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.

References

Aiyegbusi, O. L., Hughes, S. E., Turner, G., Rivera, S. C., McMullan, C., Chandan, J. S., et al. (2021). Symptoms, complications and management of long COVID: a review. J. R. Soc. Med. 114, 428–442. doi: 10.1177/01410768211032850

PubMed Abstract | CrossRef Full Text | Google Scholar

Althaus, K., Marini, I., Zlamal, J., Pelzl, L., Singh, A., Häberle, H., et al. (2021). Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood 137, 1061–1071. doi: 10.1182/blood.2020008762

PubMed Abstract | CrossRef Full Text | Google Scholar

Ananworanich, J., Mogg, R., Dunne, M. W., Bassyouni, M., David, C. V., Gonzalez, E., et al. (2021). Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19. Clin. Infect. Dis. doi: 10.1093/cid/ciab813 [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

Antonelli, M., Penfold, R. S., Merino, J., Sudre, C. H., Molteni, E., Berry, S., et al. (2022). Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID symptom study app: a prospective, community-based, nested, case-control study. Lancet Infect. Dis. 22, 43–55. doi: 10.1016/S1473-3099(21)00460-6

CrossRef Full Text | Google Scholar

Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., et al. (2021). Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416. doi: 10.1056/NEJMoa2035389

CrossRef Full Text | Google Scholar

Bhayana, R., Som, A., Li, M. D., Carey, D. E., Anderson, M. A., Blake, M. A., et al. (2020). Abdominal imaging findings in COVID-19: preliminary observations. Radiology 297, E207–E215. doi: 10.1148/radiol.2020201908

PubMed Abstract | CrossRef Full Text | Google Scholar

Bradley, B. T., Maioli, H., Johnston, R., Chaudhry, I., Fink, S. L., Xu, H., et al. (2020). Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington state: a case series. Lancet 396, 320–332. doi: 10.1016/S0140-6736(20)31305-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Brown, C. M., Vostok, J., Johnson, H., Burns, M., Gharpure, R., Sami, S., et al. (2021). Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings – Barnstable County, Massachusetts, July 2021. MMWR Morb. Mortal. Wkly Rep. 70, 1059–1062. doi: 10.15585/mmwr.mm7031e2

PubMed Abstract | CrossRef Full Text | Google Scholar

Burnier, L., Fontana, P., Kwak, B. R., and Angelillo-Scherrer, A. (2009). Cell-derived microparticles in haemostasis and vascular medicine. Thromb. Haemost. 101, 439–451. doi: 10.1160/TH08-08-0521

CrossRef Full Text | Google Scholar

Bushman, F. D., McCormick, K., and Sherrill-Mix, S. (2019). Virus structures constrain transmission modes. Nat. Microbiol. 4, 1778–1780. doi: 10.1038/s41564-019-0523-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Caccialanza, R., Formisano, E., Klersy, C., Ferretti, V., Ferrari, A., Demontis, S., et al. (2021). Nutritional parameters associated with prognosis in non-critically ill hospitalized COVID-19 patients: the NUTRI-COVID19 study. Clin. Nutr. doi: 10.1016/j.clnu.2021.06.020 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Chalmers, J. D., Crichton, M. L., Goeminne, P. C., Cao, B., Humbert, M., Shteinberg, M., et al. (2021). Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline. Eur. Respir. J. 57:2100048. doi: 10.1183/13993003.00048-2021

PubMed Abstract | CrossRef Full Text | Google Scholar

Chan, K. H., Sridhar, S., Zhang, R. R., Chu, H., Fung, A. Y., Chan, G., et al. (2020). Factors affecting stability and infectivity of SARS-CoV-2. J. Hosp. Infect. 106, 226–231. doi: 10.1016/j.jhin.2020.07.009

CrossRef Full Text | Google Scholar

Chang, L., Zhao, L., Gong, H., Wang, L., and Wang, L. (2020). Severe acute respiratory syndrome coronavirus 2 RNA detected in blood donations. Emerg. Infect. Dis. 26, 1631–1633. doi: 10.3201/eid2607.200839

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheung, C. C. L., Goh, D., Lim, X., Tien, T. Z., Lim, J. C. T., Lee, J. N., et al. (2022). Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut 71, 226–229. doi: 10.1136/gutjnl-2021-324280

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheung, K. S., Hung, I. F. N., Chan, P. P. Y., Lung, K. C., Tso, E., Liu, R., et al. (2020). Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in faecal samples from a Hong Kong cohort: systematic review and meta-analysis. Gastroenterology 159, 81–95. doi: 10.1053/j.gastro.2020.03.065

CrossRef Full Text | Google Scholar

Chiu, C. Y., Sarwal, A., Mon, A. M., Tan, Y. E., and Shah, V. (2020). Gastrointestinal: COVID-19 related ischemic bowel disease. J. Gastroenterol. Hepatol. 36:850. doi: 10.1111/jgh.15254

PubMed Abstract | CrossRef Full Text | Google Scholar

Chow, J. H., Khanna, A. K., Kethireddy, S., Yamane, D., Levine, A., Jackson, A. M., et al. (2020). Aspirin use is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized patients with COVID-19. Anesth. Analg. 132, 930–941. doi: 10.1213/ANE.0000000000005292

CrossRef Full Text | Google Scholar

Connors, J. M., Brooks, M. M., Sciurba, F. C., Krishnan, J. A., Bledsoe, J. R., Kindzelski, A., et al. (2021). Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA 326, 1703–1712. doi: 10.1001/jama.2021.17272

PubMed Abstract | CrossRef Full Text | Google Scholar

D’Amico, F., Baumgart, D. C., Danese, S., and Peyrin-Biroulet, L. (2020). Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention, and management. Clin. Gastroenterol. Hepatol. 18, 1663–1672. doi: 10.1016/j.cgh.2020.04.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Das Adhikari, U., Eng, G., Farcasanu, M., Avena, L. E., Choudhary, M. C., Triant, V. A., et al. (2021). Faecal SARS-CoV-2 RNA is associated with decreased COVID-19 survival. Clin. Infect. Dis. doi: 10.1093/cid/ciab623 Epub ahead of print

PubMed Abstract | CrossRef Full Text | Google Scholar

Deng, W., Bao, L., Gao, H., Xiang, Z., Qu, Y., Song, Z., et al. (2020). Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in rhesus macaques. Nat. Commun. 11:4400. doi: 10.1038/s41467-020-18149-6

CrossRef Full Text | Google Scholar

Di Filippo, L., De Lorenzo, R., D’Amico, M., Sofia, V., Roveri, L., Mele, R., et al. (2021). COVID-19 is associated with clinically significant weight loss and risk of malnutrition, independent of hospitalisation: a post-hoc analysis of a prospective cohort study. Clin. Nutr. 40, 2420–2426. doi: 10.1016/j.clnu.2020.10.043

PubMed Abstract | CrossRef Full Text | Google Scholar

Drucker, D. J. (2021). Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning. Cell Metab. 33, 479–498. doi: 10.1016/j.cmet.2021.01.016

CrossRef Full Text | Google Scholar

El Moheb, M., Naar, L., Christensen, M. A., Kapoen, C., Maurer, L. R., Farhat, M., et al. (2020). Gastrointestinal complications in critically ill patients with and without COVID-19. JAMA 324, 1899–1901. doi: 10.1001/jama.2020.19400

PubMed Abstract | CrossRef Full Text | Google Scholar

Fogarty, H., Townsend, L., Morrin, H., Ahmad, A., Comerford, C., Karampini, E., et al. (2021). Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J. Thromb. Haemost. 19, 2546–2555. doi: 10.1111/jth.15490

CrossRef Full Text | Google Scholar

Gao, C., Xie, R., Yu, C., Ma, R., Dong, W., Meng, H., et al. (2015). Thrombotic role of blood and endothelial cells in uremia through phosphatidylserine exposure and microparticle release. PLoS One 10:e0142835. doi: 10.1371/journal.pone.0142835

PubMed Abstract | CrossRef Full Text | Google Scholar

Gonzalez-Ochoa, A. J., Raffetto, J. D., Hernández, A. G., Zavala, N., Gutiérrez, O., Vargas, A., et al. (2021). Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. Thromb. Haemost. 121, 944–954. doi: 10.1055/a-1414-5216

CrossRef Full Text | Google Scholar

Goshua, G., Pine, A. B., Meizlish, M. L., Chang, C. H., Zhang, H., Bahel, P., et al. (2020). Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-Centre, cross-sectional study. Lancet Haematol. 7, e575–e582. doi: 10.1016/S2352-3026(20)30216-7

CrossRef Full Text | Google Scholar

Guo, M., Tao, W., Flavell, R. A., and Zhu, S. (2021). Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat. Rev. Gastroenterol. Hepatol. 18, 269–283. doi: 10.1038/s41575-021-00416-6

CrossRef Full Text | Google Scholar

Hacisuleyman, E., Hale, C., Saito, Y., Blachere, N. E., Bergh, M., Conlon, E. G., et al. (2021). Vaccine breakthrough infections with SARS-CoV-2 variants. N. Engl. J. Med. 384, 2212–2218. doi: 10.1056/NEJMoa2105000

CrossRef Full Text | Google Scholar

Hasanoglu, I., Korukluoglu, G., Asilturk, D., Cosgun, Y., Kalem, A. K., Altas, A. B., et al. (2021). Higher viral loads in asymptomatic COVID-19 patients might be the invisible part of the iceberg. Infection 49, 117–126. doi: 10.1007/s15010-020-01548-8

PubMed Abstract | CrossRef Full Text | Google Scholar

He, Z., Si, Y., Jiang, T., Ma, R., Zhang, Y., Cao, M., et al. (2016). Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease. Thromb. Haemost. 115, 738–751. doi: 10.1160/TH15-09-0710

CrossRef Full Text | Google Scholar

Ho, F. K., Man, K. K. C., Toshner, M., Church, C., Celis-Morales, C., Wong, I. C. K., et al. (2021). Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort. Mayo Clin. Proc. 96, 2587–2597. doi: 10.1016/j.mayocp.2021.07.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Hottz, E. D., Azevedo-Quintanilha, I. G., Palhinha, L., Teixeira, L., Barreto, E. A., Pão, C. R. R., et al. (2020). Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients. Blood 136, 1330–1341. doi: 10.1182/blood.2020007252

