Growing Number Of COVID-19 Deaths Among Vaccinated People: Federal Data

Authors: Katabella Roberts via The Epoch Times MY 13, 2022

An increasing number of COVID-19 deaths are occurring among individuals in the United States who have been vaccinated, according to federal data.

In August of 2021, roughly 18.9 percent of COVID-19 deaths happened among individuals who were vaccinated, an ABC News analysis of the data shows. Six months later in February 2022, that figure had risen to over 40 percent as the highly-transmissible Omicron variant made its way across the globe.

Similarly, in September 2021, just 1.1 percent of COVID-19 deaths occurred among Americans who had been fully vaccinated and boosted once. Five months later in February, that percentage had jumped to about 25 percent, according to ABC News.

A separate analysis of federal data by CNN shows that in the second half of September 2021—when the Delta variant was at its peak—less than a quarter of all COVID-19 deaths were among individuals who were vaccinated with at least two doses of the Moderna or Pfizer/BioNTech mRNA vaccines or a single dose of the Johnson & Johnson vaccine. However, just months later in January and February as Omicron surged, that figure had jumped to 40 percent.

Some experts believe the increase in deaths among fully vaccinated people or “breakthrough infections” in those who have received all their shots is not overly concerning, saying it is because while more and more people become fully vaccinated, new variants emerge and vaccine protection begins to wane as fewer people continue to get booster shots.

These data should not be interpreted as vaccines not working. In fact, these real-world analyses continue to reaffirm the incredible protection these vaccines afford especially when up to date with boosters,” said John Brownstein, an epidemiologist at Boston Children’s Hospital and an ABC News contributor.

Despite an increasing number of deaths among the vaccinated, the Centers for Disease Control and Prevention (CDC) states that vaccines are safe and effective. Data from the government agency says that overall, the risk of death from COVID-19 is roughly five times higher in unvaccinated individuals than in those who have had at least their initial dose of a vaccine.

However, in some cases, serious adverse events such as thrombosis with thrombocytopenia syndrome (blood clots), myocarditis (inflammation of the heart muscle), and pericarditis (inflammation of the outer lining of the heart) have been documented.

As of May 4, around 257.9 million people in the United States, or 77.7 percent of the total population in the nation have received at least one dose of vaccine, while roughly 219.9 million people, or 66.2 percent of the total U.S. population, have been fully vaccinated.

Around 100.9 million of those who are fully vaccinated have received a booster shot, while 49.4 percent of those eligible for booster shots have not yet had one.

As the Omicron variant swept through the nation, an increasing number of vulnerable, older populations were being hospitalized, and 73 percent of deaths have been among those 65 and older, despite the fact that 90 percent of seniors have had all of their vaccine shots.

However, a large percentage—a third of them—have not yet had their booster jab.

“This trend in increased risk among the elderly further supports the need for community-wide immunization,” Brownstein said. “Older populations, especially those with underlying conditions, continue to be at great risk of severe complications, especially as immunity wanes. The best way to protect them is to make sure everyone around them is fully immunized.”

The data comes a month after pharmaceutical and biotechnology company Moderna said that preliminary results from its study on a COVID-19 vaccine intended to protect against variants showed that it outperformed the company’s currently authorized booster shot, mRNA-1273.

Moderna said on April 19 that its mRNA-1273.211 shot, its first bivalent booster vaccine candidate, showed “superiority” against the Beta, Delta, and Omicron variants of the virus one month after being administered, compared to the booster shot of its original vaccine currently in use.

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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Intestinal Damage in COVID-19: SARS-CoV-2 Infection and Intestinal Thrombosis

Authors: Xiaoming Wu1Haijiao Jing1Chengyue Wang1Yufeng Wang1Nan Zuo1Tao Jiang2*Valerie A. Novakovic3 and Jialan Shi1,3,4* Front. Microbiol., 22 March 2022 | https://doi.org/10.3389/fmicb.2022.860931

The intestinal tract, with high expression of angiotensin-converting enzyme 2 (ACE2), is a major site of extrapulmonary infection in COVID-19. During pulmonary infection, the virus enters the bloodstream forming viremia, which infects and damages extrapulmonary organs. Uncontrolled viral infection induces cytokine storm and promotes a hypercoagulable state, leading to systemic microthrombi. Both viral infection and microthrombi can damage the gut–blood barrier, resulting in malabsorption, malnutrition, and intestinal flora entering the blood, ultimately increasing disease severity and mortality. Early prophylactic antithrombotic therapy can prevent these damages, thereby reducing mortality. In this review, we discuss the effects of SARS-CoV-2 infection and intestinal thrombosis on intestinal injury and disease severity, as well as corresponding treatment strategies.

Introduction

COVID-19 has become a worldwide pandemic causing widespread illness and mortality. SARS-CoV-2 mainly infects the respiratory tract through attachment to angiotensin-converting enzyme 2 (ACE2) receptors (Lan et al., 2020). ACE2 is also highly expressed on intestinal epithelial cells, allowing SARS-CoV-2 to infect the intestinal tract (Xiao et al., 2020a). Recent meta-analyses show that 48%–54% of fecal samples from COVID-19 patients have tested positive for viral RNA, and 15%–17% of patients have gastrointestinal (GI) symptoms (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). Additionally, live virus can be isolated from fecal samples of COVID-19 patients (Wang et al., 2020). Some studies have proposed fecal–oral transmission as the cause of intestinal infection (Guo et al., 2021). However, direct evidence for fecal–oral transmission is still lacking. Meanwhile, the virus has been detected in the blood of both symptomatic and asymptomatic patients (Chang et al., 2020), and disseminated virus could infect extrapulmonary organs (Jacobs and Mellors, 2020). Thus, the potential that intestinal infection occurs via blood transmission should be carefully considered.

Pulmonary infection triggers cytokine storm and induces a prothrombotic state (McFadyen et al., 2020Moore and June, 2020). Venous and arterial thrombosis are common in COVID-19 (Moore and June, 2020). Systematic reviews estimate that 14%–31% of in-hospital patients develop a clinically apparent thrombotic event (Suh et al., 2021Tan et al., 2021), while autopsy reports show a high prevalence of microthrombi in multiple organs, including lung, heart, liver, kidney, and gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). A cohort study showed that COVID-19 patients with intestinal ischemia had markedly elevated D-dimer levels and poor outcomes (Norsa et al., 2020). Additionally, recent studies have shown that mesenteric thrombosis often results in intestinal resection and significantly increases mortality (Bhayana et al., 2020El Moheb et al., 2020). Therefore, it is essential to outline the mechanisms of intestinal thrombosis and its contribution to intestinal damage and disease progression.

In this review, we discuss blood transmission as a potential route for intestinal infection. We then summarize the characteristics and mechanism of intestinal thrombosis formation in COVID-19. Next, we focus on the effects of intestinal infection and thrombosis on intestinal damage and disease severity. Finally, we discuss therapeutic strategies to prevent intestinal damage.

Gastrointestinal Symptoms and SARS-CoV-2 Infection

Multiple studies have reported GI symptoms in COVID-19 patients, including diarrhea, nausea, vomiting, anorexia, and abdominal pain (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). According to a meta-analysis comprising 10,890 COVID-19 patients, the pooled prevalence estimates of GI symptoms were: diarrhea (7.7%), nausea or vomiting (7.8%), and abdominal pain (2.7%; Sultan et al., 2020) with 10% of these patients reporting GI symptoms as being their initial symptoms (Cheung et al., 2020). These data indicate potential gastrointestinal infection by SARS-CoV-2, which is reported to infect and replicate in epithelial cells of human small intestinal organoids (Zang et al., 2020). Both viral nucleocapsid proteins and viral particles have been detected in infected patient intestinal biopsies (Livanos et al., 2021). Additionally, SARS-CoV-2 RNA and live virus can be found in the stool of patients (Wang et al., 2020). More importantly, SARS-CoV-2 subgenomic mRNA is transcribed in actively replicating cells and has been detected in fecal samples (Wölfel et al., 2020). Further, rectal viral shedding persists for longer than that of the respiratory system (Zhao et al., 2020). All these data demonstrate that SARS-CoV-2 directly infects and replicates in intestinal epithelial cells of patients.

Intestinal Infection and Transmission Routes

With the deepening understanding of COVID-19, GI symptoms have been recognized as early signs of the disease. The high expression of ACE2 in the GI tract, isolation of live virus from fecal samples, and a subset of patients presenting with only GI symptoms seem to suggest fecal–oral transmission. However, problems with the feasibility of this mode of transmission remain. First, studies have shown that SARS-CoV-2 loses infectivity in simulated gastric acid within 10 min (Chan et al., 2020Zang et al., 2020Zhong et al., 2020). Secondly, SARS-CoV-2, as an enveloped virus, is largely unable to withstand the detergent effect of bile salts and the activity of digestive enzymes in the duodenum (Figure 1). Although some studies have suggested that highly viscous mucus in the gastrointestinal tract protects SARS-CoV-2, allowing the virus to retain its infectivity (Guo et al., 2021Zhang H. et al., 2021), there is still a lack of direct evidence. Bushman et al. (2019) had previously investigated the links between the structures of viruses and routes of transmission and found a strong association between fecal–oral transmission and the absence of a lipid envelope. Lastly, although some studies have isolated intact viruses from feces (Wang et al., 2020Zhang Y. et al., 2020Zhou et al., 2020Xiao et al., 2020b), most of them have not further confirmed the infectivity of these viruses (Wang et al., 2020Zhang Y. et al., 2020Xiao et al., 2020b). Zhou et al. (2020) confirmed viral propagation by RT-PCR, but only in a single fecal sample. Previous research has shown that SARS-CoV-2 is completely inactivated in simulated human colonic fluid over the course of 24 h, which may explain the sporadic detection of infection-active SARS-CoV-2 from feces samples.FIGURE 1

Figure 1. Intestinal infection and transmission routes. ① Direct evidence for fecal–oral transmission is still lacking. SARS-CoV-2 may be unable to enter the small intestine from the stomach due to gastric acid, bile and digestive enzymes. ② SARS-CoV-2 released from type II alveolar cells infects alveolar capillary endothelial cells (ECs). The virus replicates in ECs and is released into the blood to form viremia. ③ SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation. ④ Blood transmission after alveolar or nasal infection is a potential route of intestinal infection. Eventually, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract. ⑤ SARS-CoV-2 in the gut can also enter the capillaries and cause viremia, leading to recurrence of disease.

