WHILE COVID’S respiratory complications are well known, the virus may well be attacking many other organs and systems. At this fall’s management of the hospitalized patient conference held virtually by the University of California San Francisco (UCSF), a neurologist, a GI physician and a cardiologist weighed in.
When the pandemic first broke out, S. Andrew Josephson, MD, director of the neurohospitalist program and chair of neurology at the University of California, San Francisco (UCSF), believed that he and his neurologist colleagues would have very little to do. It was, after all, a respiratory virus that typically wouldn’t affect the nervous system.
“We quickly found out, of course, that that was not the case,” said Dr. Josephson. One of the first reports to dispel that notion came from Wuhan, China. Published in April by JAMA Neurology—Dr. Josephson is editor in chief—the retrospective study found that 36% of patients in three covid-focused hospitals had neurologic manifestations.
Some were nonspecific, like dizziness and headache. But the ones that drew headlines were impaired consciousness, delirium, encephalopathy, and strokes and seizures.
“Many of the medications we either currently use or will soon use for covid don’t cross the blood-brain barrier.”
~ S. Andrew Josephson, MD University of California, San Francisco
There were also a variety of peripheral nervous system manifestations. “We all know about the taste and smell issues,” said Dr. Josephson. “But researchers also frequently found nerve pain and skeletal muscle injury.” The study, he added, “really changed the way we as neurologists thought about these patients.”
At the same time, Dr. Josephson said, many factors tempered their concerns that covid could be a widespread neurologic problem.
For one, nonspecific neurologic manifestations like confusion are very common in hospitalized patients with severe viral illness and pneumonia. An article published by The Lancet Psychiatry in July pointed out that while delirium is very common in covid patients, “it was also very common in patients with SARS and MERS.” But then other reports came out “that changed the way we think about covid even more,” he noted. “We began seeing covid patients with stroke.”
Are strokes common among covid patients? Likely yes, said Dr. Josephson. “Especially in critically ill patients, we see it more commonly than we would expect.” Correspondence in the New England Journal of Medicine in April described five covid patients in one New York health system, all under age 50, all with large vessel strokes.
“Hypercoagulability is probably driving a fair amount of this,” he noted, as are arrhythmia from cardiac involvement, cardiomyopathy, or carotid or vertebral dissection from coughing. Among his own patients, he’s also seen this devastating complication: hemorrhagic transformation in the bed of an ischemic stroke, taking place unexpectedly days after the initial event.
“This combination of hemorrhagic and hypercoagulable complications with covid has made us, to some extent, examine how we treat these patients,” he said. While he and his colleagues continue to give stroke patients antiplatelets or anticoagulants if they have atrial fibrillation or some other source of cardiac arrhythmia, “we are very cautious about it.”
Establishing whether covid directly infects patients’ central nervous system “would be a huge gamechanger,” said Dr. Josephson.
In a French study in NEJM of nearly 60 covid patients in the ICU with ARDS, a number of them underwent cerebrospinal fluid analysis. “They really were unable to demonstrate much in the way of inflammation,” he said. Importantly, none of those patients’ CSF tested positive for covid. That’s led him and his neurology colleagues to wonder if the virus is really invading the brain directly.
The few reported cases of hemorrhagic encephalopathy “could be either a demyelinating condition or one that’s antibody-mediated in response to an infection,” Dr. Josephson said. “The bottom line is that there have really been few convincing cases of meningitis or encephalitis directly related to the virus. Those are very, very rare, as we understand it.”
However, the well-known loss of smell in many covid patients is “due to the involvement of the upper portion of the nasal epithelium,” Dr. Josephson explained. “And that olfactory apparatus is really on the doorstep of the central nervous system. Perhaps it crosses the threshold, and the olfactory epithelium serves as a way for the virus to get into the brain itself.”
There have also been, Dr. Josephson said, rare reports of brainstem involvement. “There’s a lot of speculation that when the brainstem is involved, maybe that’s why people have such respiratory involvement.” But, he added, “this remains unproven.”
Prognosis, treatment implications
As for neuropathology, “we don’t see massive viral infiltrates or robust inflammation” in autopsies, said Dr. Josephson. “What we mainly see are signs related to systemic hypoxia with the occasional endothelial dysfunction and microthrombi.”
However, smaller autopsy-based series using more sophisticated staining did find a small number of patients with actual virus in the brain.
“That’s important,” he said. “If these neurologic conditions are in part due to direct viral involvement, that has wide-ranging implications for patients’ long-term prognosis.” It also has wide-ranging implications for treatment. “Many of the medications we either currently use or will soon use for covid don’t cross the blood-brain barrier.”