PubMed Abstract | CrossRef Full Text | Google Scholar

Hu, F., Chen, F., Ou, Z., Fan, Q., Tan, X., Wang, Y., et al. (2020). A compromised specific Humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cell. Mol. Immunol. 17, 1119–1125. doi: 10.1038/s41423-020-00550-2

CrossRef Full Text | Google Scholar

Huang, N., Pérez, P., Kato, T., Mikami, Y., Okuda, K., Gilmore, R. C., et al. (2021). SARS-CoV-2 infection of the oral cavity and saliva. Nat. Med. 27, 892–903. doi: 10.1038/s41591-021-01296-8

PubMed Abstract | CrossRef Full Text | Google Scholar

INSPIRATION Investigators Sadeghipour, P., Talasaz, A. H., Rashidi, F., Sharif-Kashani, B., Beigmohammadi, M. T., et al. (2021). Effect of intermediate-dose vs. standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 325, 1620–1630. doi: 10.1001/jama.2021.4152

PubMed Abstract | CrossRef Full Text | Google Scholar

Jacobs, J. L., and Mellors, J. W. (2020). Detection of SARS-CoV-2 RNA in blood of patients with COVID-19: what does it mean? Clin. Infect. Dis. doi: 10.1093/cid/ciaa1316 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Kaafarani, H. M. A., El Moheb, M., Hwabejire, J. O., Naar, L., Christensen, M. A., Breen, K., et al. (2020). Gastrointestinal complications in critically ill patients with COVID-19. Ann. Surg. 272, e61–e62. doi: 10.1097/SLA.0000000000004004

CrossRef Full Text | Google Scholar

Klompas, M. (2021). Understanding breakthrough infections following mRNA SARS-CoV-2 vaccination. JAMA 326, 2018–2020. doi: 10.1001/jama.2021.19063

PubMed Abstract | CrossRef Full Text | Google Scholar

Kwon, P. S., Oh, H., Kwon, S. J., Jin, W., Zhang, F., Fraser, K., et al. (2020). Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell Discov. 6:50. doi: 10.1038/s41421-020-00192-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220. doi: 10.1038/s41586-020-2180-5

CrossRef Full Text | Google Scholar

Ledford, H. (2021). Do vaccines protect against long COVID? What the data say. Nature 599, 546–548. doi: 10.1038/d41586-021-03495-2

CrossRef Full Text | Google Scholar

Leentjens, J., van Haaps, T. F., Wessels, P. F., Schutgens, R. E. G., and Middeldorp, S. (2021). COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year. Lancet Haematol. 8, e524–e533. doi: 10.1016/S2352-3026(21)00105-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lemos, A. C. B., do Espírito Santo, D. A., Salvetti, M. C., Gilio, R. N., Agra, L. B., Pazin-Filho, A., et al. (2020). Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb. Res. 196, 359–366. doi: 10.1016/j.thromres.2020.09.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, L., Huang, M., Shen, J., Wang, Y., Wang, R., Yuan, C., et al. (2021). Serum levels of soluble platelet endothelial cell adhesion molecule 1 in COVID-19 patients are associated with disease severity. J. Infect. Dis. 223, 178–179. doi: 10.1093/infdis/jiaa642

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Schneider, A. M., Mehta, A., Sade-Feldman, M., Kays, K. R., Gentili, M., et al. (2021). SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes. J. Clin. Invest. 131:e148635. doi: 10.1172/JCI148635

CrossRef Full Text | Google Scholar

Livanos, A. E., Jha, D., Cossarini, F., Gonzalez-Reiche, A. S., Tokuyama, M., Aydillo, T., et al. (2021). Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms. Gastroenterology 16, 2435.e34–2450.e34. doi: 10.1053/j.gastro.2021.02.056

CrossRef Full Text | Google Scholar

Lopes, R. D., de Barros, E., Silva, P. G. M., Furtado, R. H. M., Macedo, A. V. S., Bronhara, B., et al. (2021). Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet 397, 2253–2263. doi: 10.1016/S0140-6736(21)01203-4

CrossRef Full Text | Google Scholar

Luo, Y., Xue, Y., Mao, L., Yuan, X., Lin, Q., Tang, G., et al. (2020). Prealbumin as a predictor of prognosis in patients with coronavirus disease 2019. Front. Med. 7:374. doi: 10.3389/fmed.2020.00374

PubMed Abstract | CrossRef Full Text | Google Scholar

Lv, L., Jiang, H., Chen, Y., Gu, S., Xia, J., Zhang, H., et al. (2021). The faecal metabolome in COVID-19 patients is altered and associated with clinical features and gut microbes. Anal. Chim. Acta 1152:338267. doi: 10.1016/j.aca.2021.338267

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, R., Xie, R., Yu, C., Si, Y., Wu, X., Zhao, L., et al. (2017). Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis. Sci. Rep. 7:4978. doi: 10.1038/s41598-018-24187-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Manne, B. K., Denorme, F., Middleton, E. A., Portier, I., Rowley, J. W., Stubben, C., et al. (2020). Platelet gene expression and function in patients with COVID-19. Blood 136, 1317–1329. doi: 10.1182/blood.2020007214

PubMed Abstract | CrossRef Full Text | Google Scholar

Mao, R., Qiu, Y., He, J. S., Tan, J. Y., Li, X. H., Liang, J., et al. (2020). Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 5, 667–678. doi: 10.1016/S2468-1253(20)30126-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Marcos-Jubilar, M., Carmona-Torre, F., Vidal Laso, R., Ruiz-Artacho, P., Filella, D., Carbonell, C., et al. (2022). Therapeutic versus prophylactic bemiparin in hospitalized patients with non-severe COVID-19 pneumonia (BEMICOP): an open-label, multicenter, randomized trial. Thromb. Haemost. 122, 295–299. doi: 10.1055/a-1667-7534

PubMed Abstract | CrossRef Full Text | Google Scholar

McFadyen, D. J., Stevens, H., and Karlheinz, P. (2020). The emerging threat of (micro)thrombosis in COVID-19 and its therapeutic implications. Circ. Res. 127, 571–587. doi: 10.1161/CIRCRESAHA.120.317447

CrossRef Full Text | Google Scholar

Middleton, E. A., He, X. Y., Denorme, F., Campbell, R. A., Ng, D., Salvatore, S. P., et al. (2020). Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 136, 1169–1179. doi: 10.1182/blood.2020007008

CrossRef Full Text | Google Scholar

Moore, J. B., and June, C. H. (2020). Cytokine release syndrome in severe COVID-19. Science 368, 473–474. doi: 10.1126/science.abb8925

CrossRef Full Text | Google Scholar

Mouhat, B., Besutti, M., Bouiller, K., Grillet, F., Monnin, C., Ecarnot, F., et al. (2020). Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients. Eur. Respir. J. 56:2001811. doi: 10.1183/13993003.01811-2020

PubMed Abstract | CrossRef Full Text | Google Scholar

Norsa, L., Bonaffini, P. A., Indriolo, A., Valle, C., Sonzogni, A., and Sironi, S. (2020). Poor outcome of intestinal ischemic manifestations of COVID-19. Gastroenterology 159, 1595.e1–1597.e1. doi: 10.1053/j.gastro.2020.06.041

PubMed Abstract | CrossRef Full Text | Google Scholar

Perepu, U. S., Chambers, I., Wahab, A., Ten Eyck, P., Wu, C., Dayal, S., et al. (2021). Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial. J. Thromb. Haemost. 19, 2225–2234. doi: 10.1111/jth.15450

PubMed Abstract | CrossRef Full Text | Google Scholar

Pereyra, D., Heber, S., Schrottmaier, W. C., Santol, J., Pirabe, A., Schmuckenschlager, A., et al. (2021). Low molecular weight heparin use in COVID-19 is associated with curtailed viral persistence: a retrospective multicenter observational study. Cardiovasc. Res. 117, 2807–2820. doi: 10.1093/cvr/cvab308

PubMed Abstract | CrossRef Full Text | Google Scholar

Polak, S. B., Van Gool, I. C., Cohen, D., von der Thüsen, J. H., and van Paassen, J. (2020). A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod. Pathol. 33, 2128–2138. doi: 10.1038/s41379-020-0603-3

CrossRef Full Text | Google Scholar

Poor, H. D. (2021). Pulmonary thrombosis and thromboembolism in COVID-19. Chest 160, 1471–1480. doi: 10.1016/j.chest.2021.06.016

CrossRef Full Text | Google Scholar

Puelles, V. G., Lütgehetmann, M., Lindenmeyer, M. T., Sperhake, J. P., Wong, M. N., Allweiss, L., et al. (2020). Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592. doi: 10.1056/NEJMc2011400

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramacciotti, E., Barile Agati, L., Calderaro, D., Aguiar, V. C. R., Spyropoulos, A. C., de Oliveira, C. C. C., et al. (2022). Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 399, 50–59. doi: 10.1016/S0140-6736(21)02392-8

PubMed Abstract | CrossRef Full Text | Google Scholar

RECOVERY Collaborative Group (2022). Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 399, 143–151. doi: 10.1016/S0140-6736(21)01825-0

CrossRef Full Text | Google Scholar

RECOVERY Collaborative Group Horby, P., Lim, W. S., Emberson, J. R., Mafham, M., Bell, J. L., et al. (2020). Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 384, 693–704. doi: 10.1056/NEJMoa2021436

PubMed Abstract | CrossRef Full Text | Google Scholar

REMAP-CAP Investigators ACTIV-4a Investigators ATTACC Investigators Goligher, E. C., Bradbury, C. A., McVerry, B. J., et al. (2021a). Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N. Engl. J. Med. 385, 777–789. doi: 10.1056/NEJMoa2103417

PubMed Abstract | CrossRef Full Text | Google Scholar

REMAP-CAP Investigators ACTIV-4a Investigators ATTACC Investigators Lawler, P. R., Goligher, E. C., Berger, J. S., et al. (2021b). Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N. Engl. J. Med. 385, 790–802. doi: 10.1056/NEJMoa2105911

PubMed Abstract | CrossRef Full Text | Google Scholar

Rizvi, A., Patel, Z., Liu, Y., Satapathy, S. K., Sultan, K., and Trindade, A. J. (2021). Gastrointestinal sequelae 3 and 6 months after hospitalization for coronavirus disease 2019. Clin. Gastroenterol. Hepatol. 19, 2438.e1–2440.e1. doi: 10.1016/j.cgh.2021.06.046

