Long COVID study looks at why some can’t shake dizziness, fatigue and more

Authors: Helena Oliviero, The Atlanta Journal-Constitution

Georgia residents among thousands needed for a massive study to discover how the virus causes lingering symptoms.

Back in the summer of 2020, when the pandemic was still new and hospitals were overflowing, Emory Healthcare opened a facility to treat a perplexing group of COVID-19 survivors.

The patients had withstood the virus’s initial onslaught but couldn’t shake some of the symptoms.

At the time, Dr. Alex Truong thought the long COVID clinic might be needed for a year, maybe two.

But long COVID — a mysterious constellation of ailments that can go on for many weeks or months — has become a bigger problem than Truong could have ever imagined.

In the U.S. alone, 1 in 5 of the adults stricken with COVID-19 have developed conditions that could be considered long COVID, according to a recent study by the Centers for Disease Control and Prevention. Symptoms range from brain fog and unrelenting fatigue to gastric and cardiac issues. Among those 65 and older, the estimates are even higher — 1 in 4.

That translates into millions of Americans and more than 300,000 Georgians.

Other estimates vary wildly. There is no test for long COVID. No official statistics exist.

Clinicians at the Emory clinic have treated more than 1,000 COVID survivors. There’s now a four-month waiting list to be seen at the clinic.ExploreComplete coverage of COVID-19 in Georgia

“It’s been shocking,” said Truong, who is co-director of the clinic,located at Emory University Hospital Midtown. “I’ve never seen, with other infections, such widespread, all-over-the-body symptoms for this long.”

COVID can wreak havoc on a person’s body and damage organs – the lungs, heart, kidneys and liver. Experts worry that people who are infected multiple times have increased chances of developing long COVID.

How is long COVID defined?

A recent CDC study says that 1 in 5 of U.S. adults stricken with COVID-19 have developed conditions that could be considered long COVID, which the agency defines as symptoms lasting at least four weeks after infection.

The CDC says the following symptoms are the most common for this complex and poorly understood condition:

  • Tiredness or fatigue that interferes with daily life
  • Difficulty breathing, shortness of breath, chest pain
  • Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
  • Headache
  • Sleep problems
  • Anxiety
  • Digestive issues
  • Joint or muscle pain

“With COVID, we tend to think about the hospitalizations and deaths, and then we kind of stop there sometimes,” said Dr. Tiffany Walker, who has treated long COVID patients at Grady Memorial Hospital. “I don’t want to paint the picture of everybody’s debilitated, but some people are, and it’s people that don’t expect it. The times that people have cried in my office because they’re just so overwhelmed is like more than anything I’ve experienced before in clinical practice.”

Walker now leads a long COVID study at Grady, which is part of a massive National Institutes of Health effort to find the connection between seemingly unrelated symptoms that have afflicted patients and confounded physicians.

Scientists still do not know how the virus triggers such a wide range of problems, from minor to incapacitating, or why issues emerge in some patients but not in others, or what exactly the risk factors are for developing them.

What’s more, there is no specific treatment for longCOVID. Instead, the current approach is to deal with each symptom individually.

It’s often hard to offer satisfying answers to patients. “It’s just very upsetting and really challenging,” Walker said. “As a physician, you really want to be able to provide a prognosis at least, at a minimum to be able to express to them, this is what you can expect.”

But doctors “don’t know enough to know what the course is going to be and who’s going to get better and who isn’t, and you don’t know enough about how to treat those that aren’t getting better,” she said.

And the world’s leading health organizations don’t even have a standard definition of what constitutes long COVID, Truong said. The CDC defines long COVID, which it calls Post-COVID Conditions, as symptoms lasting four weeks or longer after infection. The World Health Organization says people cross over into long COVID after symptoms persist for at least three months.

In 2021, 60% of patients at the Emory and Grady long COVID clinics enrolled in a study aimed at gathering more information on the illness. At the time of their enrollment, patients had already been dealing with COVID symptoms for an average of 107 days.

Even people who have mild or asymptomatic COVID-19 infections can have new health problems crop up months after they’ve tested negative.

Remaining vigilant

The CDC’s study evaluated electronic medical records for nearly 2 million people. The agency compared those who had been infected with the coronavirus and those who had not. The analysis found 38% percent of the COVID patients developed one or more new health problems, compared to 16% percent of the non-COVID patients. The health problems of about 21% of the younger COVID patients in the study, those ages 18 to 64, and nearly 27% of the older people, 65 and up, could be attributed to long COVID. The study did not look at vaccination status.

A growing number of studies suggest that getting a COVID vaccine can reduce — though not eliminate — the risk of longer-term symptoms.

