Hopes High for Anti-inflammatories to Combat COVID-19 Immune System Storms
How the immune response tips so radically off-balance is unclear, but research, some drawing on recent CVD trials, ploughs on.
The body’s potent immune response to COVID-19 poses unique risks to the heart, but as accumulating data suggest, this opens the door to a host of anti-inflammatory agents as potential therapies, many of them having already been tested in the prevention of cardiovascular events.
Researchers around the world are hoping that this link, especially as it relates to interleukin-6 (IL-6) and its precursor interleukin-1 (IL-1), will provide new ways to temper symptoms and reduce complications in patients suffering a severe course of this deadly disease.
“Whereas COVID-19 is primarily a respiratory infection, it has important systemic effects including on the cardiovascular and immune systems. Patients with preexisting cardiovascular conditions represent large proportions of patients with symptomatic infection, and experience disproportionately worse outcomes at between five- to tenfold increase in mortality,” Peter P. Liu, MD (University of Ottawa, Canada), and colleagues note in a review of the topic recently published in Circulation.
Systemic inflammation has long been posited as a trigger for cardiovascular events. Here, in the setting of COVID-19, many believe anti-inflammatory agents have an important role to play in bringing the virus to heel.
“We believe that, in part, one of the relevant pathways involved in the inflammatory storm, the so-called cytokine storm, associated with COVID-19 is the IL-1/IL-6 pathway, . . . which is also very relevant in cardiovascular disease,” Jean-Claude Tardif, MD (Montreal Heart Institute, Canada), told TCTMD. Tardif led last year’s COLCOT trial showing that colchicine can reduce ischemic events post-MI.
Just solving the problem in one part of the world will not be the key. Jean-Claude Tardif
In today’s COVID-19 era, Tardif and others are taking a fresh look at colchicine, which is the focus of six studies currently listed on ClinicalTrials.gov. Among them is the randomized, double-blind, placebo-controlled COLCORONA trial with Tardif at the helm, set to enroll 6,000 patients in the US and Canada; its primary endpoint is the composite of death or the need for hospitalization due to COVID-19 infection within 30 days.
But colchicine is far from the only anti-inflammatory being investigated. Anti-COVID-19 candidates include tocilizumab (Actemra; Roche) and sarilumab (Kevzara; Sanofi/Regeneron), as well as anakinra (Kineret; Sobi), siltuximab (Sylvant; EUSA Pharma), and ruxolitinib (Jafaki; Incyte), among others. Numerous studies are examining their effects on IL-6 and/or IL-1, key actors in the body’s response to SARS-CoV-2 that can alter heart rhythm and drug absorption.
“At the moment, the potential of COVID-19 to affect the cardiovascular system is probably underestimated, at least in comparison to the respiratory system involvement,” stressed Pietro Enea Lazzerini, MD (University of Sienna, Italy). What’s key here, he commented to TCTMD, is for clinicians to be vigilant for arrhythmias in their patients and recognize the “potential pro-arrhythmic role of the high-grade systemic inflammatory state characterizing COVID-19.”
It’s also clear that COVID-19 can be prothrombotic, said Binita Shah, MD (NYU Langone Health, New York, NY), co-investigator of the COLCORONA trial at her center. She told TCTMD she’s seeing a “fair number” of MIs among COVID-19 patients.
In their review, Liu and colleagues also make the observation that inflammation’s consequences extend beyond arrhythmia. In the vascular system, they note, it can cause diffuse microangiopathy with thrombosis as well as result in myocarditis, heart failure, acute coronary syndrome, rapid deterioration, and sudden death.
Shah pointed out that there’s already evidence to back IL-6 as a target in the cardiovascular setting—in the groundbreaking CANTOS trial, researchers found the lower the IL-6 level, the better the outcomes for prior MI patients with elevated high-sensitivity C-reactive protein.
Immune System Out of Control
So how does the immune response to SARS-CoV-2 get so out of hand?
With the virus, Liu explained to TCTMD, “there is almost a deliberate strategic elimination of the key lymphocytes, particularly CD4+, which is kind of the master coordinator of T cell function. It’s almost how like HIV targets the lymphocytes.”
Why exactly this happens as the virus invades the cells isn’t clear, he said. Regardless, “it’s bringing the lymphocyte population down. And the reason we know this is lymphopenia is a very important hallmark of this condition—the lower the lymphocyte count, the worse off the patient’s going to be. . . . If you look at the lymph nodes or spleen [of a deteriorating COVID-19 patient], there are no lymphocytes there. Nobody’s home. So this is how dramatic this is.”
Typically the immune system involves a balancing act among its various players, but the decrease in lymphocytes sets off a cascade of events that hamper the body’s ability to deal with SARS-CoV-2. With the immune system partially disabled, “it leads to a situation in which the macrophages now have to deal with this virus and then neutrophils come in as a ‘replacement buddy.’ The two of them don’t do as good of a job. They start trying to do everything possible, and that’s when you start to get the cytokine storm picture,” with IL-1 and IL-6 arriving on the scene, Liu said.