As for long haulers who have persistent chronic fatigue, brain fog or overt cognitive decline, “these need to be better characterized over time,” Dr. Josephson said. “I don’t think we can call anything ‘long term’ if the longest we’ve had patients with the illness is six or seven months.” Still, “it’s something we need to be aware of, and it could have major public implications for neurologists. We are very concerned.”
While neurologists aren’t sure about covid’s direct involvement in the brain, that case is closed when it comes to GI.
“We know that ACE2 receptors are the portal of entry for the covid virus into epithelial cells,” said UCSF gastroenterologist Jonathan Terdiman, MD, during his GI update. And “ACE2 receptors are ubiquitous throughout the GI tract, with more in GI epithelial cells than in alveolar cells. There is no doubt the virus can get into the GI epithelium and replicate.”
But what about the liver? That’s not as clear, Dr. Terdiman said. While ACE2 receptors are “definitely present” in hepatocytes, cirrhotic nodules and the biliary epithelium, UCSF’s own research has not found viral particles in the liver.
“There is no doubt the virus can get into the GI epithelium and replicate.”
~ Jonathan Terdiman, MD
University of California, San Francisco
A systematic review of more than 50 studies included in the July issue of Gastroenterology found that 20% of all covid patients have significant GI symptoms. In the review, diarrhea, nausea and vomiting were common while “a small fraction” had abdominal pain.
Importantly, “a significant percentage had elevated liver function tests.” Another study, this one in September from Clinical Gastroenterology and Hepatology, found that over 50% of covid patients tested at New York Presbyterian-Queens Hospital in March had liver function test abnormalities. “Most were very mild,” he said. “Only a small percentage had severe abnormalities.”
Overall, GI symptoms with covid “are generally mild, and certainly not the driving force for almost all patients,” although some patients may have GI symptoms before respiratory ones and may have only GI symptoms. Does the severity of GI symptoms portend outcome differences?
While that question has been poorly studied, Dr. Terdiman said the take-home message is probably “no.” The exception is liver function test abnormalities; patients with abnormal values are more likely to have severe disease. “That’s not suggesting a direct hepatic injury from the virus,” he clarified. “It’s just a marker, but one that is probably worth following and paying attention to.”
A role for famotidine?
Not surprisingly, studies find that patients with chronic liver disease run a two-fold greater risk of death with covid. Patients at highest risk include those with decompensated cirrhosis and alcohol-related liver disease.
But elevated risk doesn’t necessarily apply to liver patients with liver transplants. “Even though they’re highly immuno-suppressed,” Dr. Terdiman said, “if they’re well-compensated, they weren’t found to have higher mortality risk.”
There is some controversy over how common GI medications—H2 blockers, specifically famotidine, and proton pump inhibitors—may affect covid outcomes. Dr. Terdiman pointed out that President Trump’s medical covid cocktail included famotidine.
“Evidence suggests the drug could have a direct pharmacologic impact on the virus because it binds and inhibits a protease essential to viral replication,” he said. “And taking H2 blockers, and famotidine in particular, doesn’t increase your risk for an enteric or respiratory infection.”
PPIs, on the other hand, are well-known for their associated risk for infections including C. diff, bacterial dysentery, influenza, and perhaps bacterial and viral pneumonia. And patients who take PPIs and are in the ICU with pneumonia may run a higher ventilation and mortality risk.
Two studies back the efficacy of famotidine—”and they are not terribly strong”—including one risk-factor survey, with results published in August 2020 by the American Journal of Gastroenterology. Respondents self-reported their use of either H2 blockers or PPIs and whether they had tested positive for covid.
Those who used H2 blockers had a slightly decreased risk of being positive. For patients taking PPIs, however, especially those taking two doses a day, “they were more than three-and-a-half times more likely to be covid positive than non-users.”
A second study, which is still in press, looked at 1,600 covid patients at a New York hospital who received famotidine within 24 hours of being admitted. When researchers looked at outcomes and adjusted for other risk factors, “the risk for severe disease, intubation or death was reduced by half.” That said, “we’re certainly not putting people on Pepcid with the idea that we’re preventing covid or improving outcomes.” Conversely, “we don’t withdraw anyone from a PPI who otherwise needs it.”
As for covid’s impact on patients with inflammatory bowel disease, especially those taking immunosuppressants, he and his UCSF colleagues are sending data to an international registry on IBD patients and covid.
Right now, those data are still “extremely thin,” but “there is a little bit of a signal that mortality may be a bit higher with covid” for IBD patients. Not surprisingly, “the strongest signal was for patients on corticosteroids prior to diagnosis. They had an elevated risk for a bad covid outcome.”
