coughGERD symptomsSevereCOVID-19 therapy (Not specified) +AntibioticsAcute chest pain Painful abdomenDiaphragm StomachAt presentationSurgical RepairNot mentioned
6Corrêa Neto et al [20]80 Y/FHypertensionCoronary artery diseaseDry coughFeverDyspneaCriticalCOVID-19 therapy(Not specified) +AntibioticsDiffuse abdominal pain & stiffnessSigmoidAt PresentationLaparotomy with recto-sigmoidectomy & terminal colostomyDied
7Rojo et al [21]54 Y/FHypertensionObesityDyslipidemiaEpilepsyCough,MyalgiaCostal painCriticalHydroxychloroquine Lopinavir/Ritonavir MethylprednisoloneTocilizumabFeverHemodynamic instabilityAnemiaCecum15th day of admissionLaparotomy with right colectomy and ileostomyDied
8Kühn et al [22]59 Y/MNot mentionedFeverNauseaAbdominal pain Fatigue, HeadacheNot specifiedNot mentionedAbdominal painJejunal diverticulumAt presentationOpen small bowel segmental resection & anastomosisDischarged Home
9Seeliger et al [23]31Y/MNot mentionedDyspneaSevereNot mentionedNot mentionedLeft colonAt presentationLeft HemicolectomyDischarged Home
1082 Y/FDyspnea, DiarrhoeaCriticalSigmoidAt presentationOpen drainage of peritonitisDied
1171 Y/FFeverSevereGangrenous appendixAt presentationLaparoscopic appendectomyDischarged Home
1280Y/MNot mentionedSevereSigmoiditisAt presentationHartmann procedureDischarged Home
1377 Y/MDyspneaCriticalDuodenal ulcer23rd day of admissionOpen duodenal exclusion, omega gastro-enteric anastomosisDied
14This Report70Y/MT2DMFeverCoughCriticalMethylprednisolone HydroxychloroquineOseltamivir Enoxaparin+AntibioticsBleeding per rectumHemoglobin DropCecal mass44th day of admissionConservativeDischarged Home
1537Y/MMorbid obesityDyspneaCriticalInterferon B1Lopinavir/RitonavirRibavirinHydroxychloroquineOseltamivirDexamethasone+AntibioticsAir under diaphragm was found incidentally in a follow up CXRCecum4th day of admissionConservativeDischarged Home
1674Y/MT2DMCoughDyspnea Abdominal pain.SevereLopinavir/RitonavirRibavirinMethylprednisolone+AntibioticsAbdominal painSigns of peritonitisSigmoid diverticulosis/diverticulitisAt presentationExploratory laparotomy with Hartmann’s procedureDischarged Home

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Severity of COVID-19 pneumonia is based on classification of severity by Ministry of Health-Saudi Arabia.[24]†Y = Year.M = Male.§F = Female.

Most of the previously reported cases presented initially with respiratory symptoms, 4 cases had also GI symptoms at presentation in the form of abdominal pain, stiffness, nausea and diarrhoea[19,20,22,23] [Table ​[Table2].2]. Eleven out of the 13 cases had severe-critical pneumonia that required either high flow oxygen, intubation or mechanical ventilation which is similar to our first 2 cases. This may indicate that GI perforation is more common in severe and critically ill COVID-19 cases. The most common symptoms which prompted investigations for bowel perforation were abdominal pain and distention [Table ​[Table2].2]. Other indications were signs of peritonitis,[16] worsening hemodynamics[17,18,21] and rising inflammatory markers.[15]

