[Automatically generated] From the JAMA Network, this is JAMA Clinical Reviews. Interviews and ideas about innovations in medicine, science and clinical practice. Here's your host. Welcome to this JAMA Clinical Review Podcast. I am Dr. David Simel, JAMA Associate Editor and professor Emeritus of Medicine at the Durham Veterans Affairs Medical Center in Duke University. In this podcast, we will be discussing pericarditis. I'm joined today by Dr. Paul Cremmer, who is an Associate professor of Radiology and Medicine within the Department of Cardiology at northwestern University Feinberg School of Medicine in Chicago. Dr. Cremmer is the lead author of the JAMA Narrative Review on the diagnosis, risk stratification, and treatment of pericarditis, published in the September 5th issue of JAMA. Welcome. Thank you. It's great to be with you today. Well, let's get right into it. Pericarditis means inflammation in the pericardium. Can you describe the normal pericardium for us, and then what happens in pericarditis? Sure. So normally, the pericardium is less than one millimeter in thickness, which means that it's often difficult to resolve with our imaging modalities. If we do see it, it may appear just as a thin linear stripe. Now, the pericardium consists of two components, a parietal and a visceral pericardium. The parietal pericardium has an outer fibrous sac and an inner cirrhosis lining of a single layer of mesothelial cells. Now, this layer of mesothelial cells is contiguous with the visceral pericardium or the epicardium. So I think of it like if you're to take your fist and put it into a balloon, that part of the balloon that's around your fist is that cirrhosis surface. So what happens in pericarditis? In response to an insult, which could be a viral infection, could be a direct injury to the pericardium. The pericardium increases its vascular permeability. There's fluid exudation, there's mesothelial cell desclamation, followed by formation of granulation tissue, fibroblast proliferation, and newly formed blood vessels within the pericardium. And in our clinical evaluation, in our imaging evaluation, what this means is that we can see that the pericardial thickness increases. We can assess for fluid around the pericardium, pericardial effusion, and we can also assess for this increased vascularity of the pericardium, because normally the pericardium is very minimally vascular. Well, about 5% of emergency visits in North America and western Europe for non- ischemic chest discomfort are for pericarditis. How does a patient with pericarditis describe their discomfort? Sure. So classically, acute pericarditis is diagnosed if two of four characteristics are present, including chest pain. Nearly all patients have chest pain, which is typically sharp, pleuritic, and worse when supine. So those are really the defining characteristics of pericardic chest pain. The other features we look for to secure the diagnosis are characteristic EKG changes. So this is typically widespread ST elevation and PR depression, which is present in up to 50% of patients. Patients can also have a new or worsening pericardial effusion. And in a minority of cases, there can be a pericardial friction rub. You mentioned, Dr. Simel, in North America and western Europe, where the most common cause of acute pericarditis is after a viral infection or presumed idiopathic. But in places in the world where tuberculosis is endemic, TB is the most common cause. And patients with tuberculous pericarditis can have chest pain. But importantly, prior to the chest pain, they may have night sweats, fevers, weight loss. And the other important point to emphasize about tuberculous pericarditis is it's much more common to present with constriction, with constrictive pathophysiology. You mentioned a pericardial friction rub. Can you describe what that sounds like and some of the other clinical findings that you might see in a patient with pericarditis? A pericardial friction rub usually has three components corresponding to atrial systole, early ventricular diastole during rapid filling, and ventricular systole. And this rub is thought to relate to the friction between the two inflamed layers of the pericardium that's most prominent during cardiac motion. So for example, a patient who's in atrial fibrillation, they're not going to have that atrial systole, so you won't hear that component of the rub. In general, the rub has a scratchy quality. And what I typically do in my practice is I have the patient lean forward and I auscultate along the left sternal border, usually at end expiration. So take a deep breath in, blow that air out, hold your breath and listen very closely. And then in addition, I'll auscultate during a shallow inspiration. So take a small breath in and hold it. And what I'll say is that the paracardial friction rub is very specific for paracarditis, but not heard in most cases and can be evanescent. So I think as we know, classically, that paracardial friction rub can come and go. You know, you'll hear it and then you'll grab the medical students to come listen and then it's gone. But when you do hear it, it is quite distinctive. We