Also important is that the angiotensin-converting enzyme 2 (ACE2) receptor, which serves as the binding site for SARS-CoV-2 on human cells, “has important immune modulation roles,” Liu et al point out in their review.
When SARS-CoV-2 enters a cell to replicate, it can disable or destroy it, “leading to the release of potential danger signals to activate the host’s innate immune responses,” they explain.
Furthermore, in the heart, infection can downregulate ACE2. “This is likely part of the host defense mechanism in response to the infection to limit continued viral proliferation. However, the potential consequence of this interaction is that the biologically essential role of ACE2 is also significantly diminished,” the investigators observe. “This can lead to unopposed angiotensin II effects, including pro-inflammatory, prothrombotic and pro-oxidant risks.”
I’m seeing a ton of clot in the arteries of the heart and it seems to be a lot more than what I usually see in the typical heart attack. Binita Shah
All this, they add, “can also predispose the patient to microinfarcts within multiple organs, such as the liver, heart or kidney, further exacerbating the state of multiorgan injury and failure.”
Liu told TCTMD that, in pathology samples of hearts affected thus by COVID-19, what “we see is the endothelial cells, the lining of the blood vessels, are all swollen and you actually see little clots in there. So the virus is really activating the blood vessels’ response.”
How COVID-19 promotes thrombosis is a question of growing concern, as reported by TCTMD. Shah says she’s seeing the phenomenon among COVID-19 patients who’ve had an MI. “When I bring them to the lab, I’m seeing a ton of clot in the arteries of the heart and it seems to be a lot more than what I usually see in the typical heart attack,” she said. “These patients are sometimes young—I had a 40-year-old woman the other day. It’s not just ‘I have atherosclerosis, I got COVID-19, and maybe it put a little stress on my body.’ It does seem that perhaps there’s an independent mechanism in which COVID is a trigger for a heart attack that would not have occurred otherwise,” she explained, adding that plaque composition hasn’t yet been studied.
Importantly, though, these clots are being found not just in the heart but “all over the body: in the lungs, in the legs, in the brain,” Shah emphasized.
Arrhythmia a Consequence of Inflammation
As for how the systemic inflammatory response to COVID-19 can lead to arrhythmia, it’s quite “intricate,” Lazzerini along with Mohamed Boutjdir, PhD (SUNY Downstate and NYU School of Medicine, New York, NY), and Pier Leopoldo Capecchi (University of Sienna), explain in a second Circulation paper published online.
First, there’s myocardial injury. Elevated troponin can hint at its presence, and causes may include “direct viral infection, hypoxia-induced apoptosis, and cytokine storm-related cell damage,” they write.
But, as Lazzerini noted to TCTMD during a recent video chat with all three co-authors, not all patients who develop arrhythmias have elevated troponin, indicating there are other mechanisms. For instance, “increasingly recognized by the medical community,” he said, “is that a number of drugs recently proposed for their antiviral activities,” such as the antimalarials hydroxychloroquine and chloroquine, the anti-HIV protease inhibitors like ribavirin and lopinavir/ritonavir, and the antibiotic azithromycin, “can increase the arrhythmic risk . . . by prolonging the [corrected QT (QTc)] interval on EKG.”
Earlier this month, the American Heart Association, American College of Cardiology, and Heart Rhythm Society jointly published new guidance on how to safely administer these therapies to COVID-19 patients. It emphasizes three main precautions: ECG monitoring, maintaining optimal potassium and magnesium levels, and avoiding concomitant use of other QT-prolonging agents whenever possible.
What that document did not do, however, is go into depth about inflammation.
“At the moment it is not clear why this virus is able to induce so strong an inflammatory response” that exceeds what’s usually seen for viral infections, Lazzerini observed.
The cytokines active in this response can increase the risk of arrhythmia “by modulating the expression and function of specific ion channels, which in turn regulate the electrical activity,” he explained. Moreover, they can stimulate the hypothalamus, responsible for regulating sympathetic activity, in turn affecting heart rhythm.
“Finally, IL-6 can inhibit in the liver . . . cytochrome p450, which is a key enzyme able to metabolize a wide number of frequently used drugs, including many potentially QTc-prolonging drugs. So the inhibitory effect of IL-6 can unexpectedly increase serum levels of these drugs with concomitant use and further increase the risk of QTc prolongation and also arrhythmic events,” said Lazzerini.
Targeted Therapies Being Tested
As for which anti-inflammatory to choose, Liu said the decision depends mainly on what is most easily available at each center.
Tocilizumab and sarilumab, both currently being studied in manufacturer-sponsored randomized trials, would likely be given in the ICU setting to patients who are already quite sick. For Lazzerini and colleagues, these are strong contenders for reducing the risk of fatal ventricular tachycardia/fibrillation. Prior to studying COVID-19, their research teams for many years “have been pioneering this concept that inflammation is often overlooked” as a cause of arrhythmia, Boutjdir told TCTMD.
Tocilizumab in particular was recently evaluated in a phase II clinical trial of patients without rheumatoid arthritis who had acute cardiac damage. Promisingly, the study “demonstrated that a single administration of tocilizumab reduced inflammatory response and myocardial injury, with no safety concerns (including infections) within the following 6 months,” the co-authors note.