But there’s no such evidence for patients taking anti-TNF agents. While he and his colleagues haven’t switched any IBD patients off their medications in anticipation of covid, said Dr. Terdiman, “we don’t withdraw them either if patients acquire covid. We continue them.”
According to interventional cardiologist Krishan Soni, MD, MBA, several studies this year have linked positive cardiac troponins to a host of bad outcomes in covid patients.
The most common is myocardial injury, said Dr. Soni, during a session on cardiology pearls for hospitalists. A study published in August by the Journal of the American College of Cardiology looked at the prevalence and impact of myocardial injury in close to 2,800 covid patients. In that trial, 36% had positive cardiac troponins.
Most had low-level elevations and only mild myocardial injury. However, patients with a troponin greater than 0.09 had a three-fold higher risk of mortality, he pointed out. Covid patients with a history of cardiovascular disease were also more likely to have myocardial injury, although they typically had no evidence of primary acute MI.
“We need to do a better job informing the public that they need to seek care for acute conditions.”
~ Krishan Soni, MD, MBA
University of California, San Francisco
The study also summarized some mechanisms for those positive troponins. “Rarely was it acute myocardial infarction, type-1MI or plaque rupture,” Dr. Soni explained. “Most were around either inflammation, cytokine storm, or micro- or macro-vascular thrombi, which caused sub-endocardial ischemia.”
Another study in JACC looked at the incidence of myocardial injury in covid patients across various papers. “It ranged from 1% up to 100%,” he said. “But the common theme: Positive troponin level may be related to disease severity.”
The study also laid out an approach to thinking about how to manage positive troponins in the hospital, he said. If you’re checking serial measurements and the delta is less than 20%, “that’s a non-rising troponin trend that’s more consistent with what we call chronic myocardial injury. We see that even in non-covid patients who have chronic heart failure, cardiomyopathies, hypertension or CKD.” These patients, he added, do not require additional therapies other than treatment for their underlying condition.
But more commonly in covid patients, the delta is greater than 20%. “That’s consistent with an acute myocardial injury,” he explained. If there are no signs of acute ischemia, such as chest pain or ECG changes, patients may have a primary cardiac illness such as myocarditis, stress cardiomyopathy or acute heart failure.
Or “the heart may be a bystander,” Dr. Soni said. “Non-cardiac illness can result in a positive troponin.” That’s true for any critical illness, he added, and for sepsis and pulmonary embolism.
A high delta can also indicate an acute MI, either a type-1 with plaque rupture or a type-2 with demand ischemia, which “is common among hospitalized covid patients,” he pointed out. As for the relationship between elevated cardiac troponins and various outcomes—ARDS, death, mechanical ventilation and VT/VF—”there isn’t necessarily a causation there, but absolutely a correlation. Patients who have these positive biomarkers are at much higher risk.”
When it comes to echocardiograms and covid, research published in Circulation in May evaluated 100 hospitalized covid patients who had an echo within four hours of being admitted.
Among them, 32% had a completely normal echocardiogram. But the most common finding was either RV dilation or dysfunction, seen in nearly 40% of patients.
“That’s possibly related to a pulmonary, parenchymal or vascular disease,” said Dr. Soni. One big concern is that “the heart may not be the primary actor.” As the respiratory infection becomes profound, “that either has hypoxic effects or negative effects on the pulmonary vasculature, which can put the heart at risk.”
Dr. Soni ended his comments on covid by describing the case of a 52-year-old patient who presented to his service this year. That patient didn’t have covid, but he did have an ST-elevation MI—and he didn’t come to the hospital for four days. In the hospital, he ended up needing PCI, ECMO and ventricular septal defect repair.
“Before covid, 90-day mortality in elderly STEMI patients was down to about 5.5% and the median length of stay was about two days,” he explained. This particular patient, however, was discharged on day 48, after spending 20 of those days in the ICU.
That underscores, he said, a huge problem in the covid era. Because patients are afraid of contracting the virus, “they are coming in after their disease has progressed and their mortality rates are higher. We need to do a better job informing the public that they need to seek care for acute conditions.”
Phyllis Maguire is Executive Editor of Today’s Hospitalist.
“Non-pandemic cardiology” pearls
EVEN IN THE MIDST of the pandemic, new evidence has emerged to inform what interventional cardiologist Krishan Soni, MD, MBA, called “non-pandemic cardiology.” In a session on cardiac pearls for hospitalists at this year’s UCSF hospitalized patient virtual conference, Dr. Soni discussed the following developments:
• Out-of-hospital arrest: According to Dr. Soni, one big debate is how best to manage patients with out-of-hospital arrest. Do they have underlying coronary disease, and do they need urgent catheterization in the cath lab?