Several lines of evidence suggest that SARS-CoV-2 may infect the intestinal tract via the bloodstream. Deng et al. (2020) detected SARS-CoV-2 RNA in anal swabs from intratracheally but not intragastrically infected rhesus macaques, suggesting blood transmission. Indeed, SARS-CoV-2 RNA has been detected in blood and urine samples of patients (Wang et al., 2020). The virus can also be detected in multiple organs (including heart, brain, and kidney) and is associated with organ injury, indicating that the virus can reach and infect extrapulmonary organs (Puelles et al., 2020). Another study showed that SARS-CoV-2 viremia was associated with intestinal damage, independent of disease severity (Li Y. et al., 2021). Thus, blood transmission could be the cause of intestinal infection. Specifically, SARS-CoV-2 replicating in alveolar epithelial cells and capillary ECs is released into the bloodstream and infects new vascular ECs. The capillary network is then the main route by which the virus enters and infects extrapulmonary organs. The extensive surface area of intestinal capillaries makes intestinal epithelial cells more susceptible to infection than other extrapulmonary organs. Following infection of intestinal capillaries, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract (Figure 1). Once established in the gut, SARS-CoV-2 can also reenter the capillaries, potentially leading to recurrence of disease. Consistent with this, in patients who experienced recurrence, the phylogenetic analysis of infection samples has shown that recurrent virus evolves from the original parent virus (Hu et al., 2020).

Additionally, SARS-CoV-2 RNA can also be detected in the blood and urine of asymptomatic patients, suggesting a second pathway to viremia through the nasal cavity (Chang et al., 2020Hasanoglu et al., 2021). The abundant blood vessels, thin mucous membrane, and higher levels of ACE2 (Huang et al., 2021) make it possible for the virus to initiate viremia from the nasal cavity. Specifically, SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation (Figure 1). Blood transmission after nasal infection is therefore another potential route of intestinal infection.

Intestinal Damage, Malnutrition, and Poor Outcomes

A recent study has shown that a fecal sample positive for SARS-CoV-2 RNA at any time during hospitalization was associated with higher mortality [HR: 3.4 (1.2–9.9); Das Adhikari et al., 2021]. Similarly, another study showed that small-bowel thickening on CT was strongly associated with ICU admission (Wölfel et al., 2020). This relationship did not hold for colon or rectal thickening. These data indicates that small-bowel damage contributes to poor outcomes. As the main organ for nutrient absorption, damage to the small intestine will result in malabsorption and malnutrition, both of which commonly occur in COVID-19 patients (Di Filippo et al., 2021Lv et al., 2021) and are associated with disease severity (Luo et al., 2020Zhang P. et al., 2021). A fecal metabolome study showed that feces of COVID-19 patients were enriched with important nutrients that should be metabolized or absorbed, consistent with malabsorption (Lv et al., 2021). A prospective study showed that 29% of COVID-19 patients (31% of hospitalization patients and 21% of patients quarantined at home) had lost >5% of body weight [median weight loss, 6.5 (5.0–9.0) kg or 8.1 (6.1–10.9) %; Di Filippo et al., 2021]. Those patients with weight loss had greater systemic inflammation, impaired renal function and longer disease duration. A large, multicenter study (including 3,229 patients with GI symptoms) showed that 23% of patients had malnutrition, of whom 56.4% were unable to gain weight after 6 months follow-up (Rizvi et al., 2021). Studies also showed that malnutrition was associated with higher incidences of acute respiratory distress syndrome, acute myocardial injury, secondary infection, shock, and 28-day ICU mortality (Luo et al., 2020Zhang P. et al., 2021). Overall, malabsorption and malnutrition due to damaged small intestine increased disease severity and mortality.

Nutrient absorption in the small intestine is mainly through ATP-dependent active transport. Intestinal infection, hypoxemia, and intestinal ischemia contribute to malabsorption. SARS-CoV-2 adhesion depletes ACE2 levels on intestinal epithelial cells, which alters the expression of the neutral amino acid transporter B0AT1, reducing the intake of tryptophan and the production of nicotinamide (D’Amico et al., 2020). Meanwhile, uncontrolled viral replication consumes large amounts of ATP and nutrients, resulting in decreased nutrients entering the bloodstream. More importantly, anaerobic glycolysis caused by hypoxemia and intestinal ischemia significantly decreases ATP and active transport, leading to malabsorption. Additionally, hypoxemia and intestinal ischemia can also cause anorexia, nausea, vomiting, and enteral nutrition intolerance, reducing food intake. A prospective multicenter study showed that reduced food intake was associated with higher ICU admission and mortality (Caccialanza et al., 2021).

Intestinal Ischemia and Thrombosis

Intestinal ischemia is a common manifestation in COVID-19 patients. Autopsy results have shown that 31.6% of deceased patients had focal ischemic intestinal changes (Chiu et al., 2020). In a separate imaging study, bowel wall thickening and pneumatosis intestinalis, which indicate intestinal ischemia, were found on 38.1% (16 of 42) of abdominal CT images (Bhayana et al., 2020). Of these, 4 (9.5%) patients with pneumatosis intestinalis developed severe intestinal necrosis and needed resection. In another cohort study, 55.8% (58/104) of ICU patients developed an ileus (Kaafarani et al., 2020). Although mechanical factors cannot be ruled out, insufficient intestinal motility due to intestinal ischemia was more likely to be the cause of ileus in COVID-19 patients. In these patients with ileus, 4 (3.8%) developed severe intestinal ischemia and require emergency surgery. Both studies found microthrombi in these resected intestinal samples, which were the main cause of intestinal ischemia and increased mortality.

Additional intestinal ischemia and necrosis follows the formation of mesenteric thrombosis. However, there is currently relatively little data of mesenteric thrombus in COVID-19. Therefore, we have summarized the characteristics of 40 patients in 39 case reports published on PubMed (Supplementary Table 1). The median age of these patients was 50 (20–82) years, 26 (65%) were male, 38 (95%) developed bowel ischemia or necrosis, 30 (75%) needed bowel resection, 7 (17.5%) required no surgery, at least 3 (7.5%) developed sepsis, and 13 (32.5%) died. Other abdominal thrombotic events (such as celiac aortic thrombosis) leading to mesenteric ischemia can also result in severe intestinal necrosis and require intestinal resection (Zamboni et al., 2021).

Mild intestinal ischemia can lead to reduced diet and malabsorption. Severe intestinal ischemia or necrosis leads to the dissemination of gut bacteria, endotoxins, and microbial metabolites into the blood (Figure 2 bottom), aggravating hyperinflammation and the hypercoagulability state. Such patients need emergency excision of the necrotic bowel, which significantly increases mortality.FIGURE 2

Figure 2. Intestinal thrombosis leads to intestinal mucosal necrosis and dissemination of gut bacteria, endotoxins, and microbial metabolites in blood. (Top) Mesenteric vascular endotheliitis (initiated by viremia and accelerated by cytokines), hyperactivated platelets and high levels of phosphatidylserine (PS) promote a high rate of mesenteric thrombus in COVID-19 patients (mesenteric vein is shown in Supplementary Figure 1). (Bottom) Intestinal microthrombi and hypoxemia rapidly lead to intestinal mucosal ischemia and necrosis. The damaged gut–blood barrier leads to dissemination of gut bacteria, endotoxins, and microbial metabolites in blood.

Long-Term Gastrointestinal Sequelae

Long-term GI complications are common in recovering COVID-19 patients. In one systematic review of post-acute COVID-19 manifestations, diarrhea was among the top 10 most common complaints, with a prevalence of 6%. Other long-term GI symptoms include nausea, vomiting, abdominal pain, loss of appetite, and weight loss (Aiyegbusi et al., 2021Huang et al., 2021). The exact mechanisms of the GI sequelae remain unclear. Recently, persistent endotheliopathy, higher levels of thrombin (Fogarty et al., 2021), and residual SARS-CoV-2 viral antigens in the GI tract (Cheung et al., 2022) were described in convalescent COVID-19 patients. These data suggest that prolonged intestinal infection, persistent endothelial injury (abnormal intestinal–blood barrier), and microthrombi could be causes of the persistent GI symptoms.

The Mechanisms of Intestinal Thrombosis

Damaged Endothelial Cells

Resected bowel samples from COVID-19 patients routinely exhibit thrombi and endotheliitis, indicating the important role of EC injury in mesenteric thrombosis (Bhayana et al., 2020Chiu et al., 2020Kaafarani et al., 2020). SARS-CoV-2 infection (Varga et al., 2020) and elevated inflammatory cytokines (He et al., 2016) damage mesenteric vascular ECs. In response, EC cell margins retract, extending phosphatidylserine (PS) positive filopods and releasing endothelial microparticles (MPs; Figure 3BHe et al., 2016). The PS+ filopods and MPs can be co-stained by Xa and Va and support fibrin formation (Figures 3BD). The exposed PS then activates tissue factor on ECs, triggering the extrinsic coagulation pathway (Versteeg et al., 2013). Next, higher levels of FVIII and vWF released from damaged EC contribute to the hypercoagulable state and platelet aggregation, respectively (Goshua et al., 2020). Thrombomodulin is then released from ECs in its soluble form, which has an attenuated capacity to activate Protein C due to a lack of other cofactors on ECs, such as endothelial protein C receptor (Versteeg et al., 2013). Finally, upregulation of endothelial cell adhesion molecules recruits neutrophils and platelets and further contributes to thrombosis (Tong et al., 2020Li L. et al., 2021).FIGURE 3

Figure 3. Phosphatidylserine exposure on activated/apoptotic cells and microparticles (MPs) promotes fibrin formation. (A) Phosphatidylserine is usually confined to the inner leaflet of the cell membrane. This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of non-PS by floppases (left). Upon stimulation, calcium transients will inhibit ATP-dependent transport and stimulate the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure (right). (B–D) Human umbilical vein ECs were treated with healthy human plasma and TNF-ɑ (our previous study; He et al., 2016). (B) ECs retracts the cell margins, extends PS positive filopods and releases endothelial-MPs. (C) The PS+ filopods and MPs can be co-stained by Xa and Va. (D) ECs (green) were incubated with MPs-depleted plasma (MDP) in the presence of calcium for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Considerable fibrin stands among cultured ECs along with filopodia. (E) Confocal images showed PS expression on platelets of patients stained with Alexa 488 lactadherin (our previous study; Ma et al., 2017). MPs from the activated platelet (*) had formed at the margin area located between the distinct outlines. (F) MPs from plasma were co-stained by Xa and Va (or lactadherin and annexin V; our previous study; Gao et al., 2015). (G) MPs that were incubated with recalcified MDP for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Converted fibrin networks were detected around MPs. The inset bars represent 5 μm in (B–D,G) and 2 μm in (E,F).

Hyperactivated Platelets and Phosphatidylserine Storm

Although COVID-19 patients exhibit mild thrombocytopenia, the remaining platelets are hyperactivated (Manne et al., 2020Taus et al., 2020Zaid et al., 2020). Studies have shown that platelets from COVID-19 patients have increased P-selectin and αIIbβ3 expression. P-selectin on activated platelets interacts with integrin αIIb3 on monocytes to form platelet-monocyte complexes, which induce monocyte tissue factor expression (Hottz et al., 2020). The activated platelets can also induce neutrophils to release neutrophil extracellular traps (NETs; Middleton et al., 2020). Furthermore, platelets from COVID-19 patients aggregate and adhere more efficiently to collagen-coated surfaces under flow conditions (Manne et al., 2020Zaid et al., 2020). Meanwhile, activated platelets release α- and dense-granule contents including FV, FXI, fibrinogen and vWF (Zaid et al., 2020). In addition, activated platelets also produce inflammatory cytokines, fueling cytokine storm (Taus et al., 2020Zaid et al., 2020). Most importantly, activated platelets expose higher levels of PS and release higher numbers of PS+ MPs (Figures 3EGZaid et al., 2020Althaus et al., 2021).