CrossRef Full Text | Google Scholar

Santoro, F., Nuñez-Gil, I. J., Vitale, E., Viana-Llamas, M. C., Reche-Martinez, B., Romero-Pareja, R., et al. (2022). Antiplatelet therapy and outcome in COVID-19: the health outcome predictive evaluation registry. Heart 108, 130–136. doi: 10.1136/thoraxjnl-2021-217561

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, J., and Gilbert, G. E. (2003). Lactadherin inhibits enzyme complexes of blood coagulation by completing for phospholipid binding sites. Blood 101, 2628–2636. doi: 10.1182/blood-2002-07-1951

PubMed Abstract | CrossRef Full Text | Google Scholar

Sholzberg, M., Tang, G. H., Rahhal, H., AlHamzah, M., Kreuziger, L. B., Áinle, F. N., et al. (2021). Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 375:n2400. doi: 10.1136/bmj.n2400

CrossRef Full Text | Google Scholar

Spyropoulos, A. C., Goldin, M., Giannis, D., Diab, W., Wang, J., Khanijo, S., et al. (2021). Efficacy and safety of therapeutic-dose heparin vs. standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern. Med. 181, 1612–1620. doi: 10.1001/jamainternmed.2021.6203

PubMed Abstract | CrossRef Full Text | Google Scholar

Stefan, N., Birkenfeld, A. L., and Schulze, M. B. (2021). Global pandemics interconnected – obesity, impaired metabolic health and COVID-19. Nat. Rev. Endocrinol. 17, 135–149. doi: 10.1038/s41574-020-00462-1

CrossRef Full Text | Google Scholar

Stefely, J. A., Christensen, B. B., Gogakos, T., Cone Sullivan, J. K., Montgomery, G. G., Barranco, J. P., et al. (2020). Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am. J. Hematol. 95, 1522–1530. doi: 10.1002/ajh.25979

PubMed Abstract | CrossRef Full Text | Google Scholar

Suh, Y. J., Hong, H., Ohana, M., Bompard, F., Revel, M. P., Valle, C., et al. (2021). Pulmonary embolism and deep vein thrombosis in COVID-19: a systematic review and meta-analysis. Radiology 298, E70–E80. doi: 10.1148/radiol.2020203557

CrossRef Full Text | Google Scholar

Sultan, S., Altayar, O., Siddique, S. M., Davitkov, P., Feuerstein, J. D., Lim, J. K., et al. (2020). AGA institute rapid review of the gastrointestinal and liver manifestations of COVID-19, meta-analysis of international data, and recommendations for the consultative management of patients with COVID-19. Gastroenterology 159, 320.e27–334.e27. doi: 10.1053/j.gastro.2020.05.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Susen, S., Tacquard, C. A., Godon, A., Mansour, A., Garrigue, D., Nguyen, P., et al. (2020). Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. Crit. Care 24:364. doi: 10.1186/s13054-020-03000-7

CrossRef Full Text | Google Scholar

Tan, B. K., Mainbourg, S., Friggeri, A., Bertoletti, L., Douplat, M., Dargaud, Y., et al. (2021). Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax 76, 970–979. doi: 10.1136/thoraxjnl-2020-215383

PubMed Abstract | CrossRef Full Text | Google Scholar

Taus, F., Salvagno, G., Canè, S., Fava, C., Mazzaferri, F., Carrara, E., et al. (2020). Platelets promote thromboinflammation in SARS-CoV-2 pneumonia. Arterioscler. Thromb. Vasc. Biol. 40, 2975–2989. doi: 10.1161/ATVBAHA.120.315175

PubMed Abstract | CrossRef Full Text | Google Scholar

Ten Cate, H. (2021). Surviving Covid-19 with heparin? N. Engl. J. Med. 385, 845–846. doi: 10.1056/NEJMe2111151

PubMed Abstract | CrossRef Full Text | Google Scholar

Tenforde, M. W., Self, W. H., Adams, K., Gaglani, M., Ginde, A. A., McNeal, T., et al. (2021). Association between mRNA vaccination and COVID-19 hospitalization and disease severity. JAMA 326, 2043–2054. doi: 10.1001/jama.2021.19499

CrossRef Full Text | Google Scholar

Thompson, M. G., Burgess, J. L., Naleway, A. L., Tyner, H., Yoon, S. K., Meece, J., et al. (2021). Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N. Engl. J. Med. 385, 320–329. doi: 10.1056/NEJMoa2107058

PubMed Abstract | CrossRef Full Text | Google Scholar

Tong, M., Jiang, Y., Xia, D., Xiong, Y., Zheng, Q., Chen, F., et al. (2020). Elevated expression of serum endothelial cell adhesion molecules in COVID-19 patients. J. Infect. Dis. 222, 894–898. doi: 10.1093/infdis/jiaa349

CrossRef Full Text | Google Scholar

Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., et al. (2020). Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418. doi: 10.1016/S0140-6736(20)30937-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Versteeg, H. H., Heemskerk, J. W., Levi, M., and Reitsma, P. H. (2013). New fundamentals in hemostasis. Physiol. Rev. 93, 327–358. doi: 10.1152/physrev.00016.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

von Meijenfeldt, F. A., Havervall, S., Adelmeijer, J., Lundström, A., Magnusson, M., Mackman, N., et al. (2021). Elevated factor V activity and antigen levels in patients with Covid-19 are related to disease severity and 30-day mortality. Am. J. Hematol. 96, E98–E100. doi: 10.1002/ajh.26085

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, P., Nair, M. S., Liu, L., Iketani, S., Luo, Y., Guo, Y., et al. (2021). Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135. doi: 10.1038/s41586-021-03398-2

CrossRef Full Text | Google Scholar

Wang, W., Xu, Y., Gao, R., Han, K., Wu, G., and Tan, W. (2020). Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 323, 1843–1844. doi: 10.1001/jama.2020.3786

PubMed Abstract | CrossRef Full Text | Google Scholar

Wölfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M. A., et al. (2020). Virological assessment of hospitalized patients with COVID-2019. Nature 581, 465–469. doi: 10.1038/s41586-020-2196-x

CrossRef Full Text | Google Scholar

Xiao, F., Sun, J., Xu, Y., Li, F., Huang, X., Li, H., et al. (2020a). Infectious SARS-CoV-2 in feces of patient with severe COVID-19. Emerg. Infect. Dis. 26, 1920–1922. doi: 10.3201/eid2608.200681

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiao, F., Tang, M., Zheng, X., Liu, Y., Li, X., and Shan, H. (2020b). Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 158, 1831.e3–1833.e3. doi: 10.1053/j.gastro.2020.02.055

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, Y., Xu, E., Bowe, B., and Al-Aly, Z. (2022). Long-term cardiovascular outcomes of COVID-19. Nat. Med. doi: 10.1038/s41591-022-01689-3 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Zaid, Y., Puhm, F., Allaeys, I., Naya, A., Oudghiri, M., Khalki, L., et al. (2020). Platelets can associate with SARS-CoV-2 RNA and are hyperactivated in COVID-19. Circ. Res. 127, 1404–1418. doi: 10.1161/CIRCRESAHA.120.317703

CrossRef Full Text | Google Scholar

Zamboni, P., Bortolotti, D., Occhionorelli, S., Traina, L., Neri, L. M., Rizzo, R., et al. (2021). Bowel ischemia as onset of COVID-19 in otherwise asymptomatic patients with persistently negative swab. J. Intern. Med. 291, 224–231. doi: 10.1111/joim.13385

CrossRef Full Text | Google Scholar

Zang, R., Gomez Castro, M. F., McCune, B. T., Zeng, Q., Rothlauf, P. W., Sonnek, N. M., et al. (2020). TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci. Immunol. 5:eabc3582. doi: 10.1126/sciimmunol.abc3582

CrossRef Full Text | Google Scholar

Zhang, Y., Chen, C., Zhu, S., Shu, C., Wang, D., Song, J., et al. (2020). Isolation of 2019-nCoV from a stool specimen of a laboratory- confirmed case of the coronavirus disease 2019 (COVID-19). China CDC Wkly 2, 123–124. doi: 10.46234/ccdcw2020.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, P., He, Z., Yu, G., Peng, D., Feng, Y., Ling, J., et al. (2021). The modified NUTRIC score can be used for nutritional risk assessment as well as prognosis prediction in critically ill COVID-19 patients. Clin. Nutr. 40, 534–541. doi: 10.1016/j.clnu.2020.05.051

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Shao, B., Dang, Q., Chen, Z., Zhou, Q., Luo, H., et al. (2021). Pathogenesis and mechanism of gastrointestinal infection With COVID-19. Front. Immunol. 12:674074. doi: 10.3389/fimmu.2021.674074

CrossRef Full Text | Google Scholar

Zhao, F., Yang, Y., Wang, Z., Li, L., Liu, L., and Liu, Y. (2020). The time sequences of respiratory and rectal viral shedding in patients with coronavirus disease 2019. Gastroenterology 159, 1158.e2–1160.e2. doi: 10.1053/j.gastro.2020.05.035

CrossRef Full Text | Google Scholar

Zhong, P., Xu, J., Yang, D., Shen, Y., Wang, L., Feng, Y., et al. (2020). COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduct. Target. Ther. 5:256. doi: 10.1038/s41392-020-00373-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Li, C., Liu, X., Chiu, M. C., Zhao, X., Wang, D., et al. (2020). Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 26, 1077–1083. doi: 10.1038/s41591-020-0912-6

COVID-19 and the liver

Authors: Dinesh JothimaniRadhika Venugopal,Mohammed Forhad AbedinIlankumaran Kaliamoorthy, and Mohamed Rela

J Hepatol. 2020 Nov; 73(5): 1231–1240.Published online 2020 Jun 15. doi: 10.1016/j. jhep.2020.06.006PMCID: PMC7295524PMID: 32553666

Abstract

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a major public health crisis over the past few months. Overall case fatality rates range between 2–6%; however, the rates are higher in the elderly and those with underlying comorbidities like diabetes, hypertension and heart disease. Recent reports showed that about 2–11% of patients with COVID-19 had underlying chronic liver disease. During the previous SARS epidemic, around 60% of patients were reported to develop various degrees of liver damage. In the current pandemic, hepatic dysfunction has been seen in 14–53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been reported and are associated with higher mortality. Hepatic involvement in COVID-19 could be related to the direct cytopathic effect of the virus, an uncontrolled immune reaction, sepsis or drug-induced liver injury. The postulated mechanism of viral entry is through the host angiotensin-converting enzyme 2 (ACE2) receptors that are abundantly present in type 2 alveolar cells. Interestingly, ACE2 receptors are expressed in the gastrointestinal tract, vascular endothelium and cholangiocytes of the liver. The effects of COVID-19 on underlying chronic liver disease require detailed evaluation and, with data currently lacking, further research is warranted in this area.