Some experts think that today’s omicron strains pose a lower risk for long COVID than previous variants. But they caution: Even if omicron is less likely to cause long-lasting symptoms, particularly for people who have been vaccinated, the actual number of long COVID sufferers will still grow due to the high infection rate.

It’s often hard to determine whether health problems that emerge after a case of COVID are truly triggered by the virus.

Lead Nurse Practitioner Lori Reed, who works at the Piedmont Pulmonary COVID Recovery clinic, said some patients dealing with preexisting conditions may be more aware of them after coronavirus infections. That means it’s important for clinicians to obtain thorough medical histories to pinpoint when symptoms, such as dizziness, memory loss and headaches, started and when they worsened, she said.

“One that comes up all the time is asthma because asthma can develop at any point in life,” Reed said. “We know, historically, viral illnesses can cause asthma onset, so COVID can cause asthma onset. But, with women, hormonal changes and menopause can also cause onset.”

Reed recommends patients see a doctor after a COVID infection to rule out COVID-related damage to the body, and she urges people to remain vigilant of any sign of new problems.ExploreFrom November: Georgia long-COVID patients fight for benefits, legitimacy

“Pay attention to subtle things that some people may write off,” she said. “Talk to your doctor about brain fog or things like, ‘I just forgot what I was going to make for dinner,’ or ‘You know, that bill came in, and I forgot to pay for it.’”

At long COVID clinics, a team of specialists — cardiologists, pulmonologists, neurologists, psychiatrists and others — work together to treat patients. Often, the patients undergo a comprehensive evaluation, including a series of lab tests and imaging tests, to rule out other undiagnosed medical conditions.

Lacking established therapies for long COVID symptoms, doctors often rely on approaches that have been used for other ailments with similar symptoms.

“It’s been shocking. I’ve never seen, with other infections, such widespread, all-over-the-body symptoms for this long.”

– Dr. Alex Truong, co-director of Emory Healthcare’s post-COVID clinic

Neurological stimulants such as Adderall have shown to be effective at improving energy and focus. Albuterol, an inhaled medicine frequently used to treat asthma, can improve breathing. Other medications, physical therapy and cognitive programs also can be helpful.

“I would say to people who get COVID, you didn’t ask to get COVID, and you don’t deserve to fall ill and not have answers,” said Reed. “Reach out to somebody to at least be seen and evaluated because we can do things to get you feeling better. If we can’t reverse the long-term consequences, we can at least improve your quality of life.”

A high-stakes undertaking

Close to 1,000 people in Georgia — and at least 17,000 adults across the country — are being recruited for the massive NIH study called Researching COVID to Enhance Recovery (RECOVER). Its goal is to answer fundamental questions about exactly how the virus causes long COVID, which ultimately could lead to better, more tailored treatments.

The study sites in Atlanta — Emory Hope Clinic, Grady, Morehouse School of Medicine, the Atlanta Veterans Affairs Healthcare System and Kaiser Permanente of Georgia — will work together and are slated to receive a total of about$20 million over four years for the high-stakes undertaking.

The NIH study

The Atlanta sites for the NIH are still actively recruiting patients who have had COVID-19 in the past 30 days, as well as those who have never been infected. Click here for more information.

Walker, from Grady, said clinicians have been working to recruit a diverse group of adults, and are seeking three categories of participants: those who have COVID right now, those with long COVID, and others who have never had COVID. Finding people who have never had the illness is getting increasingly difficult with an ever-changing virus and continued waves of infections.

Plenty of theories have formed around long COVID. Some researchers think people suffer prolonged symptoms because they have never really shaken COVID-19, though they think they have. Instead, the virus is still hiding in their bodies, damaging nerves and other organs. Other research suggeststhe virus may be gone, but it causes the immune system to go haywire and attack the body.

There’s also research that indicates certain medical conditions may play a role in who develops long COVID, such as Type 2 diabetes, or a reactivation of Epstein-Barr virus, which infects most people when they are young.

‘A monster’

In July 2020, Latoshia Allen Perrymond fell ill with COVID. Within a week, the 52-year-old Stone Mountain woman was struggling to catch her breath. She ended up hospitalized — for four months.

Though she survived, COVID damaged her heart and lungs. She said she’s been struggling mightily ever since. Dependent on oxygen around the clock, the former caregiver now relies on family members to help care for her.

She can no longer go on walks with her husband or cook big meals, or even sleep lying flat.

In late March, she eagerly joined the NIH study at Grady.

Like other participants in the NIH RECOVER study, she’s undergoing physical assessments.