Phosphatidylserine is the most abundant negatively charged phospholipid in mammalian cells and is usually confined to the inner leaflet of the cell membrane (Versteeg et al., 2013). This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of other phospholipids by floppases (Figure 3A left). Upon stimulation, transiently increased calcium inhibits ATP-dependent transport and stimulates the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure on the outer membrane (Figure 3A right). During this process, microvesicles derived from the budding of cellular membranes will be released. These MPs are typically <1 μm and express PS (Burnier et al., 2009). The exposure of PS on the surface of cells and MPs provides a catalytic surface for factor Xa and thrombin formation in vivo (Versteeg et al., 2013). We have previously demonstrated that PS mediates 90% of Xa and thrombin formation and significantly increases thrombosis in vivo (Shi and Gilbert, 2003).

Cytokines and virus infection can activate blood cells and ECs, resulting in higher levels of PS+ cells and MPs. As COVID-19 progresses, the developing cytokine storm activates more blood cells, leading to PS storm. Platelets are highly sensitive to circulating cytokines, releasing large amounts of cytokines and PS exposed MPs into the plasma (Taus et al., 2020Althaus et al., 2021) and thus are a major contributor to PS storm. Previous studies found an unusual elevation of FVa in severe COVID-19 patients (248 IU/dl, higher than any previous disease; Stefely et al., 2020von Meijenfeldt et al., 2021). The degree of FVa elevation in these patients may be the result of PS storm.

Collectively, SARS-CoV-2 infection is the initiating factor for injury of the intestinal vascular ECs, which is then aggravated by systemic cytokines, leading to endotheliitis. Subsequently, the hyperactivated platelets in circulation rapidly accumulate around the damaged ECs, inducing tissue factor expression, NET release, and activating the intrinsic/extrinsic coagulation pathways. Simultaneously, the high levels of PS expression in circulating cells and MPs further promote thrombin and fibrin formation (Figure 2 top).

Early Antithrombotic Treatment

Vaccines and antithrombotic therapy are effective measures to reduce intestinal damage and fight against the COVID-19 pandemic (Baden et al., 2021Chalmers et al., 2021). Vaccines induce adaptive immunity to clear the virus, reducing intestinal infection and intestinal damage. However, the usefulness of vaccines is limited by incomplete vaccine acceptance and viral mutations (Hacisuleyman et al., 2021Wang et al., 2021). Vaccines are also ineffective for already infected patients. Therefore, more attention should be paid to antithrombotic therapy. Studies had shown that thrombotic events mainly occurred within 7 days of COVID-19 diagnosis (both inpatients and outpatients; Mouhat et al., 2020Ho et al., 2021). Meanwhile, two large randomized controlled trials (RCTs) from the same platform showed that therapeutic anticoagulation reduced mortality in moderate cases but not in severe ones, suggesting that delayed anticoagulant therapy may lead to treatment failure (REMAP-CAP Investigators et al., 2021a,b). More importantly, a recent study reported three asymptomatic COVID-19 patients who developed abdominal (or intestinal) thrombosis leading to intestinal necrosis (Zamboni et al., 2021). All these data suggest that antithrombotic therapy should be initiated once COVID-19 is diagnosed (excluding patients with contraindications). Early prophylactic antithrombotic therapy can reduce the activation of vascular ECs and blood cells, preventing intestinal thrombosis, ensuring sufficient intestinal perfusion, maintaining the normal gut–blood barrier, avoiding malabsorption, malnutrition, and intestinal flora entering the bloodstream. Further, attenuated injury and decreased microthrombi in convalescent patients may lower the risk of long-term GI sequelae. Meanwhile, unobstructed systemic circulation can also accelerate the removal of SARS-CoV-2, inflammatory cytokines and damaged blood cells by the mononuclear phagocyte system.

Anticoagulation

Table 1 summarizes the RCTs of anticoagulant therapy in COVID-19 patients. For outpatients, early anticoagulant therapy reduced hospitalization and supplemental oxygen (Gonzalez-Ochoa). While, delayed treatment had no similar effect (ACTIV-4B and Ananworanich). Thus, oral anticoagulant therapy should be initiated in outpatients once COVID-19 is diagnosed. For non-critically ill patients, therapeutic doses of low molecular weight heparin (LMWH) reduced thrombotic events and mortality, and increased organ support-free days (REMAP-CAP, ACTIV-4a, ATTACC; RAPID; HEP-COVID). However, therapeutic doses of rivaroxaban did not improve clinical outcomes and increased bleeding (ACTION). This is potentially because novel oral anticoagulants do not share the anti-inflammatory and antiviral functions of heparin. Intestinal damage might also result in abnormal absorption of oral anticoagulants. Therefore, therapeutic LMWH should be the first choice for non-critically ill patients. For critically ill patients, RCTs showed that moderate and therapeutic doses were not superior to prophylactic ones. Results from several other studies suggest that the overwhelming thrombosis leads to failure of anticoagulant therapy at therapeutic doses (Leentjens et al., 2021Poor, 2021). Faced with this dilemma, an editorial in N Engl J Med argued that profibrinolytic strategies should be considered (Ten Cate, 2021). More studies are needed to explore optimal antithrombotic therapy in critically ill patients.TABLE 1

Table 1. Randomized clinical trials of anticoagulant therapy in COVID-19 patients.

Inhibition of Platelet Activation

As COVID-19 progresses, cytokine storm activates platelets, which not only participate in primary hemostasis, but also are the major components of PS storm. Autopsy results show a high prevalence of platelet-fibrin-rich microthrombi in lung and extrapulmonary organs, including the gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). Early inhibition of platelet activation can reduce platelet activity and prevent PS storm, thus decreasing thrombosis and mortality. Several observational studies have shown that aspirin decreases mechanical ventilation, ICU admission, and mortality (Chow et al., 2020Santoro et al., 2022). The RCTs testing antiplatelet agents were still preliminary. A recent RCT suggested that aspirin was associated with an increase in survival and reduction in thrombotic events (RECOVERY Collaborative Group, 2022). In addition, anti-inflammatory therapy (e.g., dexamethasone, 6 mg once daily; RECOVERY Collaborative Group et al., 2020) inhibits cytokine storm, as well as platelet activation, reducing mortality. Overall, inhibition of platelet activation is also important to reduce mortality through the prevention of thrombosis and organs damage.

Factors Influencing Antithrombotic Treatment

Thrombotic Risk Factors or Co-morbidities

Studies have shown that obesity, hyperglycemia and diabetes are associated with increased thrombotic events (including intestinal thrombosis), COVID-19 severity, and mortality (Drucker, 2021Stefan et al., 2021). Other thrombotic risk factors include previous venous thromboembolism, active cancer, known thrombophilic condition, recent trauma or surgery, age ≥70 years, respiratory/cardiac/renal failure, and inflammatory bowel disease (Susen et al., 2020). These factors or co-morbidities heighten basal inflammatory levels and endothelial damage, leading to premature cytokine and PS storms, ultimately increasing thrombosis and mortality. Thus, more active antithrombotic therapy strategies should be adopted in these patients. For patients with mild COVID-19 with these factors, the French Working Group on Perioperative Hemostasis and the French Study Group on Thrombosis and Hemostasis recommend higher (intermediate) doses of anticoagulant therapy (Susen et al., 2020). For moderately ill patients, therapeutic doses of anticoagulant therapy should be initiated as soon as possible to prevent excessive microthrombus formation. The need for extended thromboprophylaxis in discharged patients remains controversial. However, a recent RCT showed that rivaroxaban (10 mg/day, 35 days) improved clinical outcomes in discharged COVID-19 patients with higher thrombotic risk factors (Ramacciotti et al., 2022), supporting extended thromboprophylaxis in patients with these risk factors or co-morbidities.

Vaccination

Although more than half the world population has received at least one dose of the vaccines, there are relatively little data of antithrombotic therapy in vaccinated patients. Studies of viral dynamics show that the viral loads of vaccinated patients are as high as that of unvaccinated patients, but drop significantly faster (Brown et al., 2021Klompas, 2021). Thus, vaccinated patients have shorter hospital stays, and are less likely to progress to critical illness and death (Tenforde et al., 2021Thompson et al., 2021). Nevertheless, antithrombotic therapy is still beneficial for the vaccinated patients. Firstly, heparin has anti-inflammatory and antiviral functions and can interfere with the binding of SARS-CoV-2 to ACE2 and shorten the duration of virus infection (Kwon et al., 2020Pereyra et al., 2021). Secondly, antithrombotic therapy protects cells from damage, PS exposure, and microthrombi formation, maintains unobstructed blood circulation, and facilitates virus clearance (by vaccine-induced adaptive immunity). Thirdly, thrombosis remains an important factor in disease progression. Antithrombotic therapy further reduces thrombosis and mortality, especially in vaccinated patients with high risk factors or co-morbidities. Lastly, although vaccines reduce the incidence, a subset of vaccinated patients will still develop long-term sequelae or Long Covid (Ledford, 2021Antonelli et al., 2022). Persistent viral infection and microthrombi are the primary causes (Ledford, 2021Xie et al., 2022), and early antithrombotic therapy is still needed to prevent them.

Conclusion and Future Research

During COVID-19 disease progression, SARS-CoV-2 infiltrates the blood stream from the initial respiratory tract infection, causing viremia, hyperactivated platelets and PS storm. The virus settles into the vascular beds of extrapulmonary organs, ultimately causing infection of intestinal epithelial cell. Damaged ECs, combined with hyperactivated platelets and PS storm, promote intestinal thrombosis, resulting in intestinal ischemia or necrosis. The damaged gut–blood barrier leads to malabsorption, malnutrition and intestinal flora entering the bloodstream, which significantly increase disease severity and mortality. Prolonged intestinal infection, persistent endothelial injury and microthrombi contribute to the long-term GI sequelae after discharge. Early prophylactic antithrombotic therapy can prevent microthrombi, ensuring sufficient intestinal perfusion, maintaining the normal intestinal function, and reducing the risk of long-term GI sequelae. More active antithrombotic therapy should be adopted in patients with other thrombotic risk factors or co-morbidities. Even in vaccinated COVID-19 patients, antithrombotic therapy is also important to decrease (intestinal) thrombosis, mortality and the risk of long-term GI sequelae.

With the Omicron pandemic, patients requiring hospitalization and ICU treatment decline rapidly. However, people are increasingly concerned about Long Covid. In terms of long-term GI sequelae, the detailed mechanisms of prolonged intestinal infection and persistent microthrombi remain unclear. And whether anticoagulant therapy can decrease GI symptoms in patients with long-term GI sequelae deserves further study. Finally, the impact of vaccines on long-term GI sequelae remains unclear in previously infected and breakthrough infected patients.

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Covid Raises Blood Clot, DVT Risks for Months After Even Mild Infection

Authors: Michelle Fay Cortez – April 7, 2022 Bloomberg

The risk of developing serious bleeding or potentially deadly blood clots is elevated for months after experiencing even a mild Covid infection, Swedish researchers found. 