Introduction

Coronaviruses are enveloped single-stranded RNA viruses, belonging to the Coronaviridae family and Orthocoronavirinae subfamily. They are some of the largest viruses (with sizes ranging from 27–34 kilobases). Coronavirus infections are commonly seen in mammals and birds. They cause zoonotic, predominantly upper respiratory tract, infections in humans. Electron microscopic images shows a ‘halo’ or ‘crown’ around the virus which explains their name. Two coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and the middle eastern respiratory syndrome coronavirus (MERS-CoV), caused relatively recent epidemics, in 2003 and 2012, respectively.

The current coronavirus, responsible for the coronavirus disease 2019 (COVID-19) pandemic, has been labelled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Taxonomy group. Genome sequencing analysis showed SARS-CoV-2 is possibly a chimeric variant of a bat coronavirus identified in 2015 by Benvenuto and Colleagues.1 The resulting disease was termed COVID-19 by the World Health Organization (WHO) on the 11th February 2020. Viral detection studies by Zhou and colleagues2 showed an 80% homology between SARS-CoV (2003 pandemic) and the current novel coronavirus.

During the previous SARS epidemic, around 60% of patients developed various degrees of liver damage. Based on phylogenetic resemblance it is possible that SARS-CoV-2 also causes liver injury.

Epidemiology

Several cases of severe unexplained pneumonia were reported in Wuhan, China in December 2019. Bronchoalveolar lavage from an index case identified the presence of SARS-CoV-2 on the 3rd January 20203 and subsequently the WHO declared an ‘epidemic’. Following the rapid increase in COVID-19 infections across the world, the WHO declared a ‘pandemic’ on the 11th March 2020, an emergency public health situation. Wuhan was the initial epicentre for COVID-19, where the first 41 cases of severe pneumonia were reported following exposure to bats and pangolins at the Huanan Seafood Wholesale market.4 Subsequent cases were reported from the same locality by Chen and colleagues.5 However, several patients in the outbreak did not have exposure to animals, likely indicating person to person transmission.

Key point

COVID-19 is a pandemic caused by SARS-CoV-2, a virus that has 80% homology with SARS-CoV.

A WHO report from the 19th May 2020, confirmed 4,731,458 COVID-19 positive cases from 213 countries worldwide, of which 1,477,516 cases were reported in the United States of America, 231,606 cases in Spain, 225,886 cases in Italy, 246,410 in the United Kingdom, 84,500 cases in China (the origin of the pandemic) and 101,139 cases in India.6 These data indicate the rapid spread of the disease around the world, with a doubling rate of 7.2 days.

ACE2 receptors

As with SARS-CoV, angiotensin-converting enzyme 2 (ACE2) appears to be the susceptible receptor for SARS-CoV-2 and is expressed in more than 80% of alveolar cells in the lungs. In vitro studies from the SARS epidemic identified ACE2 as the host receptor for viral entry.7 Immunohistochemical studies from human tissues during the SARS pandemic showed high expression of the ACE2 receptor protein in the vascular endothelium of small and large arteries and veins. In the lungs, ACE2 is highly expressed in type 2 alveolar cells. Interestingly, fibrotic lungs had much higher staining for ACE2, whereas bronchial epithelial cells showed weaker expression. A recent study showed that SARS-CoV-2 possessed 10-20-fold higher receptor binding affinity.8 Immunohistochemical studies identified higher expression of ACE2 receptors in the gastrointestinal tract. ACE2 expression is high in the basal layer of the squamous epithelium. of the nasal, oral and nasopharyngeal mucosa. Smooth muscles of the gastric and intestinal colonic mucosa also express ACE2. In addition, ACE2 is abundantly expressed in enterocytes in the duodenum, jejunum and ileum.9

Key point

ACE2 is the host cell receptor for SARS-CoV-2; it is present in type 2 alveolar cells, the gastrointestinal tract and the liver.

Hepatic distribution of ACE2 is peculiar. It is highly expressed in the endothelial layer of small blood vessels, but not in the sinusoidal endothelium. Chai and colleagues10 found that the ACE2 cell surface receptor was more highly expressed in cholangiocytes (59.7%) than hepatocytes (2.6%). The level of ACE2 expression in cholangiocytes was similar to that in type 2 alveolar cells of the lungs, indicating that the liver could be a potential target for SARS-CoV-2. Immunohistochemistry stains for ACE2 were negative on Kupffer cells, as well as T and B lymphocytes.

A recent study from Wuhan showed that Asian men had higher expression of ACE2, indicating the possibility of a higher susceptibility to COVID-19 in this population.11 , 12

Transmission

SARS-CoV-2 started as a zoonotic infection; however, the disease spreads rapidly from person to person through coughing and sneezing, particularly amongst close contacts. SARS-CoV-2 is resilient and can remain viable for 2 hours to 14 days depending on the fomite and the weather condition.13

The transmission potential of an infection in the community is based on its basic reproduction rate which is usually denoted as disease transmission ratio (R0). This represents the number of secondary cases resulting from an index case in a susceptible population. The (R0 – R naught) of COVID-19 is 2.2.14

Previous studies showed that 19.6% to 73% of patients with SARS presented with gastrointestinal symptoms.[15][16][17][18] Active replication of SARS-CoV was detected in the enterocytes of the small intestine.15 Moreover, SARS-CoV RNA was detected in patient stool samples during the SARS pandemic, which highlighted the possibility of faeco-oral transmission. A similar pattern has been observed with SARS-CoV-2; between 3% and 79% of patients with COVID-19 develop gastrointestinal symptoms, predominantly nausea, vomiting and diarrhoea. Zhang et al. found that 53.3% and 26.7% of oral and anal swabs remained positive for SARS-CoV-2 RNA, respectively, for several days after treatment. The same study group performed paired samples on a different cohort of patients with COVID-19 and found that on day 0, 80% of patients were positive on oral swabs whereas on day 5, 75% of patients were positive on anal swabs, indicating the dynamic changes in viral tests during the course of the illness.19 Xiao and colleagues20 showed that patients with SARS-CoV-2-related respiratory illness can continue to shed the virus in stool even after a negative respiratory sample. In a series of 73 patients with COVID-19, about 53.42% had detectable RNA in their stool, of whom about 23.29% continued to have positive RT-PCR for SARS-CoV-2 RNA in faecal samples even after a negative respiratory sample.20 Yeo and colleagues21 showed that faecal shedding can continue to occur for a longer period after clinical recovery and these patients can potentially infect others. These findings illustrate the multiple routes of viral entry into a single host, viral persistence in various organ systems and possible faecal-oral transmission of SARS-CoV-2 even during the convalescence period.

Key point

In addition to droplets, SARS-CoV-2 also transmits through the faeco-oral route.

With limited therapeutic options, prevention by social distancing appears to be the cornerstone of COVID-19 management. Virus transmission can be reduced by various methods described in the WHO protocol.6 These include, maintaining safe social distance, regular hand washing for 20 seconds, using 60% alcohol hand rub, and avoiding crowded places and public events. Countries have taken different measures to reduce viral transmission and most countries have gone into ‘Lockdown’ in order to stop viral transmission. Being a large virus particle, a surgical face mask should provide adequate protection against viral inhalation. N-95 masks should be reserved for treating teams. Personal protective equipment should be worn according to institutional policy. All patients with a history of travel to affected regions should be screened for SARS-CoV-2 even if they are asymptomatic. People with high temperature, dry cough, profound tiredness, diarrhoea or other unusual symptoms with recent travel history should be tested for COVID-19. Nations will need to continually monitor their prevention, testing and treatment strategies based on guidelines issued by the WHO.

Clinical features

Initial reports from China showed that the incubation period of SARS-CoV-2 was between 3 to 7 days and occasionally 2 weeks. The longest incubation period identified was 12.5 days.14

Large studies from a Chinese population reported fever (≥38°C), dry cough, fatigue, myalgia, leukopenia and raised liver enzymes as the most common clinical features of COVID-19 on presentation, as shown in Table 1 and ​and2 .2 . Nausea, vomiting and diarrhoea were seen in 2–10% of patients with COVID-19.

Table 1

Spectrum of clinical manifestations and their frequency from recent studies on COVID-19 in China.

Clinical featuresWang et al.22
n = 138
Zhou et al.51
n = 191
Guan et al.23
n = 1,099
Fever98.6%94%88.7%
Cough59.4%79%67.8%
Sputumn.a.23%33.7%
Myalgian.a.15%14.9%
Fatigue69.6%23%38.1%
Diarrhoean.a.5%3.8%
Nausea/vomitingn.a.4%5.0%
Sore throatn.a.n.a.13.9%
Lymphopenia (<0.8 × 109/L)70.3%40%n.a.
Prolonged PT (>13.5 seconds)58%n.a.n.a.
Raised LDH (>261 U/L)39.9%n.a.n.a.

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COVID-19, coronavirus disease 2019; LDH, lactate dehydrogenase; PT, prothrombin time; n.a., data not available.

Table 2

Classification of COVID-19 into 3 groups based on severity of clinical manifestations by Chinese Center for Disease Control.23

Mild disease (reported in 81% cases)Fever, dry cough, mild dyspnoea (respiratory rate <30/min).
Severe disease (reported in 14% cases)Dyspnoea, respiratory rate >30 and/or lung infiltrates >50% within 24 to 48 hours.
Critical disease (reported in 5% cases)Respiratory failure, septic shock and/or multiple organ dysfunction or failure.

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COVID-19, coronavirus disease 2019.