have an audio sample of the rub that you submitted as part of the manuscript. Let's play the sound of the rub so that our listeners will appreciate its characteristics. Thanks for sharing the recording with us. What are some other clinical features that you might see in a patient with paracarditis? So in terms of other features, they're really sort of clinical exam findings where we get worried about paracardial tamponade. But the thing you always want to look for when you're assessing a patient with paracarditis is, first and foremost, what's the heart rate? Is the patient tachycardic? Is there any evidence of jugular venous distension? And is there a pulse as paradoxes? That's something sort of specific to the evaluation of suspected paracardial tamponade. For the paracardial friction rub, you talked about listening during respiration. does it actually change with inspiration and expiration? I haven't appreciated that, that it actually changes. I just think that hearing the respiratory sounds can interfere with actually auscultating the rub. So that's why I typically listen both at end expiration and following a shallow breath hold with inspiration. So I think it's more that it just allows you to focus on the cardiac sounds as opposed that it's actually changing in some way with respiration. You started with telling us about how thin the pericardium is and that you can't ordinarily see it with typical imaging. So when you get pericarditis, it is visible and that means that imaging is important. Can you go over the echocardiographic findings and address whether a point-of-care bed sound, ultrasound is actually adequate to diagnose pericarditis? So imaging is certainly important, though I would emphasize that pericardial tamponade, which is a life-threatening complication of pericarditis, is a hemodynamic diagnosis. So the main thing we're looking for with our imaging at the bedside are any features that may suggest pericardial tamponade, and ECHO provides a lot of insights into that. So typically, what do we look at in terms of ECHO, hemodynamic features of concern for tamponade? Well, we can look at the inferior vena cava, the size and whether the size varies with respiration. That provides some insight into what the right atrial pressure is. We can look at the size of the effusion and whether there is any collapse of the right atrium or diastolic collapse of the right ventricle. And what that's telling us is that the pericardial pressure is exceeding the right atrial pressure or the diastolic right ventricular pressure. We can also look at variation in inflow across the mitral and tricuspid valves, which is indicative of accentuated interventricular interaction, which is a feature of pericardial tamponade. And finally, we can look at the flow across the left ventricular outflow tract, which will give us some insights into the stroke volume. So yes, the imaging, the echo in particular is very helpful, but important to realize that what we're really looking at is these hemodynamic features of tamponade, and in the end, it is a hemodynamic diagnosis. And I also note that if you have a patient who's in shock and has a significant pericardial fusion, the presumptive diagnosis is pericardial tamponade. In terms of the question of is a bedside ultrasound good enough, I think that really depends on two features. I think first, it's a bit evident is what's the skill of the person performing that ultrasound, you know, how much training have they had to make some of these assessments that we just talked about? I think the second piece is some of the clinical features, and these are patient-specific features that indicate higher risk and may actually indicate a patient who you want to hospitalize with acute pericarditis. So this could be a patient who has a subacute course, meaning they've had symptoms going on for at least several days, oftentimes without a definite onset. It may be a patient with a high fever, with a very high C-reactive protein, so a patient who is very inflamed, and certainly any assessment that suggests a significant pericardial fusion. I think these are some of the features where it looks like this may be more than just uncomplicated acute viral pericarditis, where you likely would need to get a complete echocardiogram, though a lot of that is dependent upon the resources that are available. Well, that's a good segue into talking about what happens to the patients who have acute pericarditis. In your review article, you noted that 75-80 percent have a benign course, benign meaning in the sense that the pericarditis goes away and it stays away. What treatment should we be initiating to enhance that good outcome? The mainstay of treatment for acute pericarditis is high-dose NSAIDs, typically ibuprofen or aspirin and colchicine. Typically, the NSAIDs are given until the chest pain has resolved, and the C-reactive protein or the CRP, it has normalized. In general, this may be for two or three weeks. Importantly, to prevent recurrence, all patients should receive a three-month course of colchicine, and we know that doing so decreases the risk of recurrence by about half. So if you're