While the dangers of post-Covid clotting are well known, it’s less clear how long the risk lasts and what should be done to prevent it. The researchers compared the medical records of 1 million people who tested positive for the virus between February 2020 and May 2021 in Sweden to 4 million of their peers who weren’t infected. 

Bleeding rates were elevated for two months after testing positive for the virus, while there was significant risk of developing blood clots deep in the legs for 70 days after Covid-19. The danger of pulmonary embolism, when a clot travels to the lungs and can kill, was significantly higher for almost four months, according to the report published in the BMJ, a British medical journal. 

“Despite the potential for new variants of concern, most governments are removing restrictions and shifting their focus to determining how best to ‘live with Covid’,” Frederick Ho and Jill Pell from the University of Glasgow’s Institute of Health and Wellbeing, wrote in an editorial. The finding “reminds us of the need to remain vigilant to the complications associated with even mild SARS-CoV-2 infection,” they wrote. 

The results support the use of blood thinners to prevent clotting, especially for high-risk patients, and underscores the need for vaccination, the researchers concluded. The study also found that the risks declined over time, as subsequent outbreaks of Covid caused fewer of the complications than the initial wave of disease. 

The risk of bleeding was almost twice as high for Covid patients in the month after they were infected, while clots called deep vein thrombosis were almost five times higher, the study found. Pulmonary embolism was the greatest risk, with 1,761 events occurring in the 30 days after infection, compared to just 171 among the larger group of people who didn’t contract the virus. 

While the danger was highest for those with other health conditions and the most severe infections, the fact that many more people develop mild cases means they should also remain alert, the experts said. Vaccination may help alleviate the issue of clotting, the experts said. 

“Vaccination could reduce the overall risk both by preventing infection and by reducing its severity when it does occur,” they wrote. 

1000 Peer Reviewed Studies Questioning Covid-19 Vaccine Safety

Peer Reviewed Medical Papers Submitted To Various Medical Journals, Evidencing A Multitude Of Adverse Events In Covid-19 Vaccine Recipients.

The list includes studies published as of January 20, 2022 concerning the potential adverse reaction from COVID-19 vaccines, such as myocarditis, thrombosis, thrombocytopenia, vasculitis, cardiac, Bell’s Palsy, immune-mediated disease, and many more.

  1. Myocarditis after mRNA vaccination against SARS-CoV-2, a case series: https://www.sciencedirect.com/science/article/pii/S2666602221000409
  2. Myocarditis after immunization with COVID-19 mRNA vaccines in members of the US military. This article reports that in “23 male patients, including 22 previously healthy military members, myocarditis was identified within 4 days after receipt of the vaccine”: https://jamanetwork.com/journals/jamacardiology/fullarticle/2781601
  3. Association of myocarditis with the BNT162b2 messenger RNA COVID-19 vaccine in a case series of children: https://pubmed.ncbi.nlm.nih.gov/34374740/
  4. Acute symptomatic myocarditis in seven adolescents after Pfizer-BioNTech COVID-19 vaccination: https://pediatrics.aappublications.org/content/early/2021/06/04/peds.2021-052478
  5. Myocarditis and pericarditis after vaccination with COVID-19 mRNA: practical considerations for care providers: https://www.sciencedirect.com/science/article/pii/S0828282X21006243
  6. Myocarditis, pericarditis and cardiomyopathy after COVID-19 vaccination: https://www.sciencedirect.com/science/article/pii/S1443950621011562
  7. Myocarditis with COVID-19 mRNA vaccines: https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.056135
  8. Myocarditis and pericarditis after COVID-19 vaccination: https://jamanetwork.com/journals/jama/fullarticle/2782900
  9. Myocarditis temporally associated with COVID-19 vaccination: https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.055891.
  10. COVID-19 Vaccination Associated with Myocarditis in Adolescents: https://pediatrics.aappublications.org/content/pediatrics/early/2021/08/12/peds.2021-053427.full.pdf
  11. Acute myocarditis after administration of BNT162b2 vaccine against COVID-19: https://pubmed.ncbi.nlm.nih.gov/33994339/
  12. Temporal association between COVID-19 vaccine Ad26.COV2.S and acute myocarditis: case report and review of the literature: https://www.sciencedirect.com/science/article/pii/S1553838921005789
  13. COVID-19 vaccine-induced myocarditis: a case report with review of the literature: https://www.sciencedirect.com/science/article/pii/S1871402121002253
  14. Potential association between COVID-19 vaccine and myocarditis: clinical and CMR findings: https://www.sciencedirect.com/science/article/pii/S1936878X2100485X
  15. Recurrence of acute myocarditis temporally associated with receipt of coronavirus mRNA disease vaccine 2019 (COVID-19) in a male adolescent: https://www.sciencedirect.com/science/article/pii/S002234762100617X
  16. Fulminant myocarditis and systemic hyper inflammation temporally associated with BNT162b2 COVID-19 mRNA vaccination in two patients: https://www.sciencedirect.com/science/article/pii/S0167527321012286.
  17. Acute myocarditis after administration of BNT162b2 vaccine: https://www.sciencedirect.com/science/article/pii/S2214250921001530
  18. Lymphohistocytic myocarditis after vaccination with COVID-19 Ad26.COV2.S viral vector: https://www.sciencedirect.com/science/article/pii/S2352906721001573
  19. Myocarditis following vaccination with BNT162b2 in a healthy male: https://www.sciencedirect.com/science/article/pii/S0735675721005362
  20. Acute myocarditis after Comirnaty (Pfizer) vaccination in a healthy male with previous SARS-CoV-2 infection: https://www.sciencedirect.com/science/article/pii/S1930043321005549
  21. Acute myocarditis after vaccination with SARS-CoV-2 mRNA-1273 mRNA: https://www.sciencedirect.com/science/article/pii/S2589790X21001931
  22. Acute myocarditis after SARS-CoV-2 vaccination in a 24-year-old man: https://www.sciencedirect.com/science/article/pii/S0870255121003243
  23. A series of patients with myocarditis after vaccination against SARS-CoV-2 with mRNA-1279 and BNT162b2: https://www.sciencedirect.com/science/article/pii/S1936878X21004861
  24. COVID-19 mRNA vaccination and myocarditis: https://pubmed.ncbi.nlm.nih.gov/34268277/
  25. COVID-19 vaccine and myocarditis: https://pubmed.ncbi.nlm.nih.gov/34399967/
  26. Epidemiology and clinical features of myocarditis/pericarditis before the introduction of COVID-19 mRNA vaccine in Korean children: a multicenter study https://search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resourc e/en/covidwho-1360706.
  27. COVID-19 vaccines and myocarditis: https://pubmed.ncbi.nlm.nih.gov/34246566/
  28. Myocarditis and other cardiovascular complications of COVID-19 mRNA-based COVID-19 vaccines https://www.cureus.com/articles/61030-myocarditis-and-other-cardiovascular-complications-of-the-mrna-based-covid-19-vaccines
  29. Myocarditis and other cardiovascular complications of COVID-19 mRNA-based COVID-19 vaccines https://www.cureus.com/articles/61030-myocarditis-and-other-cardiovascular-complications-of-the-mrna-based-covid-19-vaccines
  30. Myocarditis, pericarditis, and cardiomyopathy after COVID-19 vaccination: https://pubmed.ncbi.nlm.nih.gov/34340927/
  31. Myocarditis with covid-19 mRNA vaccines: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.056135
  32. Association of myocarditis with COVID-19 mRNA vaccine in children: https://media.jamanetwork.com/news-item/association-of-myocarditis-with-mrna-co vid-19-vaccine-in-children/
  33. Association of myocarditis with COVID-19 messenger RNA vaccine BNT162b2 in a case series of children: https://jamanetwork.com/journals/jamacardiology/fullarticle/2783052
  34. Myocarditis after immunization with COVID-19 mRNA vaccines in members of the U.S. military: https://jamanetwork.com/journals/jamacardiology/fullarticle/2781601%5C
  35. Myocarditis occurring after immunization with COVID-19 mRNA-based COVID-19 vaccines: https://jamanetwork.com/journals/jamacardiology/fullarticle/2781600
  36. Myocarditis following immunization with Covid-19 mRNA: https://www.nejm.org/doi/full/10.1056/NEJMc2109975
  37. Patients with acute myocarditis after vaccination withCOVID-19 mRNA: https://jamanetwork.com/journals/jamacardiology/fullarticle/2781602
  38. Myocarditis associated with vaccination with COVID-19 mRNA: https://pubs.rsna.org/doi/10.1148/radiol.2021211430
  39. Symptomatic Acute Myocarditis in 7 Adolescents after Pfizer-BioNTech COVID-19 Vaccination: https://pediatrics.aappublications.org/content/148/3/e2021052478
  40. Cardiovascular magnetic resonance imaging findings in young adult patients with acute myocarditis after COVID-19 mRNA vaccination: a case series: https://jcmr-online.biomedcentral.com/articles/10.1186/s12968-021-00795-4
  41. Clinical Guidance for Young People with Myocarditis and Pericarditis after Vaccination with COVID-19 mRNA: https://www.cps.ca/en/documents/position/clinical-guidance-for-youth-with-myocarditis-and-pericarditis
  42. Cardiac imaging of acute myocarditis after vaccination with COVID-19 mRNA: https://pubmed.ncbi.nlm.nih.gov/34402228/
  43. Case report: acute myocarditis after second dose of mRNA-1273 SARS-CoV-2 mRNA vaccine: https://academic.oup.com/ehjcr/article/5/8/ytab319/6339567
  44. Myocarditis / pericarditis associated with COVID-19 vaccine: https://science.gc.ca/eic/site/063.nsf/eng/h_98291.html
  45. The new COVID-19 mRNA vaccine platform and myocarditis: clues to the possible underlying mechanism: https://pubmed.ncbi.nlm.nih.gov/34312010/
  46. Myocarditis associated with COVID-19 vaccination: echocardiographic, cardiac tomography, and magnetic resonance imaging findings: https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.121.013236
  47. In-depth evaluation of a case of presumed myocarditis after the second dose of COVID-19 mRNA vaccine: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.056038
  48. Occurrence of acute infarct-like myocarditis after COVID-19 vaccination: just an accidental coincidence or rather a vaccination-associated autoimmune myocarditis?: https://pubmed.ncbi.nlm.nih.gov/34333695/

This list is not meant to be all inclusive of all peer-reviewed potential harms from mRNA vaccines. To access any of the 1,000 Vaccine Harms published in Medical journals Click The Link Below:

https://www.informedchoiceaustralia.com/post/1000-peer-reviewed-studies-questioning-covid-19-vaccine-safety

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Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Authors.Maximilian Ackermann, M.D., Stijn E. Verleden, Ph.D., Mark Kuehnel, Ph.D., Axel Haverich, M.D., Tobias Welte, M.D., Florian Laenger, M.D., Arno Vanstapel, Ph.D., Christopher Werlein, M.D., Helge Stark, Ph.D., Alexandar Tzankov, M.D., William W. Li, M.D., Vincent W. Li, M.D., et al.