In the latest case series from Wuhan by Wang and colleagues,22 138 hospitalised patients (including 40 healthcare workers and 17 already hospitalised for other conditions) with COVID-19; median age was 56 years (IQR 22–92 years) and 54.3% were males. Clinical features were fever (98.6%), fatigue (69.6%), dry cough (59.4%), lymphopenia <0.8 × 109/L (70.3%), prolonged prothrombin time (58%), and raised lactate dehydrogenase (LDH) 261 U/L (39.9%). Thirty-six patients (26.1%) received intensive care unit (ICU) care for acute respiratory distress syndrome (ARDS) (61.1%), cardiac arrhythmias (44.4%) and shock (30.6%). Onset and the progression of symptoms were dramatic, with a median time from symptoms to ARDS of only 8 days. Patients requiring intensive care were older (66 vs. 51, years) and more often had comorbidities (72% vs. 32%). Patients admitted to the ICU had higher LDH (435 U/L vs. 212 U/L, p <0.001), aspartate aminotransferase (AST) (52 U/L vs. 29 U/L, p <0.001) and hypersensitive cardiac troponin (11 ng/ml vs. 5.1 ng/ml, p = 0.004). All 138 patients showed bilateral pneumonia in the thoracic scan. Analysis between the survivors and non-survivors showed higher white blood cell count with severe progressive lymphopenia in the non-survivors. With disease progression, these patients required organ support with progressive deterioration in renal function before death.

In the largest database analysis of 1,099 patients with confirmed COVID-19 from China, by Guan and colleagues,23 the median age of presentation was 47 years (IQR 35–58 years) and 58% were male. The most common presenting symptoms were fever (88.7%), cough (67.8%), nausea or vomiting (5%), and diarrhoea (3.8%). CT chest radiography revealed ground glass opacity (56.4%) and bilateral patchy shadows (51.8%). Of 1,099 patients, 5% were admitted to the ICU, 2.3% underwent invasive ventilation and 1.4% died. COVID-19 disease was classified according to the clinical severity into 3 groups by the Chinese CDC by Guan and colleagues23 as shown in Table 2.

Key point

2–11% of patients with COVID-19 have been reported to have underlying chronic liver disease.Go to:

COVID-19 and hepatic dysfunction

It is intriguing to know the pattern of liver injury in COVID-19. Hepatic involvement in COVID-19 could be related to the direct cytopathic effect of the virus, an uncontrolled immune reaction, sepsis or drug-induced liver injury. Given the higher expression of ACE2 receptors in cholangiocytes, the liver is a potential target for SARS-CoV-2. Moreover, COVID-19 may cause worsening of underlying chronic liver disease, leading to hepatic decompensation and acute-on-chronic liver failure, with higher mortality.

A summary of recently published studies is provided in Table 3 . Overall, 2–11% of patients with COVID-19 were reported to have underlying chronic liver disease and 14-53% with COVID-19 developed hepatic dysfunction,24 particularly those with severe COVID-19. Hepatic dysfunction was significantly higher in critically ill patients and was associated with poor outcome.

Table 3

Studies of COVID-19 and hepatic manifestations.

AuthorCountryComments
Chen et al.26ChinaHigher ALT and AST in deceased patients.
High mortality in patients with acute liver injury (76.9%).
Li et al.74China7% of patients with COVID-19 had underlying chronic liver disease.
Wang et al.22China3.9% of patients with COVID-19 had underlying chronic liver disease.
Mortality 4.3%.
Guan et al.23China2.1% of patients with COVID-19 had chronic hepatitis B infection.
Mortality 1.4%.
Huang et al.4ChinaMortality 15%.
1 (4%) patient with COVID-19 had underlying chronic liver disease.
Fan et al.28ChinaPatients with abnormal LFT had longer hospital stay (16.4 vs. 12.6 days).
Cai et al.75ChinaHigher AST, ALT and GGT in patients with severe disease.
Patients with NAFLD had severe disease.
Cao W.76ChinaHigher ALT and AST in patients with severe COVID-19.
Shi et al.77China7 (3%) patients with COVID-19 had underlying chronic liver disease.
Wu et al.78China3% (7) had underlying CLD.
Bilirubin was significantly higher in patients with ARDS-related death.
Graselli et al.79Italy15-30% mortality in patients between 50–70 years of age.
Arentz et al.80USA3 (14.7%) patients developed acute liver injury.
Zhang et al.24ChinaMortality 1.7%.

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ALD, alcohol-related liver disease; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; CLD, chronic liver disease; COVID-19, coronavirus disease 2019; GGT, gamma glutamyltransferase; ICU, intensive care unit; LFT, liver function test; NAFLD, non-alcoholic fatty liver disease.

In the recent series from Wuhan, by Wang and colleagues,22 4 patients (2.9%) with COVID-19 had underlying chronic liver disease. Another study from China23 showed that 23 (2.1%) patients were positive for HBsAg, of whom only one had severe COVID-19. Interestingly, a study from outside Wuhan by Xu and colleagues25 identified 26 patients with COVID-19 in whom 11% had underlying chronic liver disease. In another study, comparing 113 non-survivors and 161 survivors showed that 4% had underlying chronic hepatitis B.26 Cases of acute liver injury were reported in 13 (5%) out of 274 patients of whom 10 (76.9%) died.26

With the current evidence, it is clear that elevated liver enzymes are observed predominantly in severe and critical cases of COVID-19. Raised AST was noted in 8/13 (62%) patients in ICU compared to 7/28 (25%) in the non-ICU setting.24 The peak alanine aminotransferase (ALT) and AST levels noted were 7,590 U/L and 1,445 U/L, respectively, in severe COVID-19.27 Interestingly, a higher proportion of enzyme elevation was noted in patients receiving lopinavir/ritonavir therapy (56.1% vs. 25%).28 It was unclear whether the elevated liver enzymes were due to the disease per se or drug-induced liver injury in this population. There is a possible effect of liver damage due to inflammatory cytokine storm in severe COVID-19.29

Key point

14–53% of patients with COVID-19 have been reported to develop some form of hepatic dysfunction.

Interestingly, despite the presence of ACE2 in cholangiocytes, more patients developed raised transaminases. An, unpublished data from Wuhan, China, by Xu et al. showed increased gamma glutamyltransferase (GGT) levels in severe cases of COVID-19.30 Whether COVID-19 aggravates cholestasis in patients with primary biliary cholangitis and primary sclerosing cholangitis requires further analysis.31 It is possible that hepatic dysfunction may result from cytokine storm rather than the direct cytopathic effects of the virus. More data is required to ascertain the pattern and the degree of liver injury in patients with COVID-19.

COVID-19 liver histology

Xu et al. reported the first post-mortem findings of a patient who succumbed to severe COVID-19. In his study, the liver histology revealed moderate microvesicular steatosis and mild inflammatory infiltrates in the hepatic lobule and portal tract. However, at this stage, it is unclear whether these changes are related to the viral infection or to the drugs. In addition, peripheral blood examination showed significantly reduced but hyper-reactive CD4 and CD8 cells in a proinflammatory state, with increased CCR6+ Th17 CD4 T cells and cytotoxicity granulations in CD8 cells, which may also contribute to hepatocellular dysfunction.32

In another report by Tian S et al., post-mortem liver biopsies in 4 patients with COVID-19 showed mild sinusoidal dilatation and focal macrovesicular steatosis. There was mild lobular lymphocytic infiltration, which was not significant in portal areas. SARS-CoV-2 RNA was isolated from liver tissue through RT-PCR in one of the patients. Though the bile duct epithelium expresses higher levels of ACE2 receptors, there was not much evidence to point towards bile duct damage.33

During the SARS-CoV outbreak in 2002, 23% to 60% of patients had hepatic dysfunction and few patients underwent liver biopsy. This revealed mild to moderate lobular lymphocytic inflammation, ballooning of hepatocytes and apoptosis. The most prominent feature was high mitotic figures indicative of a rapidly proliferative state (positive Ki-67). The Ki proliferative index of hepatocytes in chronic hepatitis C infection is around 0.45 to 1% suggestive of high replicative phase of hepatocytes in chronic hepatitis C infection. Immunohistochemistry studies showed that the Ki proliferative index of hepatocytes during SARS-CoV infection was much higher than during chronic hepatitis C infection and liver regeneration. The mitotic index was probably due to cell cycle arrest following SARS-CoV infection. It is possible that COVID-19 has a similar pathogenesis.34

Liver abnormality in SARS

SARS was a major pandemic in 2003. Hepatic dysfunction was described in patients with SARS. Up to 10% of patients had underlying chronic liver disease, particularly, chronic hepatitis B, probably owing to the geographic location of the SARS outbreak. Over 50% of patients developed abnormal liver function tests (mostly mild) and the majority recovered. However, in some studies, elevated liver function tests were associated with severe disease and, in particular, high ALT predicted ICU admission and death. This raised the possibility that SARS caused liver dysfunction rather than simply being associated with it.[35][36][37][38][39][40][41]

Liver abnormality in MERS

The first case of MERS-CoV infection was reported in 2012 in Saudi Arabia.42 Unlike SARS-CoV and SARS-CoV-2, MERS-CoV utilises dipeptidyl peptidase-4 (DPP-4), which is abundant in the liver, as the cell entry receptor.43 Low albumin was found to be an independent predictor of severe MERS-CoV infection.44 The liver biopsy in patients with MERS showed lobular lymphocytic infiltration and mild hydropic degeneration of hepatocytes.45 , 46 In patients with MERS, non-survivors had a higher incidence of liver injury than survivors (91.3% vs. 77.9%, respectively).47 , 48 Mortality was higher in patients with comorbidities.49 , 50

Clinical outcome of COVID-19

According to Wang and colleagues,22 disease progression manifested as increasing respiratory distress leading to pneumonia. In these patients, CT showed bilateral ground glass appearance and patchy pneumonia in almost 100% of patients. Most patients recovered with no sequalae. Overall, in patients with severe COVID-19, 19.6% developed ARDS, 16.7% had myocarditis which manifested as arrhythmias and 8.7% developed septic shock. However, this number was higher in patients admitted to the ICU; ARDS (61%), arrhythmias (44.4%), and shock (30.6%). These patients required mechanical ventilation and extracorporeal membrane oxygenation (ECMO).