Only one of our cases had abdominal pain and tenderness at presentation. Another developed anemia due to active lower GI bleeding which is similar to the case published by Rojo et al[21] where the patient developed anemia and found to have hemoperitoneum with pericecal hematoma. This is probably explained by the site of perforation since both had cecal perforation. Our other case was diagnosed incidentally after demonstration of air under diaphragm in routine CXR. GI perforation was diagnosed from first day up to 23rd day of presentation with COVID-19 [Table ​[Table2].2]. Our patients had similar variable timing of GI perforation in relation to presentation with COVID-19. It ranged from the first day of diagnosis up to 40 days after presentation with COVID-19 pneumonia. This may tell us that GI perforation could happen at any time during the course of the infection. Our report demonstrates different presentation of GI perforation with COVID-19 since in 2 of the 3 cases, the infection predisposed to having perforation of an underlying GI lesions (cecal mass and diverticulosis). Only Kuhn et al reported similar presentation where the patient had perforation of jejunal diverticulum.[22] This may tell us that having COVID-19 predispose patients with underlying GI lesions to perforation. In addition, in our first case, we think that the source of Candidemia was most probably the bowel since it was persistent even after clearance of Candida Albican from the urine, but it was overlooked due to the absence of GI symptoms at the time of developing the Candidemia. In a study of 62 cases with peritonitis secondary to gastric perforation, Candida species was isolated in 23 cases in peritoneal fluid culture.[26] Therefore, in presence of Candidemia especially in absence of clear source, evaluation of the bowel as a potential source should always be kept in mind.

The effect of SARS-COV-2 virus on the GI system can be explained by different mechanisms. First, the virus uses the same access to enter respiratory and GI tract epithelium which are Angiotensin converting enzyme 2 receptors giving the virus the chance to replicate inside GI cells.[27] In addition, faecal-oral transmission has also been postulated, due to the presence of viral RNA in stool samples.[28] Perforation could result from altered colonic motility due to neuronal damage by the virus[29] in addition to local ischemia resulting from hypercoagulable state caused by the virus especially in critically ill patients.[30] Corrêa Neto et al reported finding ischemia of the entire GI tract during exploratory laparotomy for sigmoid perforation with COVID-19.[20] In addition, Rojo et al reported presence of microthrombi and wall necrosis in the pathology examination of his COVID-19 case with bowel perforation.[21] Other possible implicating factors are the use of Tocilizumab and high dose steroids.[21,31] Both are indicated in severe and critically ill COVID-19 cases. Steroids were used in all of our 3 cases since it is indicated in severe COVID-19 pneumonia according Saudi Arabian Ministry of health guidelines[24] but none of our patients received Tocilizumab. Some of these mechanisms could explain the higher risk of GI perforation in severe and critically ill COVID-19 patients.

The diagnosis of GI perforation is based mainly on radiological findings on CT scan. The most specific findings are segmental bowel wall thickening, focal bowel wall defect, or bubbles of extraluminal gas concentrated in close proximity to the bowel wall.[32] Treatment of GI perforation is mainly surgical in order to improve survival.[33] This is in line with the previously published cases where all were managed surgically except the one reported by Kangas-Dick et al due to the patient’s critical condition, so he was managed conservatively but unfortunately, he died.[17] However, in selected cases where there are no active signs of peritonitis, abdominal sepsis or having sealed perforation, conservative treatment is an acceptable management strategy.[34,35] This was the case in 2 of our cases who were managed conservatively. Fortunately, they did very well and had good outcome.

4. Conclusion

GI manifestations are common in patients with COVID-19. However, GI perforation is rarely reported in the literature. Severe and critically ill COVID-19 patients seem to be at a higher risk of this complication. It has a variable presentation in patients with COVID-19 ranging from incidental finding discovered only radiographically to acute abdomen. The presence of underlying GI lesion predisposes patients with COVID-19 to perforation. High index of suspicion is required in order to manage those patients further and thus, improve their outcome.

Author contributions

Conceptualization: Reem J. Al Argan, Safi G. Alqatari

Data curation: Reem J. Al Argan, Abdulsalam Noor, Lameyaa A. Al Sheekh

Writing – original draft: Reem J. Al Argan, Lameyaa A. Al Sheekh, Feda’a H. Al Beladi

Writing – review & editing: Reem J. Al Argan, Safi G. Alqatari, Abir H. Al Said, Raed M. AlsulaimanGo to:

Footnotes

Abbreviations: COVID-19 = corona virus disease-2019, CT = computed tomography, CXR = chest X-ray, ED = emergency department, GI = gastrointestinal, ICU = intensive care unit, LDH = lactate dehydrogenase, O2 sat = oxygen saturation, PCR = polymerase chain reaction, PR = Pulse rate, RA = room air, RR = respiratory rate, Temp = Temperature, T2DM = Type 2 diabetes mellitus.