“In the case of patients with ST elevation on ECG, the data are relatively clear: Bring them emergently to the cath lab, as long as its appropriate given their comorbidities, life expectancy and clinical situation,” he said. But for patients without clear evidence of ST elevation, “the question of immediate coronary angiography and its benefit have not been well-addressed.”
An April 2019 study in the New England Journal of Medicine did address that question. The multicenter trial randomized about 550 patients to either immediate coronary angiography or angiography delayed until patients had neurologic recovery.
Among those with immediate angiography, one-third were found to have no significant coronary disease. In the delayed group, 65% did end up getting coronary angiography—but their median time from arrest to angiography was about five days. The big takeaway: Neither group had significantly better 90-day survival.
A meta-analysis in JACC this October offered further insights. The research likewise found no difference in 30-day mortality, neurological status or rate of PCI between patients with early vs. later angiography. Instead, “30-day mortality was determined more by comorbidities than by whether or not patients were revascularized,” Dr. Soni said.
The study also offered a way to think about patients with out-of-hospital arrest. In deciding whether to go immediately to the cath lab, clinicians should consider patients’ prior cardiac status and if they have coronary disease, heart failure or depressed ejection fraction.
The authors also urged physicians to assess patients’ noncardiac status. How’s their neurologic function as well as the function of their other organs? Unfavorable characteristics for early angiography include unwitnessed arrest, no bystander resuscitation, nonshockable rhythms, older age, longer resuscitation times, and either a very low pH or high lactate.
Finally, consider patients’ short- and long-term goals and “what the realistic outcomes are,” Dr. Soni said. “Some treatments may have stronger evidence, like therapeutic hypothermia for patients who are unstable when they come in.”
• Colchicine: Hospitalists are familiar with colchicine to treat gout and pericarditis. Dr. Soni pointed out that the drug is receiving new interest as an anti-inflammatory agent, with researchers trying to find out if its anti-inflammatory properties can benefit patients with coronary disease.
“Monoclonal antibodies can reduce inflammation and may improve outcomes with coronary artery disease,” he explained. “But they’re much more expensive. Can something as simple as colchicine have a similar effect?”
Two recent studies suggest that it can. The first, published in December 2019 by the New England Journal of Medicine, randomized more than 4,700 patients who’d had a recent MI to either low-dose colchicine (0.5 mg a day) or placebo. Researchers adopted a composite endpoint of a host of bad outcomes including death from cardiovascular causes, stroke, MI, resuscitated arrest, or urgent hospitalization for angina before revascularization.
“They found a significant reduction in the composite primary outcome, from about 7% to 5.5%,” Dr. Soni said. “That was driven mainly by reductions in stroke and in urgent revascularization for angina.”
The second study was published in NEJM in November 2020. Researchers looked at the drug’s possible role in the medical regimen of patients with stable coronary artery disease, randomizing more than 5,500 patients to, again, 0.5 mg of colchicine (in addition to other agents including aspirin and statins) or placebo. The results: Patients taking colchicine had fewer cardiovascular events.
About 15% of the patients in the trial didn’t undergo randomization because of GI upset, “so that remains a consideration,” said Dr. Soni. “But in patients able to tolerate colchicine, evidence suggests that it benefits long-term vascular outcomes.”
• Antiplatelet therapy after TAVR: Over the past several years, transcatheter aortic valve replacement (TAVR) has become the mainstay treatment for aortic stenosis. “It’s replaced surgery not only for high-risk patients,” said Dr. Soni, “but those at moderate- and low-risk as well.”
But the question has been: What do patients need in terms of antiplatelets to prevent valve thrombosis? The standard has been dual antiplatelet therapy of aspirin and clopidogrel for the first three to six months following TAVR.
“But many patients are elderly with multiple bleeding risks of as high as 20% or 30%,” he said. A study in October 2020 in NEJM looked at whether patients given aspirin alone had better outcomes than with dual therapy. At one year, roughly 15% of the aspirin-only group had a significant non-procedural bleed vs. close to 27% of those on dual therapy.
While the counterbalance has always been the worry about valve thrombosis, stroke or a vascular event, the study found no difference in those between the two groups. “That suggests that maybe less is more, particularly in elderly patients after TAVR. We can probably get away with an aspirin-only strategy.”Published in the December 2020 issue of Today’s Hospitalist