Case fatality rates of 3.6–15% have been reported in 4,292 Chinese patients. Mortality was higher in men (3.25:1), those aged >75 years and those with comorbidities (diabetes mellitus, hypertension and cardiovascular disease). These comorbidities were noted in 48% of patients in a study by Zhou and colleagues51 reporting on 191 patients with COVID-19: 54 died (28.2% mortality) of whom 36 (66.6%) had underlying chronic disease. Fig. 1 illustrates the distribution of comorbidities in deceased patients. In the largest case series by Wu and colleagues,52 the overall mortality was 2.3%; however, the mortality rate was 49% in patients with critical disease. In a recent report from Italy by Remuzzi and colleagues,53 mortality related to COVID-19 was 6% (827 patients), with a male:female ratio of 4:1 and a mean age of 81 years among those who died. More than 60% of these patients had comorbidities. The median time from presentation to death was 14 days.4 , 22 Age-adjusted mortality in these 2 large series is shown in Fig. 2 .

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Fig. 1

Distribution of comorbidities in deceased patients with COVID-19.

COVID-19, coronavirus disease 2019.

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Fig. 2

Comparison of the case fatality rates of COVID-19 based on respective age groups in 2 large cohorts from China52 and Italy.53

COVID-19, coronavirus disease 2019. n.a., no data were available for age groups 50-59, 60-69, >90 years in the Chinese cohort.

According to a meta-analysis of 8 studies, including 46,248 patients, which analysed the prevalence of comorbidities in COVID-19, the most common comorbidities were hypertension (14–22%), followed by diabetes mellitus (6–11%), cardiovascular diseases (4–7%) and respiratory disease (1–3%).54 The mortality rate was higher in patients with hypertension (48%), followed by 21% in diabetics, 14% in patients with cardiovascular illness, 10% in those with chronic lung disease, and 4% each for malignancy, chronic kidney disease and cerebrovascular diseases.26 However, the mortality rate in patients with underlying chronic liver disease was 0–2%.55 In this analysis, hypertension (48% vs. 24%), diabetes (21% vs. 14%), and cardiovascular disease (14% vs. 4%) were more common in non-survivors. Fatty liver disease is likely seen as part of the metabolic syndrome in this group of patients, which can complicate the issue.

Another study from Wuhan reported on the characteristic features of deceased patients (n = 113). AST, ALT, alkaline phosphatase, GGT and bilirubin levels were significantly higher in non-survivors than survivors. Elevated AST (>40 U/L) was observed in 59 (52%) deceased and 25 (16%) recovered patients and likewise elevated ALT (>41 U/L) was found in 30 (27%) deceased and 30 (19%) recovered patients. Similarly, hypoalbuminemia (<32 g/L) was found in 74 (65%) deceased patients compared to 22 (14%) recovered patients. Serum bilirubin was 12.6 μmol and 8.4 μmol in the deceased and recovered patients, respectively. In a recent report by Chen et al., 13 (5%) patients with COVID-19 developed acute liver injury during the course of the illness of whom 10 (76.9%) died.26 Although the numbers are small, this conveys an important message on patients with COVID-19 and hepatic dysfunction.

Key point

Hepatic dysfunction was significantly more frequent in critically ill patients and was associated with poor outcome.

Diagnosis

Diagnosis of COVID-19 was based on Real time reverse transcription polymerase chain reaction (RT-PCR). In the case series described by Wang and colleagues22 centrifuged throat swab samples were used for testing. The total viral RNA was extracted within 2 hours using an RNA isolation kit. RT-PCR of the suspension was performed and amplification of Open reading frame (ORIF) and nucleocapsid protein were carried out using respective forward, reverse primers and the probe. Diagnosis were also obtained using nasal swabs, oral and rectal swabs. Interestingly, Xiao and colleagues20 showed patients with SARS CoV-2 related respiratory illness can continue to shed virus in stool even after a negative respiratory sample.

Management

Although the evidence is less clear, the current treatment recommendations include antiviral drugs, antibiotics, intravenous fluids and corticosteroids. Oseltamivir was utilised in 89.9% of patients in the Wuhan series. Remdisivir was though initially promising, a recent randomized control study did not show clinical benefit in COVID-19 except non significant faster clinical recovery. Moreover, liver injury was observed in 10-13 % of remdisivir treated group.56 Being an RNA virus, one would expect broad spectrum ribavirin to work; unfortunately, during the SARS outbreak, ribavirin was associated with significant toxicity including severe haemolysis. Interestingly, Omrani and colleagues57 found interferon alpha 2 A in combination with ribavirin to improve survival at day 14 (70% vs. 17%, p = 0.004) but not day 28 (30% vs. 17%, p = 0.054) during the MERS-CoV outbreak.

Lopinavir/ritonavir, approved for HIV infection showed in vitro activity against SARS-CoV and was beneficial in MERS-CoV.58 These drugs are being tried in COVID-19. Lopinavir, a protease inhibitor, has been shown to be effective in controlling SARS-CoV. Ritonavir was added to increase the trough level of lopinavir through CYP450 enzyme inhibition in liver. A recently published open labelled, randomised controlled trial on 199 patients with severe COVID-19 showed no benefit of lopinavir and ritonavir (99 patients). It was debated

Key point

Current treatment recommendations for COVID-19 include corticosteroids, antiviral drugs, antibiotics and intravenous fluids.

whether the trial should have been conducted in less sick patients and treatment should have been initiated in an earlier phase of COVID-19. In this study, 20.5% and 41% of patients had elevated AST and ALT prior to randomisation, respectively; however, the presence of cirrhosis, ALT or AST >5 times the upper limit normal were exclusion criteria in this trial. Increased bilirubin and elevated AST were noted in 3.2% and 2.1% of patients in the treatment group, respectively.59 Importantly, using ritonavir to inhibit CYP450 will increase the trough levels of calcineurin inhibitors, the most commonly used immunosuppression in solid organ transplant recipients, leading to potential drug toxicity.

Antibiotics such as fluoroquinolones and third-generation cephalosporins were used to reduce secondary infection. Corticosteroids (methylprednisolone) have been used in patients with COVID-19 to curtail inflammation22 and, recently, dexamethasone has been found to reduce mortality. Their use can lead to the reactivation of chronic hepatitis B. Thus, HBsAg-positive patients should be given antiviral therapy and we recommend checking hepatitis B core antibody status and, if positive, treating patients with antivirals for the duration of steroid therapy.

Recently, Chen et al. constructed a 3-dimensional crystal structure model of SARS-CoV-2 proteases. Virtual screening of the active viral site demonstrated that hepatitis C NS5A inhibitors could be effective in controlling SARS-CoV-2. Ledipasvir and velpatasvir readily inhibited SARS-CoV proteases in their model. However, more evidence is required.

COVID-19 and HCC

Patients with underlying cancer are often immunosuppressed, as result of the natural history of the disease and chemotherapy. In a nationwide study of 1,590 cancer patients with COVID-19 across 575 hospitals in China, it was observed that patients with cancer were at higher risk of contracting SARS-CoV-2 infection and developing severe illness. They also had worse outcomes than those without cancer.61 Most patients with hepatocellular carcinoma (HCC) have underlying chronic liver disease and therefore, they fall under this high-risk category and are likely to have worse outcomes. AASLD currently recommends delaying HCC surveillance by 2 months; however, HCC-related treatments should be carried out without much delay.31 EASL recommends avoiding HCC surveillance in COVID-19-positive patients, postponing locoregional therapy and temporarily withholding immune checkpoint inhibitor therapy.62

COVID-19 and deceased donor transplantation

There has been a significant decline in cadaveric organ donation during the COVID-19 pandemic.63 This can affect patients awaiting liver or other solid organ transplantation, leading to increased waiting list mortality. There has been a recent debate on harvesting organs from SARS-CoV-2-positive donors, like the discussion around HCV-positive donors.64 However, the risk of disease transmission to the transplant team remains a major concern.65 This may be an interesting option in the future, when effective vaccination comes available.

Post-liver transplant COVID-19

COVID-19 leaves no stone unturned, including liver transplant recipients. A recent case report from Wuhan described a 37-year-old man with hepatitis B and HCC, who developed fever on the third day post transarterial chemoembolisation. He was initially treated with antibiotics and subsequently liver transplantation on day 7. His fever continued on day 9, and a CT scan of his chest showed hypostatic changes in both lung fields. A repeat CT on the third week showed bilateral ground glass appearance. His nasopharyngeal swab confirmed COVID-19. His tacrolimus dose was reduced and maintained under 10 ng/ml. His liver enzymes increased by the fourth week but settled gradually. His PCR remained positive for nearly 2 months and subsequently cleared.66

Another case of post-transplant COVID-19 was described recently. The patient underwent cadaveric liver transplantation in July 2017. He presented recently with high fever and developed severe COVID-19. His tacrolimus was discontinued for a month, but he received corticosteroid therapy. His allograft function remained normal.67

Some immunosuppressive drugs possess antiviral activity by virtue of their mechanism of action. Studies from SARS identified an interaction between SARS-CoV non-structural proteins and cyclophilins, resulting in modulation of T cell immune responses. In vitro studies showed that cyclosporine inhibited SARS-CoV at higher doses. However, its clinical utility was limited by its profound immunosuppressive effects.68 Similarly, mycophenolic acid exhibited potent antiviral properties against MERS-CoV in vitro.69 Interestingly, mTOR inhibitors (everolimus) showed effectiveness against SARS-CoV and MERS-CoV infections by blocking early viral entry and post-entry consequences.70 , 71 Although in vitro studies, the antiviral properties of these drugs may offer some protection against COVID-19 in transplant recipients, particularly to ameliorate disease severity.