How to cite this article: Al Argan RJ, Alqatari SG, Al Said AH, Alsulaiman RM, Noor A, Al Sheekh LA, Al Beladi FH. Gastrointestinal perforation secondary to COVID-19: Case reports and literature review. Medicine. 2021;100:19(e25771).

The authors have no funding and conflicts of interests to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

References

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Review of COVID-19, part 1: Abdominal manifestations in adults and multisystem inflammatory syndrome in children

Authors: Devaraju Kanmaniraja,a,⁎ Jessica Kurian,a Justin Holder,a Molly Somberg Gunther,a Victoria Chernyak,b Kevin Hsu,a Jimmy Lee,a Andrew Mcclelland,a Shira E. Slasky,a Jenna Le,a and Zina J. Riccia

Abstract

The coronavirus disease 2019 (COVID -19) pandemic caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected almost every country in the world, resulting in severe morbidity, mortality and economic hardship, and altering the landscape of healthcare forever. Although primarily a pulmonary illness, it can affect multiple organ systems throughout the body, sometimes with devastating complications and long-term sequelae. As we move into the second year of this pandemic, a better understanding of the pathophysiology of the virus and the varied imaging findings of COVID-19 in the involved organs is crucial to better manage this complex multi-organ disease and to help improve overall survival. This manuscript provides a comprehensive overview of the pathophysiology of the virus along with a detailed and systematic imaging review of the extra-thoracic manifestation of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and features of MIS-C will be reviewed. In Part II, manifestations of COVID-19 in the musculoskeletal, central nervous and vascular systems will be reviewed.

Keywords: Abdominal imaging, COVID-19, Multisystem inflammatory syndrome

1. Abdominal findings of COVID019 in adults

The coronavirus 2019 disease (COVID-19), which originated in Wuhan, China, has quickly become a global pandemic, bringing normal life to a standstill in almost all countries around the world. The severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a novel virus preceded by two other recent coronavirus infections, the severe acute respiratory syndrome coronavirus (SARS-CoV-1) and the Middle Eastern respiratory syndrome coronavirus (MERS–CoV), but it has more far-reaching and devastating consequences. As of March 2021, the COVID-19 pandemic has resulted in over 29 million cases in the United States and over 121 million cases globally. As of April 2021, it is responsible for the deaths of over half a million people in the United States and more than 2 ½ million worldwide [1]. As the disease has evolved over the past year, so has our understanding of the virus, including its pathophysiology, clinical presentation and imaging manifestations. Although COVID-19 is predominately a pulmonary illness, it is now established to have widespread extra-pulmonary involvement affecting multiple organ systems. The SARS-CoV-2 has a highly virulent spike protein which binds efficiently to the angiotensin converting enzyme 2 (ACE2) receptors which are expressed in many organs, including the airways, lung parenchyma, several organs in the abdomen, particularly the kidneys and GI system, central nervous system and the smooth and skeletal muscles of the body [2]. The virus initially induces a specific adaptive immune response, and when this response is ineffective, it results in uncontrolled inflammation, which ultimately results in tissue injury [2].

This article provides a comprehensive review of the pathophysiology and imaging findings of the extra-thoracic manifestations of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and the varying features of multisystem inflammatory syndrome in children will be reviewed, with imaging findings summarized in Table 1Table 2 . In Part II, manifestations of COVID-19 in the musculoskeletal system, the central nervous system and central and peripheral vascular systems will be reviewed.

Table 1

Summary of abdominal imaging findings in COVID-19 in adults.

OrganImaging findings
Liver• Hepatomegaly
• Increased or coarsened echogenicity on US
• Hypoattenuation on non-contrast or contrast enhanced CT
• Periportal edema and heterogeneous enhancement on CT
• Loss of signal on opposed-phase sequences on MRI
• Portal vein thrombus
Pancreas• Features of acute interstitial pancreatitis
Biliary Tree• Biliary ductal dilatation
Kidney• Increased or heterogeneous parenchymal echogenicity on US
• Loss of corticomedullary differentiation on US
• Preserved cortical thickness
• Perinephric fat stranding and thickening of Gerota’s fascia on CT
• Wedge shaped perfusion defects on CT or MRI
• Thrombus in the renal artery or vein
Gallbladder• Distension
• Mural edema
• Sludge
• Acalculous cholecystitis
Urinary Bladder• Bladder wall thickening
• Mural hyperenhancement
• Perivesicular stranding
Bowel• Mural thickening
• Ileus
• Fluid-filled colon
• Pneumatosis intestinalis
• Portal vein gas
• Pneumoperitoneum
• Acute mesenteric ischemia
• Vascular occlusion (superior mesenteric artery, superior mesenteric vein, or portal vein)
• Mesenteric fat stranding, ascites
• Active gastrointestinal bleeding (duodenal or gastric ulcer) on CTA
• Clostridium difficile colitis
• Ischemic colitis
Spleen• Wedge shaped perfusion defects on CT or MRI
• Thrombus in the splenic artery or vein