July 9, 2020 N Engl J Med 2020; 383:120-128 DOI: 10.1056/NEJMoa2015432

Abstract

BACKGROUND

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.

METHODS

We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.

RESULTS

In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).

CONCLUSIONS

In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans is associated with a broad spectrum of clinical respiratory syndromes, ranging from mild upper airway symptoms to progressive life-threatening viral pneumonia.1,2 Clinically, patients with severe coronavirus disease 2019 (Covid-19) have labored breathing and progressive hypoxemia and often receive mechanical ventilatory support. Radiographically, peripheral lung ground-glass opacities on computed tomographic (CT) imaging of the chest fulfill the Berlin criteria for acute respiratory distress syndrome (ARDS).3,4 Histologically, the hallmark of the early phase of ARDS is diffuse alveolar damage with edema, hemorrhage, and intraalveolar fibrin deposition, as described by Katzenstein et al.5 Diffuse alveolar damage is a nonspecific finding, since it may have noninfectious or infectious causes, including Middle East respiratory syndrome coronavirus (MERS-CoV),6 SARS-CoV,7 SARS-CoV-2,8-10 and influenza viruses.11

Among the distinctive features of Covid-19 are the vascular changes associated with the disease. With respect to diffuse alveolar damage in SARS-CoV7 and SARS-CoV-2 infection,8,12 the formation of fibrin thrombi has been observed anecdotally but not studied systematically. Clinically, many patients have elevated d-dimer levels, as well as cutaneous changes in their extremities suggesting thrombotic microangiopathy.13 Diffuse intravascular coagulation and large-vessel thrombosis have been linked to multisystem organ failure.14-16 Peripheral pulmonary vascular changes are less well characterized; however, vasculopathy in the gas-exchange networks, depending on its effect on the matching of ventilation and perfusion that results, could potentially contribute to hypoxemia and the effects of posture (e.g., prone positioning) on oxygenation.17

Despite previous experience with SARS-CoV18 and early experience with SARS-CoV-2, the morphologic and molecular changes associated with these infections in the peripheral lung are not well documented. Here, we examine the morphologic and molecular features of lungs obtained during autopsy from patients who died from Covid-19, as compared with those of lungs from patients who died from influenza and age-matched, uninfected control lungs.

Methods

PATIENT SELECTION AND WORKFLOW

We analyzed pulmonary autopsy specimens from seven patients who died from respiratory failure caused by SARS-CoV-2 infection and compared them with lungs from seven patients who died from pneumonia caused by influenza A virus subtype H1N1 (A[H1N1]) — a strain associated with the 1918 and 2009 influenza pandemics. The lungs from patients with influenza were archived tissue from the 2009 pandemic and were chosen for the best possible match with respect to age, sex, and disease severity from among the autopsies performed at the Hannover Medical School. Ten lungs that had been donated but not used for transplantation served as uninfected control specimens. The Covid-19 group consisted of lungs from two female and five male patients with mean (±SD) ages of 68±9.2 years and 80±11.5 years, respectively (clinical data are provided in Table S1A in the Supplementary Appendix, available with the full text of this article at NEJM.org). The influenza group consisted of lungs from two female and five male patients with mean ages of 62.5±4.9 years and 55.4±10.9 years, respectively. Five of the uninfected lungs were from female donors (mean age, 68.2±6.9 years), and five were from male donors (mean age, 79.2±3.3 years) (clinical data are provided in Table S1B). The study was approved by and conducted according to requirements of the ethics committees at the Hannover Medical School and the University of Leuven. There was no commercial support for this study.

All lungs were comprehensively analyzed with the use of microCT, histopathological, and multiplexed immunohistochemical analysis, transmission and scanning electron microscopy, corrosion casting, and direct multiplexed gene-expression analysis, as described in detail in the Methods section of the Supplementary Appendix.

STATISTICAL ANALYSIS

All comparisons of numeric variables (including those in the gene-expression analysis) were conducted with Student’s t-test familywise error rates due to multiplicity set at 0.05 with the use of the Benjamini–Hochberg method of controlling false discovery rates. Original P values are reported only for the tests that met the criteria for false discovery rates. All confidence intervals have been calculated on the basis of the t-distribution, as well. Additional details are provided in the Methods section of the Supplementary Appendix.

Results

GROSS EXAMINATION

The mean (±SE) weight of the lungs from patients with proven influenza pneumonia was significantly higher than that from patients with proven Covid-19 (2404±560 g vs. 1681±49 g; P=0.04). The mean weight of the uninfected control lungs (1045±91 g) was significantly lower than those in the influenza group (P=0.003) and the Covid-19 group (P<0.001).

ANGIOCENTRIC INFLAMMATION

Figure 1. Lymphocytic Inflammation in a Lung from a Patient Who Died from Covid-19.

All lung specimens from the Covid-19 group had diffuse alveolar damage with necrosis of alveolar lining cells, pneumocyte type 2 hyperplasia, and linear intraalveolar fibrin deposition (Figure 1). In four of seven cases, the changes were focal, with only mild interstitial edema. The remaining three cases had homogeneous fibrin deposits and marked interstitial edema with early intraalveolar organization. The specimens in the influenza group had florid diffuse alveolar damage with massive interstitial edema and extensive fibrin deposition in all cases. In addition, three specimens in the influenza group had focal organizing and resorptive inflammation (Fig. S2). These changes were reflected in the much higher weight of the lungs from patients with influenza.

Immunohistochemical analysis of angiotensin-converting enzyme 2 (ACE2) expression, measured as mean (±SD) relative counts of ACE2-positive cells per field of view, in uninfected control lungs showed scarce expression of ACE2 in alveolar epithelial cells (0.053±0.03) and capillary endothelial cells (0.066±0.03). In lungs from patients with Covid-19 and lungs from patients with influenza, the relative counts of ACE2-positive cells per field of view were 0.25±0.14 and 0.35±0.15, respectively, for alveolar epithelial cells and 0.49±0.28 and 0.55±0.11, respectively, for endothelial cells. Furthermore, ACE2-positive lymphocytes were not seen in perivascular tissue or in the alveoli of the control lungs but were present in the lungs in the Covid-19 group and the influenza group (relative counts of 0.22±0.18 and 0.15±0.09, respectively). (Details of counting are provided in Table S2.)

In the lungs from patients with Covid-19 and patients with influenza, similar mean (±SD) numbers of CD3-positive T cells were found within a 200-μm radius of precapillary and postcapillary vessel walls in 20 fields of examination per patient (26.2±13.1 for Covid-19 and 14.8±10.8 for influenza). With the same field size used for examination, CD4-positive T cells were more numerous in lungs from patients with Covid-19 than in lungs from patients with influenza (13.6±6.0 vs. 5.8±2.5, P=0.04), whereas CD8-positive T cells were less numerous (5.3±4.3 vs. 11.6±4.9, P=0.008). Neutrophils (CD15 positive) were significantly less numerous adjacent to the alveolar epithelial lining in the Covid-19 group than in the influenza group (0.4±0.5 vs. 4.8±5.2, P=0.002).

A multiplexed analysis of inflammation-related gene expression examining 249 genes from the nCounter Inflammation Panel (NanoString Technologies) revealed similarities and differences between the specimens in the Covid-19 group and those in the influenza group. A total of 79 inflammation-related genes were differentially regulated only in specimens from patients with Covid-19, whereas 2 genes were differentially regulated only in specimens from patients with influenza; a shared expression pattern was found for 7 genes (Fig. S1).

THROMBOSIS AND MICROANGIOPATHY

Figure 2. Microthrombi in the Interalveolar Septa of a Lung from a Patient Who Died from Covid-19.

The pulmonary vasculature of the lungs in the Covid-19 group and the influenza group was analyzed with hematoxylin–eosin, trichrome, and immunohistochemical staining (as described in the Methods section of the Supplementary Appendix). Analysis of precapillary vessels showed that in four of the seven lungs from patients with Covid-19 and four of the seven lungs from the patients with influenza, thrombi were consistently present in pulmonary arteries with a diameter of 1 mm to 2 mm, without complete luminal obstruction (Figs. S3 and S5). Fibrin thrombi of the alveolar capillaries could be seen in all the lungs from both groups of patients (Figure 2). Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (mean [±SD] number of distinct thrombi per square centimeter of vascular lumen area, 159±73 and 16±16, respectively; P=0.002). Intravascular thrombi in postcapillary venules of less than 1 mm diameter were seen in lower numbers in the lungs from patients with Covid-19 than in those from patients with influenza (12±14 vs. 35±16, P=0.02). Two lungs in the Covid-19 group had involvement of all segments of the vasculature, as compared with four of the lungs in the influenza group; in three of the lungs in the Covid-19 group and three of the lungs in the influenza group, combined capillary and venous thrombi were found without arterial thrombi.

The histologic findings were supported by three-dimensional microCT of the pulmonary specimens: the lungs from patients with Covid-19 and from patients with influenza showed nearly total occlusions of precapillary and postcapillary vessels.

ANGIOGENESIS

Figure 3. Microvascular Alterations in Lungs from Patients Who Died from Covid-19

.

We examined the microvascular architecture of the lungs from patients with Covid-19, lungs from patients with influenza, and uninfected control lungs with the use of scanning electron microscopy and microvascular corrosion casting. The lungs in the Covid-19 group had a distorted vascularity with structurally deformed capillaries (Figure 3). Elongated capillaries in the lungs from patients with Covid-19 showed sudden changes in caliber and the presence of intussusceptive pillars within the capillaries (Figure 3C). Transmission electron microscopy of the Covid-19 endothelium showed ultrastructural damage to the endothelium, as well as the presence of intracellular SARS-CoV-2 (Figure 3D). The virus could also be identified in the extracellular space.

Figure 4.Numeric Density of Features of Intussusceptive and Sprouting Angiogenesis in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).

In the lungs from patients with Covid-19, the density of intussusceptive angiogenic features (mean [±SE], 60.7±11.8 features per field) was significantly higher than that in lungs from patients with influenza (22.5±6.9) or in uninfected control lungs (2.1±0.6) (P<0.001 for both comparisons) (Figure 4A). The density of features of conventional sprouting angiogenesis was also higher in the Covid-19 group than in the influenza group (Figure 4B). When the pulmonary angiogenic feature count was plotted as a function of the length of hospital stay, the degree of intussusceptive angiogenesis was found to increase significantly with increasing duration of hospitalization (P<0.001) (Figure 4C). In contrast, the lungs from patients with influenza had less intussusceptive angiogenesis and no increase over time (Figure 4C). A similar pattern was seen for sprouting angiogenesis (Figure 4D).Figure 5.elative Expression Analysis of Angiogenesis-Associated Genes in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).

A multiplexed analysis of angiogenesis-related gene expression examining 323 genes from the nCounter PanCancer Progression Panel (NanoString Technologies) revealed differences between the specimens from patients with Covid-19 and those from patients with influenza. A total of 69 angiogenesis-related genes were differentially regulated only in the Covid-19 group, as compared with 26 genes differentially regulated only in the influenza group; 45 genes had shared changes in expression (Figure 5).