Literature from SARS-CoV and MERS-CoV showed that post-liver transplant patients on immunosuppression were not at higher risk of mortality. Similar data on SARS-CoV-2 are very limited.72

Rapid clinical deterioration in COVID-19 is often due to a cytokine storm associated with elevated interleukin (IL)-6, IL-8 and tumour necrosis factor-alpha levels. The combined effects of SARS-CoV-2 infection and immunosuppression are not well established. However, stopping immunosuppressive medications in transplant patients may lead to rejection. In patients with COVID-19 on high dose steroids, the dose needs to be tapered and maintained at 10 mg/day. When there is lymphopenia, fever and worsening lung condition, azathioprine, mycophenolate and calcineurin inhibitor doses need to be reduced but not stopped. Caution needs to be exercised when considering initiation of steroids or other immunosuppressive therapy in patients with severe alcoholic hepatitis, autoimmune hepatitis etc.31 Patients on immunosuppression may be more infectious as they have higher viral titres.73

The American Society of Transplantation has provided a few recommendations specifically for those awaiting liver transplantation and transplant recipients during the current pandemic. The recommendations include patient education, hand hygiene and social distancing, provision for patients to contact the transplant centre via telephone if they develop fever, cough or flu-like symptoms. Each hospital should provide layout protocols for managing these high-risk patients. Allograft function and drug interactions should be carefully monitored in transplant recipients with COVID-19, because ritonavir can potentially inhibit the CYP34A enzyme, leading to increasing trough levels of mTOR and calcineurin inhibitors, and possibly drug toxicity. In addition, they have recommended postponing elective surgeries including living donor transplantation and non-urgent deceased donor transplantations in areas with a high prevalence of COVID-19. In addition, potential deceased donors should be adequately tested for SARS-CoV-2 with nucleic acid assays.73

Conclusion

COVID-19 is currently a pandemic, with an overall mortality rate of 2–6% in infected patients, which increases with age and comorbidities. COVID-19 causes pneumonia, but hepatic dysfunction can occur in severe cases and is associated with fatal outcome. Cases of severe acute liver injury have been reported with higher mortality. Larger studies with long-term follow-up are required to characterise the extent and cause of liver damage in COVID-19. The effects of COVID-19 on underlying chronic liver disease require detailed evaluation, with further research warranted in this area.

Abbreviations

ACE2, angiotensin-converting enzyme 2; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; GGT, gamma glutamyltransferase; HCC, hepatocellular carcinoma; ICU, intensive care unit; MERS, Middle East respiratory syndrome; MERS-CoV, MERS coronavirus; NAFLD, non-alcoholic fatty liver disease; RT-PCR, reverse transcription PCR; SARS, severe acute respiratory syndrome; SARS-CoV, SARS coronavirus; SARS-CoV-2, SARS coronavirus 2; SIRS, systemic inflammatory response syndrome; WHO, World Health Organization.

Financial support

The authors received no financial support to produce this manuscript.

Authors’ contributions

Dinesh Jothimani: Conceptualization; Project Administration; Supervision; Writing -original draft; Writing – review & editing. Radhika Venugopal: Data curation; Resources; Software; Writing – review & editing. Mohammed Forhad Abedin: Resources; Writing – review & editing; Ilankumaran Kaliamoorthy: Supervision; Validation; Writing – review & editing; Mohamed Rela: Conceptualization; Supervision; Writing – review & editing.

Conflict of interest

The authors declare no conflicts of interest that pertain to this work.

Please refer to the accompanying ICMJE disclosure forms for further details.

Footnotes

Author names in bold designate shared co-first authorship

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2020.06.006.

Supplementary data

disclosures.pdf:Click here to view.(185K, pdf)Go to:

References

1. Benvenuto D., Giovanetti M., Ciccozzi A., Spoto S., Angeletti S., Ciccozzi M. The 2019-new coronavirus epidemic: evidence for virus evolution. J Med Virol. 2020;92(4):455–459. [PMC free article] [PubMed] [Google Scholar]

2. Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273. [PMC free article] [PubMed] [Google Scholar]

3. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J. China novel coronavirus investigating and research team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–733. [PMC free article] [PubMed] [Google Scholar]

4. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. [PMC free article] [PubMed] [Google Scholar]

5. Chen J. Pathogenicity and transmissibility of 2019-nCoV-A quick overview and comparison with other emerging viruses. Microbes Infect. 2020;22(2):69–71. [PMC free article] [PubMed] [Google Scholar]

6. World Health Organization Situation report – 120; Coronavirus disease 2019 (COVID-19) 2020. www.who.int Available at. Accessed May 20, 2020.

7. Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450–454. [PMC free article] [PubMed] [Google Scholar]

8. Guo Y.R., Cao Q.D., Hong Z.S., Tan Y.Y., Chen S.D., Jin H.J. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res. 2020;7(1):11. [PMC free article] [PubMed] [Google Scholar]

9. Hamming I., Timens W., Bulthuis M.L., Lely A.T., Navis G., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637. [PMC free article] [PubMed] [Google Scholar]

10. Chai X., Hu L., Zhang Y., Han W., Lu Z., Ke A. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. BioRxiv. 2020 doi: 10.1101/2020.02.03.931766.  [CrossRef] [Google Scholar]

11. Zhao S., Lin Q., Ran J., Musa S.S., Yang G., Wang W. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak. Int J Infect Dis. 2020;92:214–217. [PMC free article] [PubMed] [Google Scholar]

12. Zhou C. Evaluating new evidence in the early dynamics of the novel coronavirus COVID-19 outbreak in Wuhan, China with real time domestic traffic and potential asymptomatic transmissions. medRxiv. 2020 doi: 10.1101/2020.02.15.20023440. [CrossRef] [Google Scholar]

13. van Doremalen N., Bushmaker T., Morris D.H., Holbrook M.G., Gamble A., Williamson B.N. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564–1567. [PMC free article] [PubMed] [Google Scholar]

14. Li Q., Guan X., Wu P., Wang X., Zhou L., Tong Y. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199–1207. [PMC free article] [PubMed] [Google Scholar]

15. Leung W.K., To K.F., Chan P.K., Chan H.L., Wu A.K., Lee N. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology. 2003;125(4):1011–1017. [PMC free article] [PubMed] [Google Scholar]

16. Peiris J.S., Chu C.M., Cheng V.C., Chan K.S., Hung I.F., Poon L.L., HKU/UCH SARS Study Group Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–1772. [PMC free article] [PubMed] [Google Scholar]

17. Lee N., Hui D., Wu A., Chan P., Cameron P., Joynt G.M. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003;348(20):1986–1994. [PubMed] [Google Scholar]

18. Tian Y., Rong L., Nian W., He Y. Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;51(9):843–851. [PMC free article] [PubMed] [Google Scholar]

19. Zhang W., Du R.H., Li B., Zheng X.S., Yang X.L., Hu B. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9(1):386–389. [PMC free article] [PubMed] [Google Scholar]

20. Xiao F., Tang M., Zheng X., Liu Y., Li X., Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158(6):1831–1833.e3. [PMC free article] [PubMed] [Google Scholar]

21. Yeo C., Kaushal S., Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible. Lancet Gastroenterol Hepatol. 2020;5(4):335–337. [PMC free article] [PubMed] [Google Scholar]

22. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–1069. [PMC free article] [PubMed] [Google Scholar]

23. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X., China Medical Treatment Expert Group for Covid-19 Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720. [PMC free article] [PubMed] [Google Scholar]

24. Zhang C., Shi L., Wang F.S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol. 2020;5(5):428–430. [PMC free article] [PubMed] [Google Scholar]

25. Xu X.W., Wu X.X., Jiang X.G., Xu K.J., Ying L.J., Ma C.L. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606. [PMC free article] [PubMed] [Google Scholar]

26. Chen T., Wu D., Chen H., Yan W., Yang D., Chen G. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. [PMC free article] [PubMed] [Google Scholar]

27. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513. [PMC free article] [PubMed] [Google Scholar]

28. Fan Z., Chen L., Li J., Tian C., Zhang Y., Huang S. Clinical features of COVID-19 related liver damage. medRxiv. 2020 doi: 10.1101/2020.02.26.20026971. [CrossRef] [Google Scholar]

29. Alqahtani S.A., Schattenberg J.M. Liver injury in COVID-19: The current evidence. United European Gastroenterol J. 2020;8(5):509–519. [PMC free article] [PubMed] [Google Scholar]

30. Xu L., Liu J., Lu M., Yang D., Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020;40(5):998–1004. [PMC free article] [PubMed] [Google Scholar]

31. Clinical insights for hepatology and liver transplant providers during the covid-19 pandemic American Association for the Study of Liver Diseases. www.aasld.org Available at. Released March 23, 2020. [PMC free article] [PubMed]

32. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420–422. [PMC free article] [PubMed] [Google Scholar]

33. Tian S., Xiong Y., Liu H., Niu H., Guo J., Liao M. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020;33(6):1007–1014. [PMC free article] [PubMed] [Google Scholar]

34. Chau T.N., Lee K.C., Yao H., Tsang T.Y., Chow T.C., Yeung Y.C. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology. 2004;39(2):302–310. [PMC free article] [PubMed] [Google Scholar]

35. Chang H.L., Chen K.T., Lai S.K., Kuo H.W., Su I.J., Lin R.S. Hematological and biochemical factors predicting SARS fatality in Taiwan. J Formos Med Assoc. 2006;105(6):439–450. [PMC free article] [PubMed] [Google Scholar]

36. Chan H.L., Kwan A.C., To K.F., Lai S.T., Chan P.K., Leung W.K. Clinical significance of hepatic derangement in severe acute respiratory syndrome. World J Gastroenterol. 2005;11(14):2148–2153. [PMC free article] [PubMed] [Google Scholar]

37. Yang Z., Xu M., Yi J.Q., Jia W.D. Clinical characteristics and mechanism of liver damage in patients with severe acute respiratory syndrome. Hepatobiliary Pancreat Dis Int. 2005;4(1):60–63. [PubMed] [Google Scholar]

38. Wu K.L., Lu S.N., Changchien C.S., Chiu K.W., Kuo C.H., Chuah S.K. Sequential changes of serum aminotransferase levels in patients with severe acute respiratory syndrome. Am J Trop Med Hyg. 2004;71(2):125–128. [PubMed] [Google Scholar]

39. Duan Z.P., Chen Y., Zhang J., Zhao J., Lang Z.W., Meng F.K. Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndromeZhonghua Gan Zang Bing Za Zhi. 2003;11(8):493–496. Chinese. [PubMed] [Google Scholar]

40. Chan H.L., Leung W.K., To K.F., Chan P.K., Lee N., Wu A. Retrospective analysis of liver function derangement in severe acute respiratory syndrome. Am J Med. 2004;116(8):566–567. [PMC free article] [PubMed] [Google Scholar]

41. Peiris J.S., Lai S.T., Poon L.L., Guan Y., Yam L.Y., Lim W., SARS study group Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003;361(9366):1319–1325. [PMC free article] [PubMed] [Google Scholar]

42. Raj V.S., Mou H., Smits S.L., Dekkers D.H., Müller M.A., Dijkman R. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495(7440):251–254. [PMC free article] [PubMed] [Google Scholar]

43. Boonacker E., Van Noorden C.J. The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol. 2003;82(2):53–73. [PubMed] [Google Scholar]