“I feel good about the study because it means that I’m part of the answers,” she said. “I’m willing to do whatever they need because this COVID and long COVD is a monster and it’s still creepy. I’m learning to live with this new norm for me, but I hope that I can get better.”

Doctors are also eager for more answers.

“My hope is to find a pathology that unifies all of these symptoms,” said Truong. “My hope is, as the pandemic progresses, the variants become less virulent and less likely to cause long haul issues, and more and more patients are getting vaccinated. I hope we learn from this pandemic so that, when the next pandemic comes, we are a lot smarter, a lot more nimble in our approach, and more aware of the long haul issues.”

For now, the best way to try to avoid long COVID is to try to avoid the virus, Truong said. Get vaccinated and boosted and wear masks – especially indoors around crowds of people.

“It’s as simple as that,” he said. “But, unfortunately, I don’t think people want to hear it.”

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COVID-19 Can Infect and Harm Digestive Organs

Authors: E.J. Mundell

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

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

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

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

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

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

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

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

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

That seems to be borne out by the Boston study.

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

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

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

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

Introduction

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

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

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

Gastrointestinal Symptoms and SARS-CoV-2 Infection

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

Intestinal Infection and Transmission Routes

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

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

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

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

Intestinal Damage, Malnutrition, and Poor Outcomes

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

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

Intestinal Ischemia and Thrombosis

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

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

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

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

Long-Term Gastrointestinal Sequelae

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

The Mechanisms of Intestinal Thrombosis

Damaged Endothelial Cells

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

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

Hyperactivated Platelets and Phosphatidylserine Storm

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

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

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

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

Early Antithrombotic Treatment

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

Anticoagulation

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

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

Inhibition of Platelet Activation

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

Factors Influencing Antithrombotic Treatment

Thrombotic Risk Factors or Co-morbidities

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

Vaccination

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

Conclusion and Future Research

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

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

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HOW COVID-19 AFFECTS THE GUT: SCIENTISTS UNCOVER A RARE SIDE EFFECT

Authors: published on The Conversation by Vincent Ho at Western Sydney University.

Although we might think of Covid-19 as a respiratory disease, we know it involves the gut. In fact, SARS-CoV-2, the virus that causes Covid-19, enters our cells by latching onto protein receptors called ACE2. And the greatest numbers of ACE2 receptors are in the cells that line the gut.

Covid-19 patients with gut symptoms are also more likely to develop severe disease. That’s partly because even after the virus has been cleared from the respiratory system, it can persist in the gut of some patients for several days. That leads to a high level of virus and longer-lasting disease.

We also suspect the virus can be transmitted via the fecal-oral route. In other words, the virus can be shed in someone’s poo, and then transmitted to someone else if they handle it and touch their mouth.

WHAT TYPE OF GUT SYMPTOMS ARE WE TALKING ABOUT?

review of more than 25,000 Covid-19 patients found about 18% had gastrointestinal symptoms. The most common was diarrhea followed by nausea and vomiting. Abdominal pain was considered rare. In another study only about 2% of Covid-19 patients had abdominal pain.

Some people believe Covid-19 causes abdominal pain through inflammation of the nerves of the gut. This is a similar way to how gastroenteritis (gastro) causes abdominal pain.

Another explanation for the pain is that Covid-19 can lead to a sudden loss of blood supply to abdominal organs, such as the kidneys, resulting in tissue death (infarction).

ARE GUT SYMPTOMS RECOGNIZED?

The US Centers for Disease Control has added diarrhea, nausea, and vomiting to its list of recognized Covid-19 symptoms.

However, the World Health Organization still only lists diarrhea as a gastrointestinal Covid-19 symptom.

In Australia, nausea, diarrhea, and vomiting are listed as other Covid-19 symptoms, alongside the classic ones (which include fever, cough, sore throat and shortness of breath). But abdominal pain is not listed.

Advice of symptoms that warrant testing may vary across different states and territories.

HOW LIKELY IS IT?

Doctors often use the concept of pre-test probability when working out if someone has a particular disease. This is the chance a person has the disease before we know the test result.

What makes it difficult to determine the pre-test probability for Covid-19 is we don’t know how many people in the community truly have the disease.

We do know, however, Covid-19 in Australia is much less common than in many other countries. This affects the way we view symptoms that aren’t typically associated with Covid-19.

It’s far more common for people’s abdominal pain to be caused by something other than Covid-19. For example, about a quarter of people at some point in their lives are known to suffer from dyspepsia (discomfort or pain in the upper abdomen). But the vast majority of people with dyspepsia do not have Covid-19.