Discussion

In this study, we examined the morphologic and molecular features of seven lungs obtained during autopsy from patients who died from SARS-CoV-2 infection. The lungs from these patients were compared with those obtained during autopsy from patients who had died from ARDS secondary to influenza A(H1N1) infection and from uninfected controls. The lungs from the patients with Covid-19 and the patients with influenza shared a common morphologic pattern of diffuse alveolar damage and infiltrating perivascular lymphocytes. There were three distinctive angiocentric features of Covid-19. The first feature was severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes. Second, the lungs from patients with Covid-19 had widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries.12,19 Third, the lungs from patients with Covid-19 had significant new vessel growth through a mechanism of intussusceptive angiogenesis. Although our sample was small, the vascular features we identified are consistent with the presence of distinctive pulmonary vascular pathobiologic features in some cases of Covid-19.

Our finding of enhanced intussusceptive angiogenesis in the lungs from patients with Covid-19 as compared with the lungs from patients with influenza was unexpected. New vessel growth can occur by conventional sprouting or intussusceptive (nonsprouting) angiogenesis. The characteristic feature of intussusceptive angiogenesis is the presence of a pillar or post spanning the lumen of the vessel.20 Typically referred to as an intussusceptive pillar, this endothelial-lined intravascular structure is not seen by light microscopy but is readily identifiable by corrosion casting and scanning electron microscopy.21 Although tissue hypoxia was probably a common feature in the lungs from both these groups of patients, we speculate that the greater degree of endothelialitis and thrombosis in the lungs from patients with Covid-19 may contribute to the relative frequency of sprouting and intussusceptive angiogenesis observed in these patients. The relationship of these findings to the clinical course of Covid-19 requires further research to elucidate.

A major limitation of our study is that the sample was small; we studied only 7 patients among the more than 320,000 people who have died from Covid-19, and the autopsy data also represent static information. On the basis of the available data, we cannot reconstruct the timing of death in the context of an evolving disease process. Moreover, there could be other factors that account for the differences we observed between patients with Covid-19 and those with influenza. For example, none of the patients in our study who died from Covid-19 had been treated with standard mechanical ventilation, whereas five of the seven patients who died from influenza had received pressure-controlled ventilation. Similarly, it is possible that differences in detectable intussusceptive angiogenesis could be due to the different time courses of Covid-19 and influenza. These and other unknown factors must be considered when evaluating our data.22 Nonetheless, our analysis suggests that this possibility is unlikely, particularly since the degree of intussusceptive angiogenesis in the patients with Covid-19 increased significantly with increasing length of hospitalization, whereas in the patients with influenza it remained stable at a significantly lower level. Moreover, we have shown intussusceptive angiogenesis to be the predominant angiogenic mechanism even in late stages of chronic lung injury.21

ACE2 is an integral membrane protein that appears to be the host-cell receptor for SARS-CoV-2.23,24 Our data showed significantly greater numbers of ACE2-positive cells in the lungs from patients with Covid-19 and from patients with influenza than in those from uninfected controls. We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of Covid-19. Endothelial cells in the specimens from patients with Covid-19 showed disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane. The presence of SARS-CoV-2 virus within the endothelial cells, a finding consistent with other studies,25 suggests that direct viral effects as well as perivascular inflammation may contribute to the endothelial injury.

We report the presence of pulmonary intussusceptive angiogenesis and other pulmonary vascular features in the lungs of seven patients who died from Covid-19. Additional work is needed to relate our findings to the clinical course in these patients. To aid others in their research, our full data set is available on the Vivli platform (https://vivli.org/. opens in new tab) and can be requested with the use of the following digital object identifier: https://doi.org/10.25934/00005576. opens in new tab.

Supported by grants (HL94567 and HL134229, to Drs. Ackermann and Mentzer) from the National Institutes of Health, a grant from the Botnar Research Centre for Child Health (to Dr. Tzankov), a European Research Council Consolidator Grant (XHale) (771883, to Dr. Jonigk), and a grant (KFO311, to Dr. Jonigk) from Deutsche Forschungsgemeinschaft (Project Z2).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on May 21, 2020, at NEJM.org.

We thank Kerstin Bahr, Jan Hinrich Braesen, Peter Braubach, Emily Brouwer, Annette Mueller Brechlin, Regina Engelhardt, Jasmin Haslbauer, Anne Hoefer, Nicole Kroenke, Thomas Menter, Mahtab Taleb Naghsh, Christina Petzold, Vincent Schmidt, and Pauline Tittmann for technical support; Peter Boor of the German Covid-19 registry; and Lynnette Sholl, Hans Kreipe, Hans Michael Kvasnicka, and Jean Connors for helpful comments. Dr. Jonigk thanks Anita Swiatlak for her continued support.

Author Affiliations

From the Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten–Herdecke, Wuppertal (M.A.), the Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz (M.A.), the Institute of Pathology (M.K., F.L., C.W., H.S., D.J.), the Department of Cardiothoracic, Transplantation, and Vascular Surgery (A.H.), and the Clinic of Pneumology (T.W.), Hannover Medical School, and the German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) (M.K., A.H., T.W., F.L., C.W., H.S., D.J.), Hannover — all in Germany; the Laboratory of Respiratory Diseases, BREATH, Department of Chronic Diseases, Metabolism, and Aging, KU Leuven, Leuven, Belgium (S.E.V., A.V.); the Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland (A.T.); and the Angiogenesis Foundation, Cambridge (W.W.L., V.W.L.), and the Laboratory of Adaptive and Regenerative Biology and the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston (S.J.M.) — all in Massachusetts.

Address reprint requests to Dr. Mentzer at the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, or at smentzer@bwh.harvard.edu.

Supplementary Material

Supplementary AppendixPDF1523KB
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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Authors: Juan Pablo Robles 1Magdalena Zamora 1Elva Adan-CastroLourdes Siqueiros-MarquezGonzalo Martinez de la EscaleraCarmen Clapp

Open AccessDOI:https://doi.org/10.1016/j.jbc.2022.101695

Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNF⍺, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

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https://www.jbc.org/action/showPdf?pii=S0021-9258%2822%2900135-1

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

Authors: Eleonora Calabretta, 1 , 12 Jose M. Moraleda, 2 Massimo Iacobelli, 3 Ruben Jara, 4 Israel Vlodavsky, 5 Peter O’Gorman, 6 Antonio Pagliuca, 7 Clifton Mo, 8 Rebecca M. Baron, 9 Alessio Aghemo, 10 , 12 Robert Soiffer, 8 Jawed Fareed, 11 Carmelo Carlo‐Stella, 1 , 12 , * and Paul Richardson 8 , *

Br J Haematol. 2021 Apr; 193(1): 43–51.Published online 2021 Feb 4.  doi:  10.1111/bjh.17240 PMCID:  PMC8014053PMID: 33538335

Introduction

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development.

Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed.

In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).Go to:

Endothelial cells are a preferential target of COVID‐19 resulting in widespread endotheliitis

Emerging evidence suggests that endothelial damage and subsequent morphological and functional changes in the endothelium play important roles in COVID‐19‐induced hyperinflammation. The virus, which binds to the angiotensin‐converting enzyme 2 (ACE2) receptor, 9 displays a profound tropism for human lung and small intestine epithelium, as well as the vascular endothelium. 10 In an important case series from Varga et al., 11 postmortem histology from three patients affected by late‐stage COVID‐19, revealed viral inclusions in endothelial apoptotic cells and microvascular lymphocytic endotheliitis, with infiltration of inflammatory cells around the vessels and endothelial cells (ECs), as well as evidence of endothelial apoptotic cell death in the lung, kidney, small bowel and heart. Additionally, autopsy findings of 27 patients in another series confirmed the detection of the SARS‐CoV‐2 in multiple organs, including the respiratory tract, pharynx, heart, liver, brain, and kidneys. 12 Immunofluorescence of kidney specimens from six of the 27 patients showed the presence of SARS‐CoV‐2 protein in all renal compartments, and in three of the patients preferentially in the endothelium of the glomerulus. Similar microscopic findings were also noted in lung specimens from seven patients with COVID‐19, which displayed small vessel endotheliitis, microvascular thrombosis and angiogenesis, along with the presence of SARS‐CoV‐2 in pulmonary ECs, an observation strongly supporting the vascular tropism of the virus. 13 Lastly, Stahl et al. 14 have identified in the plasma and serum of 19 critically ill patients with COVID‐19 evidence of disruption of the endothelial glycocalyx, reflected by increased levels of the Tie‐2 receptor and syndecan‐1 (SDC‐1), a heparan sulphate (HS) proteoglycan. This particular observation is of interest as the endothelial glycocalyx covers the luminal surface of ECs, and its integrity is vital for the maintenance of vascular homeostasis.

Such findings suggest that virus‐mediated apoptosis may promote endothelial barrier disruption with interstitial oedema and increased recruitment of circulating activated immune cells, thus causing widespread endothelial dysfunction, as well as activation of platelets and the coagulation cascade leading to venous and arterial thrombosis. 15 Altered pro‐inflammatory and pro‐thrombotic status is confirmed by the presence of elevated inflammation‐related indices (e.g. C‐reactive protein and serum ferritin), humoral biomarkers [interleukin (IL)‐2, IL‐6, IL‐7, granulocyte‐colony stimulating factor (G‐CSF), tumour necrosis factor‐alpha (TNF‐α)], and indicators of an increased pro‐coagulant‐fibrinolytic state [e.g. von Willebrand factor (VWF), D‐dimer, fibrinogen]. Further, factor VIII (FVIII), a potent and key factor in the coagulation process, is greatly increased in ICU patients with COVID‐19. 16

In this setting, it has been proposed that the systemic hyperinflammation observed in severe COVID‐19 is comparable to a cytokine release syndrome (CRS), or cytokine storm. IL‐6 has a central role in the generation of the cytokine storm, and is commonly elevated in the serum of severely ill patients with COVID‐19. 17 High levels of IL‐6 activate ECs, thus resulting in vascular leakage, further cytokine secretion and activation of the complement and coagulation cascades. 18 Interestingly, a population of IL‐6 producing monocytes was found to be expanded in the peripheral blood of ICU patients 19 and an aberrant macrophage response exhibiting increased levels of pro‐inflammatory cytokines has been detected in bronchoalveolar fluid, especially in severely ill patients. 20 Although the exact driver of monocyte activation remains unclear, such cells are attracted to the endothelium, where the release of highly noxious molecules, such as reactive oxygen species (ROS), contributes to endothelial dysfunction and promotes hyperinflammation. 21 Further, activated monocytes enhance tissue factor expression and form aggregates with platelets through P‐selectin interaction and hence augmenting the pro‐coagulant response. 22 Indeed, significantly increased levels of VWF and FVIII and thrombomodulin, 16 aberrant coagulation, thrombosis and microangiopathy are very common in critically ill patients with COVID‐19, resulting in a disseminated intravascular coagulation (DIC)‐like syndrome characterised by massive fibrin formation and organ dysfunction. 23 Likewise, adaptive immunity actively participates in the establishment of the inflammatory response; specifically, activated and proliferating CD8+ T cells are prevalent in mild COVID‐19, whereas critically ill patients display higher levels of hyperactive IL‐6‐producing CD4+ T cells, which may contribute to disease severity, even after viral clearance. 17 Interestingly, T cells show phenotypical signs of an exhausted, functionally unresponsive state, thus allowing viral escape from immune surveillance. 22 Once initiated, the endotheliitis and resultant cytokine storm become self‐sustaining, leading to widespread organ damage. Some patients may also display features of haemophagocytic lymphohistiocytosis, such as cytopenias, hyperferritinaemia and rapid onset of MOF.