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Table 2

Summary of imaging findings in Multisystem Inflammatory Syndrome in Children.

RegionImaging findings
Cardiothoracic• Bilateral symmetric diffuse airspace opacities with lower lobe predominance on CXR
• Diffuse ground glass opacity, septal thickening, and mild hilar lymphadenopathy on CT
• Bilateral pleural effusions
• Cardiomegaly
• Pericardial effusion
• Myocarditis pattern on cardiac MRI
Abdominal• Mesenteric lymphadenopathy, most common in right lower quadrant
• Mesenteric edema
• Ascites
• Bowel wall thickening
• Ileus
• Hepatosplenomegaly
• Gallbladder wall thickening

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2. Abdominal findings of COVID-19 in adults

2.1. Hepatobiliary derangement

Varying derangements of the liver, biliary system, gallbladder, portal vein and pancreas may occur in COVID-19 with hepatic parenchymal injury and biliary stasis reported with highest frequency. The mechanism of involvement of these structures appears to be multifactorial. The most direct form of injury results from SARS CoV-2 entry into host cells by binding to ACE2 receptors detected in several locations in the hepatobiliary system, including biliary epithelial cells (cholangiocytes), gallbladder endothelial cells and both pancreatic islet cells and exocrine glands [[3][4][5][6]].

2.1.1. Hepatic injury

Direct SARS CoV-2 entry into cholangiocytes may cause liver damage by disrupting bile acid transportation or by triggering acid accumulation resulting in liver injury [7]. Systemic inflammation, hypoxia inducing hepatitis and adverse drug reactions may incite liver injury [8]. Several drugs commonly used to treat COVID-19 patients, including acetaminophen, lopinavir and ritonavir can be hepatotoxic [9]. One study excluding COVID-19 patients receiving hepatotoxic drugs, still found patients with liver injury. Therefore, liver damage in COVID-19 patients is likely not entirely drug-induced but may also be due to acute infection [8,9]. Furthermore, since patients with chronic liver disease such as cirrhosis, autoimmune liver disease and prior liver transplantation are more susceptible to COVID-19 infection [9], underlying conditions may also contribute to liver injury.

The most frequent hepatic derangement is abnormal liver function tests reported in 16–53% of patients [10,11] and including raised levels of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase with mild elevation of bilirubin. The majority of cases are mild and self-limited, with severe liver damage rare [7]. Liver injury is most prevalent in the second week of COVID-19 infection, and has a higher incidence in those with gastrointestinal symptoms and more severe infection [9]. Based on a meta-analysis of hepatic autopsy findings of deceased COVID-19 patients in 7 countries, hepatic steatosis (55%), hepatic sinus congestion (35%) and vascular thrombosis (29%) were the most common [10]. In a retrospective study of abdominal imaging findings of 37 COVID-19 patients, 27% who underwent ultrasound had increased hepatic echogenicity considered to represent fatty liver with elevated liver enzymes being the most frequent indication for ultrasound [4]. It should be noted that since obesity is a major risk factor for severe COVID-19 infection, it might contribute to the frequency of steatosis identified on imaging. In another retrospective abdominal sonographic study of 30 ICU patients with COVID-19, the most common finding was hepatomegaly (56%), with most cases having increased hepatic echogenicity and elevated liver function tests [12]. In the only retrospective case-control study of 204 COVID-19 patients who underwent non-contrast chest CT scan, steatosis was found in 31.9% of cases and only 7.1% of controls [13]. Steatosis was based on a single ROI measurement in the right lobe with an attenuation value ≤ 40 HU. However, underlying risk factors for steatosis such as diabetes, obesity, hypertension and abnormal lipid profile, were not available to exclude preexisting conditions leading to steatosis. Finally, unlike in the spleen and kidney where infarcts are reported in COVID-19, hepatic infarction is not a distinct feature. This is likely due to the liver’s unique dual blood supply.