Similarly, irritable bowel syndrome affects about 9% of Australians, and causes diarrhea. Again, the vast majority of people with irritable bowel syndrome do not have Covid-19.

SO HOW ABOUT THIS LATEST CASE?

In the Queensland case, we know the nurse was worried he could have had Covid-19 because he was in close contact with Covid-19 patients.

As he seemed otherwise healthy before developing new abdominal symptoms, and considering he worked on a Covid ward, his pre-test probability was high. Doctors call this a “high index of suspicion” when there is a strong possibility someone may have symptoms due to a disease such as Covid-19.

WHAT DOES THIS MEAN FOR ME?

If you have new gastrointestinal symptoms and you’ve potentially been in contact with someone with COVID-19 or if you also have other classic Covid-19 symptoms (fever, cough, shortness of breath and sore throat) you should definitely get tested.

If you have just gastrointestinal symptoms, you may need to get tested if you’re in a “hotspot” area, or work in a high-risk occupation or industry.

If you have gastrointestinal symptoms alone, without any of these additional risk factors, there is no strong evidence to support testing.

However, if Covid-19 becomes even more common in the community, these symptoms now regarded as uncommon for Covid-19 will become more common.

If you have concerns about any gastrointestinal symptoms, seeing your GP would be sensible. Your GP will provide a balanced assessment based on your medical history and risk profile.

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

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

Abstract

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

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

1. Abdominal findings of COVID019 in adults

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

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

Table 1

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

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

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Table 2

Summary of imaging findings in Multisystem Inflammatory Syndrome in Children.

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

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2. Abdominal findings of COVID-19 in adults

2.1. Hepatobiliary derangement

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

2.1.1. Hepatic injury

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

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

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

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

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

Oxygen Levels and the Digestive System

Authors: by Lung Health | Jun 9, 2016 | Oxygen LevelsResources

It might sound strange, but the respiratory system and the digestive system depend on one another for optimal function. Because oxygen is essential to the proper functioning of the body, one of the main concerns for people with chronic lung diseases is maintaining enough oxygen in their blood. The body needs energy and oxygen, so let’s take a closer look at oxygen levels and the digestive system.

What does the digestive system do?

The digestive system breaks down food so that it can become energy for the body. The digestive system is comprised of a complex system of organs, nerves, hormones, bacteria and blood work together to digest food. Digestive organs include the stomach, small intestines, large intestines, liver, pancreas and gall bladder.

What’s the connection between the respiratory system, oxygen levels and the digestive system?

The respiratory and digestive systems work together to power the body. A properly functioning respiratory system delivers adequate oxygen to the blood. Because the digestive system breaks down food and uses muscular contractions to move food through the digestive tract, it needs oxygen to function properly.

In turn, the respiratory system depends on a properly functioning digestive system to provide the fuel it needs to work effectively. Each function of the body depends on other functions, and all parts of the body need fuel and oxygen.

What are the risks of having lung disease and digestive system conditions?

In many cases, oxygen levels and the digestive system go hand-in-hand. COPD and other chronic lung diseases carry a risk for certain digestive disorders. Because some foods and drinks can cause symptom flare-ups, it’s important to know what to eat and what to avoid. Foods such as dairy and cruciferous vegetables are linked to increased mucus production and gas. Certain foods can also make GERD symptoms worse.

GERD or gastroesophageal reflux disease is common among people with COPD. GERD is a digestive disorder in which the stomach valve that keeps stomach acid down weakens or malfunctions, allowing stomach acid into the esophagus. If stomach acid reaches the lungs, it can result in irritation, increased coughing and shortness of breath.

GERD Symptoms include:

  • Dry cough
  • Chest pain
  • Difficulty swallowing
  • Hoarseness or sore throat
  • Burning in the chest or throat
  • Sensation of a lump in the throat
  • Regurgitation of stomach contents

What can I do to improve my blood oxygen levels?

Talk with your doctor about any new or worsening symptoms. See your doctor regularly, even if you’re feeling well. Now that you have information about oxygen levels and the digestive system, discuss your oxygen, food and exercise needs with your doctor. You and your physician can decide, together, on the best treatment plan for you.

Cellular therapy also helps many people with chronic lung diseases breathe easier by promoting the healing of lung tissue from within the body. The Lung Health Institute extracts cells from a patient’s blood separates them and then returns them intravenously. The cells may travel with the blood through the heart and into the lungs to become oxygenated. Once in the lungs, the majority of the cells become trapped in the pulmonary trap, and the now oxygen-rich blood travels to the rest of the body. In fact, many patients report improved lung function and are able to come off their supplemental oxygen after treatment.