Rheumatologist Michael Pillinger, MD (NYU Langone Health), who’s leading the US arm of the COLCORONA trial along with Shah in New York City, said that colchicine takes a different tack. “We’re using all sorts of fancy biologic therapies in the ICUs, but they’re very expensive. The whole point is to keep people out of the ICU,” he commented, and colchicine might be the best contender to achieve that goal. “This particular medication is really something that could be used generally, not only here but even in third world countries where there hardly are ICUs. We think it could be very important for that reason.”
The whole point is to keep people out of the ICU. Michael Pillinger
Pillinger said that he uses these more-potent anti-inflammatories in his rheumatoid arthritis patients. But “they’re upwards of $20,000-30,000 a year and so they’re not something you want to use in everybody,” he said. By contrast, “colchicine in the United States is about $5 a pill [and] around the world it’s about a dime. It could be a public health medicine.”
One concern is that anticytokine drugs, in theory, could limit the body’s defenses and increase vulnerability to infection. “Our opinion is that in the short term, as usual in the COVID-19 population, this problem is not relevant,” Lazzerini said.
On the whole, colchicine “is not associated, as far as anybody knows, with rises in infection or impairment of immunity as opposed to inflammation,” Pillinger said. “We’re all worried about suppressing immune systems too much and impairing the ability of the patient’s body to fight the virus. We don’t have data on [this in COVID-19] but based on long experience this is probably not doing any harm in that regard even as it’s keeping the inflammatory response within moderation.”
In another nod to safety, COLCORONA is recruiting COVID-19 positive patients by asking them to call a hotline. If they are eligible and enroll in the trial, their assigned study drug is couriered to them within hours. Follow-up consists of two phone calls or video check-ins over the course of a month.
‘Impending Storm’ Ahead?
For Liu, the main clinical takeaway for cardiologists is to take heed of biomarkers. “When you see biomarkers rising it does mean that some of these processes are at play, and it means that we really need to pay attention to the patient,” he said, stressing that this is particularly important given than many patients with CVD have heightened ACE2 activity to begin with, making them vulnerable to SARS-CoV-2.
“Rather than saying this is a passive process we can’t do much about, we should be much more aware about what these markers are telling us and be much more proactive about working with internal medicine and intensive care folks to really help protect the heart,” Liu commented.
One challenge posed by COVID-19 is its diverse presentations, with everything from “people who are practically asymptomatic to patients who are dying in front of your eyes, within hours,” he said. “A lot of this has to do with the balance between the virus and the immune response, in a way.”
Some patients come in with minimal troponin release and see their levels settle, Liu noted. “In contrast, you have patients who have much higher levels of these markers. [With them] you see CRP start rising very dramatically, troponin also rising, and then you see IL-6 coming in and you know that there is an impending storm, essentially, so this is a situation where you really need to get all your tools out.”
In their paper, Liu et al advise, “these patients should be followed closely, monitored for organ failure, with efforts made to restore immune balance. If viral proliferation is still continuing, strategies to attenuate the virus may be critical. The ability to restore immune balance, with approaches such as type I interferon, immunoglobulin, and recovered serum, may be considered.”
The jury is still out on whether anti-inflammatory strategies will prove helpful, they note. “However, intervention will likely need to be instituted early, before the immune amplification process is fully underway.”
You see CRP start rising very dramatically, troponin also rising, and then you see IL-6 coming in and you know that there is an impending storm, essentially, so this is a situation where you really need to get all your tools out. Peter Liu
In treating COVID-19 patients, Shah said, it’s important to consider the whole picture. “We need to keep an open mind about what we’re seeing on EKG and on the bloodwork in terms of biomarker rises and how the patient is presenting,” she suggested.
“We’re learning as we go, and it’s just a moving target. We all need to communicate with each other as much as possible so the information’s out there,” noted Shah.
For Tardif, colchicine naturally stands out as the right choice.
“We have a drug that is inexpensive, orally administered. Its safety and tolerability profile has been known for decades. It is available in all drug stores in all countries around the world. It can be a solution for both developed countries as well as low income, emerging economy countries,” he said. “Here we are using colchicine not only to prevent cardiovascular complications related to COVID-19. We believe colchicine will also prevent noncardiovascular complications like acute respiratory distress syndrome [ARDS] and all of the multiorgan failure complications that can occur.”
A safe and effective vaccine is of course the ultimate target. But colchicine may also be a part of the solution, Tardif said. “If we prevent the complications of COVID-19 and transform [it] into sort of a benign, viral, common cold-like disease, this will immediately transform the landscape worldwide, because the next morning we can implement that therapy around the world. . . . We can really have a major impact worldwide. That’s the key: just solving the problem in one part of the world will not be the key.”
Lazzerini PE, Boutjdir M, Capecchi PL. COVID 19, arrhythmic risk and inflammation: mind the gap! Circulation. 2020;Epub ahead of print.
Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system. Circulation. 2020;Epub ahead of print.