On imaging the liver may be enlarged. On ultrasound, the liver of patients with abnormal liver function tests may be coarsened and/or increased in echogenicity (Fig. 1Fig. 2 ). On CT scan, the liver may be hypoattenuated on non-contrast or contrast-enhanced exam due to steatosis (Fig. 3 ). Periportal edema and heterogeneity of hepatic enhancement may be seen on contrast-enhanced CT or MRI due to parenchymal inflammation. On MRI, loss of signal on opposed-phase sequences (Fig. 4 ) may be seen due to steatosis and periportal edema may be conspicuous on T2-weighted images or on contrast-enhanced images [7,8,14]. Periportal lymphadenopathy, typical of chronic liver disease, is not reported in COVID-19 [8]. In patients with severe COVID-19 infection, ancillary manifestations of hepatic inflammation and injury, such as parenchymal attenuation changes and abscesses may be seen (Fig. 5 ).

This Article Presents a Detailed Overview with Imaging. To View the Rest of This Analysis Click Here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223038/

Covid-19: UK studies find gastrointestinal symptoms are common in children

Authors: Susan Mayor BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3484 (Published 07 September 2020)Cite this as: BMJ 2020;370:m3484

Gastrointestinal symptoms are common in children infected with SARS-CoV-2 and should trigger tests for the virus, researchers have said.

A prospective study of 992 healthy children (median age 10.1 years) of healthcare workers from across the UK found that 68 (6.9%) tested positive for SARS-CoV-2 antibodies.1 Half of the children testing positive reported no symptoms, but for those that did the commonest were fever (21 of 68, 31%); gastrointestinal symptoms, including diarrhoea, vomiting, and abdominal cramps (13 of 68, 19%); and headache (12 of 68, 18%).

Latest findings from the Covid-19 Symptom Study app,2 which was launched in late March to track people’s symptoms, also show that gastrointestinal symptoms occur frequently in children with positive swab tests.3

Tom Waterfield, lead author of the antibodies study, told The BMJ, “Based on our findings I think that gastrointestinal symptoms should be added to the current list—high temperature, cough, and loss or change in sense of smell or taste—that trigger testing for coronavirus.” He added, “Diarrhoea and vomiting in children should trigger a test.”

Modelling showed that gastrointestinal symptoms were significantly associated with the presence of SARS-CoV-2 antibodies, in addition to known household contact with confirmed SARS-CoV-2, fatigue, and changes in sense of smell or taste.

“Although diarrhoea and vomiting may not be on the official covid-19 testing strategy, we need to be cautious in children with these symptoms,” said Waterfield, senior lecturer at Queen’s University Belfast and paediatric emergency medicine physician at the Royal Belfast Hospital for Sick Children. “They need to have had 48 hours clear of gastrointestinal symptoms before they go back to school to help reduce the potential spread of the virus.”

Tim Spector, the study lead and professor of genetic epidemiology at King’s College London, said, “Looking at data from 250 000 children we found those with a positive swab test have a different range of symptoms to adults. Cough and shortness of breath are much less frequent and gastrointestinal problems, especially loss of appetite, more frequent. Fever is still a feature, as in adults.”

He said that the study confirmed the need to add a wider range of symptoms to those listed for covid-19. “Around 50% of children did not have the three core adult symptoms (high temperature, cough, and loss or change in sense of smell or taste) and may present with a wide range of non-specific symptoms, such as malaise and loss of appetite, although skin rash affected one in six,” he said. “The key is for parents to keep children at home with these non-specific signs until they feel better, until tests get more rapid and accessible.”

Spector is asking parents to start logging information for their children on the app, which invites users to report regularly on their health. He added that the team is adding school specific features to help provide data on infection rates related to schools.