44. Saad M., Omrani A.S., Baig K., Bahloul A., Elzein F., Matin M.A. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis. 2014;29:301–306. [PMC free article] [PubMed] [Google Scholar]

45. Ng D.L., Al Hosani F., Keating M.K., Gerber S.I., Jones T.L., Metcalfe M.G. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am J Pathol. 2016;186(3):652–658. [PMC free article] [PubMed] [Google Scholar]

46. Alsaad K.O., Hajeer A.H., Al Balwi M., Al Moaiqel M., Al Oudah N., Al Ajlan A. Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection – clinicopathological and ultrastructural study. Histopathology. 2018;72(3):516–524. [PMC free article] [PubMed] [Google Scholar]

47. Arabi Y.M., Al-Omari A., Mandourah Y., Al-Hameed F., Sindi A.A., Alraddadi B., Saudi Critical Care Trial Group Critically ill patients with the Middle East respiratory syndrome: a multicenter retrospective cohort study. Crit Care Med. 2017;45(10):1683–1695. [PubMed] [Google Scholar]

48. Hwang S.M., Na B.J., Jung Y., Lim H.S., Seo J.E., Park S.A. Clinical and laboratory findings of Middle East respiratory syndrome coronavirus infection. Jpn J Infect Dis. 2019;72(3):160–167. [PubMed] [Google Scholar]

49. Assiri A., Al-Tawfiq J.A., Al-Rabeeah A.A., Al-Rabiah F.A., Al-Hajjar S., Al-Barrak A. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013;13(9):752–761. [PMC free article] [PubMed] [Google Scholar]

50. Arabi Y.M., Arifi A.A., Balkhy H.H., Najm H., Aldawood A.S., Ghabashi A. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160(6):389–397. [PubMed] [Google Scholar]

51. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. [PMC free article] [PubMed] [Google Scholar]

52. Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. [PubMed] [Google Scholar]

53. Remuzzi A., Remuzzi G. COVID-19 and Italy: what next. Lancet. 2020;395(10231):1225–1228. [PMC free article] [PubMed] [Google Scholar]

54. Yang J., Zheng Y., Gou X., Pu K., Chen Z., Guo Q. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–95. [PMC free article] [PubMed] [Google Scholar]

55. Bangash M.N., Patel J., Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol. 2020;5(6):529–530. [PMC free article] [PubMed] [Google Scholar]

56. Wang Y., Zhang D., Du G., Du R., Zhao J., Jin Y. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569–1578. [PMC free article] [PubMed] [Google Scholar]

57. Omrani A.S., Saad M.M., Baig K., Bahloul A., Abdul-Matin M., Alaidaroos A.Y. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090–1095. [PMC free article] [PubMed] [Google Scholar]

58. Chu C.M., Cheng V.C., Hung I.F., Wong M.M., Chan K.H., Chan K.S., HKU/UCH SARS Study Group Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252–256. [PMC free article] [PubMed] [Google Scholar]

59. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787–1799. [PMC free article] [PubMed] [Google Scholar]

60. Chen Y.W., Yiu C.B., Wong K.Y. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Res. 2020;9:129. [PMC free article] [PubMed] [Google Scholar]

61. Liang W., Guan W., Chen R., Wang W., Li J., Xu K. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335–337. [PMC free article] [PubMed] [Google Scholar]

62. Boettler T., Newsome P.N., Mondelli M.U., Maticic M., Cordero E., Cornberg M. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper. JHEP Rep. 2020;2(3):100113. [PMC free article] [PubMed] [Google Scholar]

63. Loupy A., Aubert O., Reese P.P., Bastien O., Bayer F., Jacquelinet C. Organ procurement and transplantation during the COVID-19 pandemic. Lancet. 2020;395(10237):e95–e96. [PMC free article] [PubMed] [Google Scholar]

64. Kates O.S., Fisher C.E., Rakita R.M., Reyes J.D., Limaye A.P. Use of SARS-CoV-2 infected deceased organ donors: should we always “just say no?” Am J Transplant. 2020;20(7):1787–1794. [PMC free article] [PubMed] [Google Scholar]

65. Shah M.B., Lynch R.J., El-Haddad H., Doby B., Brockmeier D., Goldberg D.S. Utilization of deceased donors during a pandemic: an argument against using SARS-CoV-2 positive donors. Am J Transplant. 2020;20(7):1795–1799. [PMC free article] [PubMed] [Google Scholar]

66. Qin J., Wang H., Qin X., Zhang P., Zhu L., Cai J. Perioperative presentation of COVID-19 disease in a liver transplant recipient. Hepatology. 2020 doi: 10.1002/hep.31257. Epub ahead of print. [PubMed] [CrossRef] [Google Scholar]

67. Liu B., Wang Y., Zhao Y., Shi H., Zeng F., Chen Z. Succssful treatment of severe COVID-19 pneumonia in a liver transplant recipient. Am J Transplant. 2020;20(7):1891–1895. [PubMed] [Google Scholar]

68. Tanaka Y., Sato Y., Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses. 2013;5(5):1250–1260. [PMC free article] [PubMed] [Google Scholar]

69. Chan J.F., Chan K.H., Kao R.Y., To K.K., Zheng B.J., Li C.P. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67(6):606–616. [PMC free article] [PubMed] [Google Scholar]

70. Kindrachuk J., Ork B., Hart B.J., Mazur S., Holbrook M.R., Frieman M.B. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrobial Agents Chemother. 2015;59(2):1088–1099. [PMC free article] [PubMed] [Google Scholar]

71. Zumla A., Chan J.F., Azhar E.I., Hui D.S., Yuen K.Y. Coronaviruses – drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327–347. [PMC free article] [PubMed] [Google Scholar]

72. D’Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl. 2020;26(6):832–834. [PubMed] [Google Scholar]

73. American Society of Transplantation 2019-nCoV (Coronavirus): FAQs for organ donation and transplantation. www.myast.org Updated 20 Mar 2020. Available at. Accessed May 20, 2020.

74. Li L., Li S., Xu M., Li L., Li S., Xu M. Risk factors related to hepatic injury in patients with corona virus disease 2019. medRxiv. 2020 doi: 10.1101/2020.02.28.20028514. [CrossRef] [Google Scholar]

75. Cai Q., Huang D., Ou P., Yu H., Zhu Z., Xia Z. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. medRxiv. 2020 doi: 10.1101/2020.02.17.20024018. [PubMed] [CrossRef] [Google Scholar]

76. Cao W. Clinical features and laboratory inspection of novel coronavirus pneumonia (COVID-19) in Xiangyang, Hubei. medRxiv. 2020 doi: 10.1101/2020.02.23.20026963. [CrossRef] [Google Scholar]

77. Shi H., Han X., Jiang N., Cao Y., Alwalid O., Gu J. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425–434. [PMC free article] [PubMed] [Google Scholar

]78. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1–11. [PMC free article] [PubMed] [Google Scholar]

79. Grasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A., COVID-19 Lombardy ICU Network Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA. 2020;323(16):1574–1581. [PMC free article] [PubMed] [Google Scholar]

80. Arentz M., Yim E., Klaff L., Lokhandwala S., Riedo F.X., Chong M. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state. JAMA. 2020;323(16):1612–1614. [PMC free article] [PubMed] [Google Scholar]

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

Authors: Rouzbeh ShadidiAsilaSetarehMahmoodiaAmirZamaniaAzadehHakakzadehbcElenaJamalid

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

Highlights

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

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

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

Abstract

Introduction

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

Case presentation

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

Conclusion

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

1. Introduction

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

2. Case presentation

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

Fig. 1
Fig. 2

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

Fig. 3

3. Discussion

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

4. Conclusions

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

Provenance and peer review

Not commissioned, externally peer-reviewed.

Sources of fundings

There was no funding source for this study.

Ethical approval

Ethical approval not required.

Consent

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

Research registration

N/A.

Guarantor

Dr. Amir Zamani.

Author contribution

All authors made a major contribution in preparing this manuscript.

Declaration of competing interest

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

References

[1]S.B. Omer, P. Malani, C. Del RioThe COVID-19 pandemic in the US: a clinical updateJAMA, 323 (18) (2020), pp. 1767-1768 View PDFView Record in ScopusGoogle Scholar

[2]M.H. Cha, M. Regueiro, D.S. SandhuGastrointestinal and hepatic manifestations of COVID-19: a comprehensive reviewWorld J. Gastroenterol., 26 (19) (2020), pp. 2323-2332View Record in ScopusGoogle Scholar

[3]R.A. Agha, T. Franchi, C. Sohrabi, G. Mathew, A. Kerwan, A. Thoma, et al.The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelinesInt. J. Surg., 84 (2020), pp. 226-230ArticleDownload PDFView Record in ScopusGoogle Scholar

[4]N. Zhu, D. Zhang, W. Wang, X. Li, B. Yang, J. Song, et al.A Novel Coronavirus from Patients with Pneumonia in China, 2019N. Engl. J. Med., 382 (8) (2020), pp. 727-733 View PDFCrossRefGoogle Scholar [5]J. Gu, B. Han, J. WangCOVID-19: gastrointestinal manifestations and potential fecal–oral transmissionGastroenterology, 158 (6) (2020), pp. 1518-1519ArticleDownload PDFView Record in ScopusGoogle Scholar

[6]Y. Tian, L. Rong, W. Nian, Y. HeGastrointestinal features in COVID-19 and the possibility of faecal transmissionAliment. Pharmacol. Ther., 51 (9) (2020), pp. 843-851 View PDFCrossRefView Record in ScopusGoogle Scholar\

[7]F. D’Amico, D.C. Baumgart, S. Danese, L. Peyrin-BirouletDiarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention, and managementClin. Gastroenterol. Hepatol., 18 (8) (2020 Jul 1), pp. 1663-1672ArticleDownload PDFView Record in ScopusGoogle Scholar

[8]F. Xiao, M. Tang, X. Zheng, Y. Liu, X. Li, H. ShanEvidence for gastrointestinal infection of SARS-CoV-2Gastroenterology, 158 (6) (2020), pp. 1831-1833e3 View PDFView Record in ScopusGoogle Scholar

[9]G.C. Cardona, L.D.Q. Pájaro, I.D.Q. Marzola, Y.R. Villegas, L.R.M. SalazarNeurotropism of SARS-CoV 2: mechanisms and manifestationsJ. Neurol. Sci., 412 (2020), Article 116824