Overall, once hyperinflammation and CRS develop, rates of mortality significantly increase. 24 25 26 As direct viral activation of the vascular endothelium has an important role in initiating and maintaining the hyperinflammatory response, attempting to blunt such a response with endothelial‐protective agents is a very rational strategy. Controlled clinical trials focussing on the use of anti‐cytokine antibodies, including tocilizumab (IL‐6 inhibitor), have failed to show significant activity in this stage of the disease. 27 However, increasing evidence suggests that the altered homeostasis of the endothelium may be a key initiating event in the pathogenesis of the disease, therefore representing a potentially more promising target. 28Go to:

Endothelial cell‐related disorders in haematology: post‐bone marrow transplantation syndromes and sickle cell disease and the overlap with the pathobiology of COVID‐19

Clinically and histopathologically, COVID‐19‐associated endotheliitis resembles a spectrum of post‐bone marrow and stem cell transplantation (BMT) syndromes characterised by disruption of endothelial homeostasis and consequently dysregulation of coagulation, vascular tone, endothelial permeability and vascular inflammation. 29 These disorders include hepatic veno‐occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), idiopathic pneumonia syndrome (IPS), transplant‐associated thrombotic microangiopathy and graft‐versus‐host disease (GvHD).

Hepatic VOD/SOS develops as a result of endothelial damage to hepatic sinusoids and subsequent hepatocyte necrosis 30 . Damage to the ECs leads to a hypercoagulable state, production of inflammatory mediators, and the upregulation as well as release of heparanase. 31 Heparanase degrades the heparan sulphate scaffold of the subendothelial basement membrane, consequently allowing the extravasation of blood‐borne cells, including activated T lymphocytes, neutrophils and macrophages. 32 This cascade of events leads to postsinusoidal hypertension, hyperinflammation and ultimately MOF. Severe VOD/SOS associated with MOF without effective therapy is fatal in >80% of cases. 33 Interestingly, the histopathological examination of lung lesions in VOD/SOS shows early alveolar epithelial and lung endothelial injury, resulting in accumulation of protein‐ and fibrin‐rich inflammatory oedematous fluid in the alveolar space and progression to interstitial fibrosis, 34 35 as is also seen in fatal COVID‐19 cases.

Similarly, IPS, a widespread alveolar injury in the absence of identifiable infectious or non‐infectious causes, is characterised by histological evidence of EC injury with fibrin accumulation, luminal thrombosis and fibrotic processes. Adhesion molecules, such as intercellular adhesion molecule 1 (ICAM‐1) and/or vascular cell adhesion molecule 1 (VCAM‐1), are commonly upregulated, thus reflecting profound endothelial activation. 36 It has been suggested that TNF‐α directly causes endothelial injury, and increased levels of angiopoietin‐2 (Ang‐2), have been recently reported in cases of acute exacerbations of IPS, 37 similar to that seen in severely ill patients with COVID‐19. 38

Likewise, multifactorial endothelial damage has been also implicated in the development of transplant‐associated thrombotic microangiopathy, where micro‐vessel intimal swelling and necrosis lead to the formation of luminal microthrombi and subsequent microangiopathic haemolytic anaemia. Plasma levels of markers of EC injury and inflammation, such as thrombomodulin, plasminogen activator inhibitor‐1 (PAI‐1), ICAM‐1, VCAM‐1, IL‐1, TNF‐α, interferon gamma and IL‐8 are commonly elevated. 39 40 Endothelial dysfunction predominantly affects the kidneys and the brain, but may become widespread and progress to MOF, which in turn is associated with high mortality.

Lastly, acute GvHD (aGvHD) develops as a consequence of the activation of the immune system. Antigen‐presenting cells become activated by endothelial and tissue damage derived from direct toxicity of the conditioning regimen, thus initiating an alloreactive T‐cell response directed against recipient tissues. 41 As a result, SDC‐1 is commonly elevated in the serum of patients with GvHD and correlates with disease severity. 42 In addition to cell‐mediated cytotoxic damage, the cytokine storm generated in response to T‐cell activation and proliferation causes targeted organ damage involving mainly the skin, liver and gut. 43 It has recently been suggested that endothelial vulnerability and pro‐thrombotic shift precedes clinically evident aGvHD and that angiogenesis driven by early endothelial activation is an initiating event. 44 Indeed, increased plasma levels of VWF, 45 Ang‐2 46 and TNF receptor 1 47 have been detected in patients prior to development of aGvHD, correlating with response to therapy.

Similarly, markers of endothelial dysfunction and inflammatory activation have been detected also in the serum of patients with sickle cell disease (SCD), especially during vaso‐occlusive episodes. SCD is characterised by a chronic course of relapsing‐remitting episodes of ischaemia and then reperfusion. The polymerisation of defective haemoglobin S upon deoxygenation initiates many pathological processes, such as complement activation, generation of ROS and pro‐thrombotic molecules, secretion of numerous pro‐inflammatory cytokines and chemokines and ultimately leucocyte recruitment. 48 Oxidative stress and endothelial dysregulation plays a key role in vaso‐occlusion; ECs activated by substances released by the haemolytic process and by red blood cell adhesion initiate production and release of soluble mediators such as IL‐1β, IL‐8, IL‐6, IL‐1α and PAI‐1, 49 50 and increase the expression of adhesion molecules such as VCAM‐1, ICAM‐1, E‐selectin and P‐selectin, 51 52 reflecting a pro‐inflammatory and pro‐thrombotic shift. Vaso‐occlusive phenomena commonly affect the lung vasculature, provoking acute chest syndrome (ACS), a spectrum of diseases ranging from mild pneumonia to ARDS and MOF, which is the leading cause of morbidity and mortality in SCD. 53 Lung specimens from ACS cases showed micro‐thrombotic occlusion, endothelial VWF deposition and arterial vessel re‐modelling with initial fibrotic processes, 54 fascinatingly all comparable to the histopathological findings in COVID‐19. 55 Importantly, heme‐mediated endothelial damage to alveolar cells is regulated by the p38 mitogen‐activated protein kinase (MAPK) pathway, which plays a crucial role in the biosynthesis of pro‐inflammatory cytokines and collagen production. 56 This key pathway is also upregulated in COVID‐19 as a result of decreased ACE2 tissue functionality consequent to viral binding, and may consequently promote endotheliitis, hypercoagulation and end‐stage fibrosis. 57 58

In summary, post‐BMT syndromes, vaso‐occlusive organ dysfunction in SCD and COVID‐19‐associated endotheliitis share common pathological mechanisms including: i) dysregulation of the homeostasis of the endothelial milieu toward a pro‐inflammatory and pro‐thrombotic phenotype with thrombotic microangiopathy; ii) hyperproduction of inflammatory cytokines such as IL‐6, IL‐8 and TNF‐α; 59 60 61 62 and iii) small vessel endotheliitis and endothelial barrier dysfunction, leading to oedema of the microvascular bed, protein and fibrin accumulation and subsequent fibrotic shift. 34 36 All these conditions if untreated irremediably lead to MOF and display similar microscopic and macroscopic features in target organs upon pathological examination. At the molecular level, the p38 MAPK pathway may also be critical in promoting vasoconstrictive and inflammatory phenomena; its activation is described in SCD, COVID‐19 and also as a result of conditioning regimen‐induced endothelial damage in BMT. 63 Together, these findings support the notion that the pleiotropic character of the endothelium as a key regulator of the internal homeostasis, vascular tone, blood coagulation and the inflammatory process and therefore of so called ‘immune‐thrombosis’ events, make it an intriguing therapeutic target for post‐BMT disorders, SCD, and COVID‐19.Go to:

Agents targeting EC‐related disorders

Heparins

Classically, heparins have been the most widely used drugs for the treatment and prevention of endothelial cell disorders. Several animal studies and clinical trials have suggested that, in addition to its well‐known anticoagulant effects, heparin also possesses anti‐inflammatory properties, mainly mediated by inhibition of IL‐6 release and its activity, 64 a phenomena also demonstrated in patients with COVID‐19 treated with low‐molecular‐weight heparin. 65 Further, heparin is structurally related to HS, 66 a negatively charged glycosaminoglycan as described earlier, which serves as binding sites for growth factors, cytokines, selectins, extracellular‐matrix molecules, and a large number of human viruses, 67 including the SARS‐CoV‐2 virus. 68 69 Indeed, Clausen et al. 70 have recently demonstrated that the SARS‐CoV‐2 spike protein must bind both the ACE2 receptor and HS to enter human cells. The structural analogies between heparin and HS may result in competitive inhibition, where heparin and related compounds compete with the cell surface HS for viral binding to target cells, 68 69 thus potentially blocking or at least attenuating viral entry. The beneficial effects of heparin‐based therapies are also linked to their inhibition of circulating heparanase enzymatic activity. 32 Heparanase, an endo‐β‐glucuronidase, physiologically cleaves HS chains located in extracellular matrices and on cell surfaces. 32 It is often overexpressed during viral infections and act as a regulator of virus release after replication has occurred, promoting its dissemination. 71 72 73 74 Additionally, it may be upregulated by pro‐inflammatory molecules such as IL‐1 and TNF‐α. Once activated, heparanase stimulates the expression and release of pro‐inflammatory cytokines, including TNF‐α, IL‐1 and IL‐6. 75 The enzyme has been implicated in cancer progression, inflammation, 76 VOD/SOS development 77 and other vascular pathologies. 71

Currently, numerous clinical trials are underway to investigate the therapeutic potential of intravenous and subcutaneous heparin, as well as the appropriate dose regimen in COVID‐19. Further, nebulised heparin delivered directly to the airways may be effective in preventing infection and mitigating lung disease (clinicaltrials.gov; NCT04545541NCT04511923). Notwithstanding their anticoagulant, anti‐inflammatory and anti‐viral properties, the use of heparins is associated with a substantially increased risk of systemic bleeding, and other challenging ‘off‐target’ effects, making its use potentially part of the standard of care, but not without qualification, as well as highlighting the need for combination approaches.