References

  1. Waterfield T, Watson C, Moore R, et al. Seroprevalence of SARS-CoV-2 antibodies in children: a prospective multicentre cohort study. medRxiv 2020.08.31.20183095 [Preprint]. 2 September 2020. www.medrxiv.org/content/10.1101/2020.08.31.20183095v1.
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    . Covid-19: Researchers launch app to track spread of symptoms in the UK. BMJ2020;368:m1263. doi:10.1136/bmj.m1263 pmid:32220898FREE Full Text

Study reveals mouth as primary source of COVID-19 infection

While most COVID-19 research has focused on the nose and lungs, this is the first study to identify the mouth as a primary site for coronavirus infection and underscores the importance of wearing a face covering and physical distancing.

By University Communications, Thursday, October 29th, 2020

A team of researchers led by the University of North Carolina at Chapel Hill and the National Institute of Dental and Craniofacial Research reveals coronavirus can take hold in the salivary glands where it replicates, and in some cases, leads to prolonged disease when infected saliva is swallowed into the gastrointestinal tract or aspirated to the lungs where it can lead to pneumonia.

While most COVID-19 research has focused on the nose and lungs, this is the first study to identify the mouth as a primary site for coronavirus infection and underscores the importance of wearing a face covering and physical distancing. The results have not been peer-reviewed.

“Our results show oral infection of COVID-19 may be underappreciated,” said senior study author Kevin M. Byrd, research instructor at the UNC Adams School of Dentistry and the Anthony R. Volpe Research Scholar at the American Dental Association Science and Research Institute. “Like nasal infection, oral infection could underlie the asymptomatic spread that makes this disease so hard to contain.”

Byrd along with Blake Warner, chief of the Salivary Disorders Unit at the National Institute of Dental and Craniofacial Research, coordinated the research conducted at the National Institutes of Health, Wellcome Sanger Institute, UNC Marsico Lung Institute and the J. Craig Venter Institute.

Researchers are just beginning to explore the oral symptoms patients experience during COVID-19, such as loss of taste or smell and persistent dry mouth.

In the study, researchers report preliminary results from a clinical trial of 40 subjects with COVID-19 which showed sloughed epithelial cells lining the mouth can be infected with SARS-CoV-2, the coronavirus that causes COVID-19. The amount of virus in patient saliva was positively correlated with taste and smell changes, according to the study.

Relying on oral cell identity maps, researchers also looked at where in the mouth the virus infects. They surveyed oral tissues with the highest levels of ACE2, the receptor that helps coronavirus grab and invade human cells.

Based on ACE2 expression and analysis of cadaver tissue, the most likely sites of infection in the mouth are the salivary glands, tongue and tonsil, the study showed.

The findings provide more evidence of the role of saliva in COVID-19. COVID-19 infection, specifically in the mouth, can allow the virus to spread internally and to others as the infected person breathes, speaks and coughs.

For More Information: https://www.unc.edu/posts/2020/10/29/study-reveals-mouth-as-primary-source-of-covid-19-infection/

COVID-19-associated diarrhea

World J Gastroenterol. 2021 Jun 21; 27(23): 3208–3222.Published online 2021 Jun 21. doi: 10.3748/wjg.v27.i23.3208PMCID: PMC8218355PMID: 34163106

Authors: Klara MegyeriÁron DernovicsZaid I I Al-Luhaibi, and András Rosztóczy

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218355/

GUT SYMPTOMS LINKED WITH COVID-19: A SYSTEMATIC REVIEW

Literature Review of COVID-19 G.I. Complications

Authors: Md. Rayhan Mahmud, University of Helsinki, Md Karim Uddin, University of Helsinki, Md. Sajjad Hossain, Jagannath University – Bangladesh, Sharmin Akter, Jagannath University – Bangladesh

Gastrointestinal Symptoms Associated With Unfavorable Prognosis of COVID-19 Patients: A Retrospective

The roles of nausea and vomiting in COVID-19: did we miss something?ArticleFull-text available

ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis

COVID-19 and the gastrointestinal tract: More than meets the eye

Clinical Features of 2019 Novel Coronavirus Pneumonia Presented Gastrointestinal Symptoms But Without Fever Onset

Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome

Gastrointestinal Symptoms and outcomes in hospitalized COVID-19 patients

Gut microbiota and Covid-19- possible link and implications

For More Information: https://www.researchgate.net/publication/353917998_GUT_SYMPTOMS_LINKED_WITH_COVID-19_A_SYSTEMATIC_REVIEW