Defibrotide

The use of defibrotide (DF), which has both comparable but distinct properties from heparins and negligible haemorrhagic risk 78 may therefore be warranted, especially given the established propensity for the development of DIC later in the COVID‐19 clinical course. DF is a naturally derived, complex mixture of poly‐deoxyribonuleotides extracted originally from bovine lung and now exclusively from porcine gut mucosa. 79 80 Since its original isolation >30 years ago, DF has demonstrated locally acting pro‐fibrinolytic, 81 82 83 84 anti‐thrombotic, 85 86 anti‐ischaemic and anti‐inflammatory activities, which exert protective effects on small vessel endothelia. It is currently approved for the treatment of paediatric and adult hepatic VOD/SOS with MOF. 87 88 89 In this setting, DF has demonstrated efficacy and safety in critically ill patients with MOF, as well as a significant reduction in PAI‐1 and other markers of endothelial stress in patients with VOD/SOS and MOF successfully treated with DF. 89 90 91 Furthermore, in a pivotal Phase III trial, DF prophylaxis reduced the incidence and severity of VOD/SOS in high‐risk children undergoing BMT. 92 In a more recent study, Palomo et al. 93 demonstrated that DF directly interacts with the cell membrane and becomes internalised by ECs, thus providing physical evidence of its endothelial‐protective properties. In particular, DF appears to decrease levels of pro‐inflammatory proteins, such as TNF‐α, 94 IL‐6, vascular endothelial growth factor (VEGF) 95 and to downregulate major histocompatibility complex (MHC) Class I and Class II molecules, 96 97 therefore attenuating both the inflammatory and immune responses. Furthermore, it appears to decrease interaction between leucocytes and ECs by downregulating P‐selectin, 98 ICAM‐1 95 and VCAM‐1. 99 Lastly, DF displays potent adenosine agonism. 100 Such activity may be clinically relevant, not least based on substantial improvement observed in an animal model of acute lung injury upon treatment with adenosine receptor agonists. 101

Based on such properties, the use of DF can be reasonably extended to other post‐BMT syndromes and other microangiopathies involving CRS complicating a variety of disease states and treatment modalities, such as chimeric antigen receptor (CAR) T‐cell therapy. 102 Indeed, paediatric and adult patients receiving DF as VOD/SOS prophylaxis also exhibited a reduced incidence of aGvHD, 92 103 a finding that is strongly supported by a preclinical model of aGvHD. 99 Additionally, a retrospective survey from paediatric patients treated with DF for transplant‐associated thrombotic microangiopathy showed resolution of clinical disease in 77% of patients. 104 Currently, Phase II studies investigating the use of DF for prevention of transplant‐associated thrombotic microangiopathy and VOD, and in the same context the treatment of ACS are ongoing (clinicaltrials.gov; NCT03384693NCT03805581NCT02675959). Notably, DF suppresses the expression of heparanase transcripts, cell surface expression and enzymatic activity, 95 suggesting that DF may have anti‐viral properties, although this remains to be confirmed. 71 72 73 Heparanase is putatively upregulated by the cytokine storm of advanced COVID‐19 and may contribute to further inflammation, oedema of the microvascular bed and coagulopathy. 28 75 105 106 DF is a potent inhibitor of heparanase in terms of both cell surface and gene expression, and therefore is especially attractive. Furthermore, the therapeutic use of DF in a murine model of IPS significantly improved survival compared to untreated controls by reducing, among other biomarkers, the levels of Ang‐2, 107 which is known to correlate with ARDS and is markedly elevated in critically ill patients with COVID‐19. 38

In addition, ICU‐admitted patients with COVID‐19 may display increased platelet activation and subsequent formation of platelet‐monocyte aggregates upon interaction with P‐selectin, thus stimulating monocyte‐induced inflammation and thrombosis. 22 By reducing P‐selectin and other adhesion molecules expression, DF may inhibit monocyte‐derived inflammatory and pro‐coagulant signals. Lastly and most importantly, DF has also been shown to decrease the activity of p38 MAPK and its pathway, 93 the importance of which is increasingly recognised in the pathogenesis of the COVID‐19 hyperinflammation syndrome and this may be a key therapeutic target in this process. 58 108

In summary, the multitargeted endothelial‐based therapeutic properties of DF and its relative safety, as well as its regulatory approval, make it an ideal potential therapeutic candidate for the treatment of COVID‐19 vascular complications. 28 In contrast to heparin, DF also exhibits broader anti‐cytokine, anti‐inflammatory and endothelial‐stabilising properties. Importantly, by acting on the heparanase‐HS axis, 74 102 DF may limit viral infectivity given its capacity to i) compete with HS and thereby possibly inhibit virus–cell adhesion and entry, ii) inhibit heparanase enzymatic activity and thereby attenuate virus detachment/release and spread 74 and iii) inhibit heparanase‐mediated activation of immune cells and thereby upregulation of pro‐inflammatory cytokines and the associated self‐sustaining systemic inflammatory host response (Fig 1). Actively accruing, international Phase II clinical trials are now underway and should shed critical light on DF’s therapeutic potential in patients with COVID‐19 (examples include clinicaltrials.gov; NCT04348383NCT04335201). Strikingly, two critically ill paediatric patients treated with DF for a SARS‐CoV‐2‐associated multisystem inflammatory syndrome experienced complete resolution and no attributable toxicity, with correlative studies supporting the mechanistic effects described above, as well as favourable effects seen on complement activation. 109 Similarly, preliminary results from the current studies as part of the international DEFACOVID (Defibrotide as Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome of COVID‐19) study group support both safety and promising potential efficacy to date.Fig 1

Potential mechanisms of action of defibrotide in the treatment of COVID‐19. Left, defibrotide limits viral attachment by interfering with Syndecan‐1, the primary cell surface heparan sulfate on ECs, and reduces viral dissemination, by inhibiting HPSE‐mediated viral release. Right, effects of defibrotide on endothelial‐mediated pathological processes. Viral infection of ECs promotes apoptosis with breakdown of endothelial barrier and exposure of the subendothelium, with subsequent platelet activation and thrombotic phenomena. Defibrotide inhibits platelet activation and leukocyte recruitment and blocks the generation of the cytokine storm; specifically, HPSE‐mediated activation of immune cells is suppressed, thus limiting the development of cytokine release syndrome. Sars‐Cov‐2, severe acute respiratory syndrome coronavirus‐2; ACE2, angiotensin‐converting enzyme 2; Ang‐2, angiopoietin‐2; GI, gastrointestinal; IL, interleukin; NFKB, nuclear factor kappa‐light chain‐enhancer of activated B cells; TNF‐α, tumor necrosis factor‐alpha; VWF, von Willebrand Factor.

Other heparanase inhibitors

Given the heparanase‐inhibiting activity of heparin, effort has been directed towards modifications of its structure to endow candidate molecules with potentiated anti‐heparanase activity while limiting anticoagulant effects. Specifically, N‐acetylated and glycol‐split heparins are promising agents presenting such characteristics. Indeed, administration of N‐acetylheparin (NAH) in murine models of sepsis ameliorated lung and intestinal injury and subsequent oedema by reducing tissue neutrophilic infiltration and suppressing IL‐6, IL‐1β and TNF‐α production. 110 111 Furthermore, roneparstat, the most developed glycol‐split NAH, restored pathological renal cellular damage caused by ischaemia‐reperfusion by reducing release of pro‐inflammatory cytokines and reverted established fibrotic processes, thus restoring normal tissue histology in preclinical models. 112 This aspect is especially relevant, considering the extensive formation of fibrosis and irreversible end‐organ damage in post‐BMT syndromes, SCD and advanced COVID‐19.

Additionally, much interest has been directed towards the novel heparanase‐inhibiting agent pixatimod, a modified oligosaccharide glycoside with heparan sulphate‐mimetic properties. Pixatimod is a potent inhibitor of Type 1 T‐helper cells (Th1)/Th17 effector functions, 113 IL‐6 expression, 114 M2 macrophage activation, 115 angiogenesis and tumour progression in vivo. Furthermore, it exhibits mild anticoagulant activity and despite transient infusion reactions is otherwise generally well tolerated. Guimond et al. 116 have recently demonstrated that pixatimod interacts with the SARS‐CoV‐2 spike protein binding site, and this is coherent with its heparan sulphate‐mimetic activity. Moreover, pixatimod was found to markedly inhibit SARS‐CoV‐2 infectivity, 116 supporting its clinical application as a novel therapeutic intervention for prophylaxis and treatment of COVID‐19. Taken together, heparanase emerges as a host‐encoded virulence factor that once activated enhances viral spread and triggers downstream inflammatory cascades. These preliminary data indicate that heparanase inhibitors currently under development are possible candidates for multisystem inflammatory conditions, such as COVID‐19, sepsis, thrombotic microangiopathies and cancer, but as of now studies remain preclinical with clinical application pending.

Conclusions

In conclusion, increasing evidence suggests that the SARS‐CoV‐2 directly targets ECs, promoting the release of pro‐inflammatory and pro‐thrombotic molecules. Endothelial dysfunction appears to be a crucial initiating step in the pathogenesis of the disease and its ensuing morbidity and mortality. Endotheliitis with the hyperproduction of cytokines leading to CRS, hypercoagulability and thrombotic microangiopathy are hallmarks shared by COVID‐19, VOD/SOS and other endothelial injury syndromes, underpinned by inflammation and including the vaso‐occlusive crises of SCD, so providing a common pathobiology across these respective syndromes. Most importantly, endothelial‐protective agents, such as DF, represent a promising and rational therapeutic strategy in COVID‐19, with DF currently under investigation in a variety of settings and combinations. As a unifying concept, heparanase inhibition, with the modulation of related pathways and other effects on endothelial stress responses may thus be crucial in mediating anti‐viral and anti‐inflammatory activity. In particular, as this relates to endotheliitis, it may directly abrogate CRS and its sequelae, which in turn may lead to improved patient outcome.

Author Contributions

Eleonora Calabretta, Jose M. Moraleda, Israel Vlodavsky, Ruben Jara, Carmelo Carlo‐Stella and Paul Richardson drafted the manuscript; all authors participated in the critical revision and approval of the final report.Go to:

Conflict of interest

Jose M. Moraleda declares Advisory Board fees from Jazz Pharmaceuticals; Antonio Pagliuca has received Advisory Board and Speaker fees from Jazz Pharmaceuticals; Rebecca M. Baron is on a Merck Advisory Board and a Consultant for Genentech. Robert Soiffer serves on the Board of Directors for Kiadis and Be The Match/National Marrow Donor Program; provided consulting for Gilead, Rheos Therapeutics, Cugene, Precision Bioscience, Mana Therapeutics, VOR Biopharma, and Novartis; and Data Safety Monitoring Board for Juno/Celgene; Paul Richardson is an Advisory Committee Member for Jazz Pharmaceuticals; Carmelo Carlo‐Stella is a Consultant/Advisory Board Member for Genente Science srl, ADC Therapeutics, Novartis, Roche, Karyopharm, Sanofi, Boehringer Igelheim and Servier. The remaining authors declare nothing to disclose.

Acknowledgments

This work was supported in part by a grant from the Italian Association for Cancer Research (AIRC, grant #20575 to CC‐S).Go to:

Contributor Information

Carmelo Carlo‐Stella, Email: ue.deminuh@alletsolrac.olemrac.

Paul Richardson, Email: ude.dravrah.icfd@nosdrahcir_luap.Go to:

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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.

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