following CRP, that means you need to get a CRP at the time you're evaluating a patient. Are there other laboratory tests you should get and then follow along with the patient? Well, the CRP is the big one, which is our assessment of the level of systemic inflammation. The other test beyond the routine assessments is to check cardiac troponin. And this is most helpful when there's other diagnostic considerations, such as myocardial ischemia, or if there's concern for concomitant myocarditis. Paul, if you're using NSAIDs, does it matter which NSAID you use or which dose? And for colchicine, how do we dose that? I would say there's not a lot of high quality evidence to favor one NSAID over another. We typically will use ibuprofen starting at doses of 600 to 800 milligrams three times a day. Part of the advantage practically of using ibuprofen is that it has a lot of options for titrating the dose. So you can come down from 600 milligrams three times a day to 400 milligrams to 200 milligrams. So in managing the patient's symptoms, having that ability to titrate is often helpful. And then high dose aspirin, which we often use. I think the important point there is that we're talking 650 to 975 milligrams of aspirin three times a day. sometimes I see patients with acute pericarditis who've just been treated with a single 325 aspirin. So it really does need to be high dose. And again, when you're using that kind of dosing of aspirin, you do have a lot of options to titrate based on the patient's clinical response. In terms of the colchicine dosing within the United states, we have 0.6 milligram doses most commonly, and it's weight based. So in general, if a patient is over 70 kilograms, we'll dose it at 0.6 milligrams twice a day. Whereas if a patient is under 70 kilograms, we'll use 0.6 milligrams once a day. Now, gastrointestinal side effects are common with colchicine, so that's something to definitely be aware of. I'll say oftentimes it doesn't mean that you need to completely stop the colchicine, but you may need to reduce the dose. Paul, for the patient who is not sick enough to require admission and you start them on NSAIDs and colchicine, how soon do you see them back in the clinic or do a phone call follow up? It depends a bit on whether or not there's a pericardial fusion and how quickly that needs to be followed up. But let's assume that we're not worried about a pericardial infusion that could be increasing in size and require intervention. If it's really just about symptom management, you would like to follow up and check a C-reactive protein in about a week. So that's our typical practice. If you think it's an uncomplicated case, a discharge from your outpatient clinic, urgent care, emergency room, check the CRP and check in and see how they're feeling about a week after the initial visit. Can you give me a sense of the range of time it takes for the CRP to normalize? Right. I think it depends on the treatments that the patient's receiving and of course how bad the underlying disease is. In general, you would expect the CRP to normalize within a week or two. And in fact, patients who don't normalize their CRP at about a week are higher risk patients. That's something that we really follow closely. And if the CRP is remaining elevated beyond a week, that's where I worry about, okay, we need maybe need to escalate our anti-inflammatory therapy. And is this a patient who's progressing to have what we would call incessant paracarditis? So that's paracarditis symptoms that persist for several weeks, usually more than four to six weeks. And that's a higher risk group that does have a higher risk of developing complications such as effusive constrictive paracarditis. I think by higher risk, you also are implying that they may get recurrent paracarditis after their initial episode resolves. Tell me about how you approach those patients who have recurrent paracarditis. Yeah, and that's right. I think if the risk factors for developing recurrence certainly include how high the C-reactive protein is initially, failure to normalize the C-reactive protein within about a week, and then patients who've had this subacute course where the symptoms have been going on for a while, patients with fever. these are kind of the risk factors that immediately jump to mind and saying, okay, this is a patient who's higher risk for having a recurrence. In terms of our management, recurrence is typically defined as a patient has had an acute episode of paracorditis, they're treated, their symptoms resolve or near completely resolve, the chest pain is gone. And then at greater than four to six weeks after that, they have recurrent paracorditis symptoms. And so the initial treatment approach is going to be very similar to what you did for the acute paracorditis episodes. It's going to be back to the NSAIDs, back to the colchicine. The main thing we would do in that case, especially if the patient initially responded to NSAIDs and colchicine, is to extend the colchicine course longer. So with that first occurrence, we may give the patient colchicine for, say, a total of six months, and even sometimes longer. Whereas with the acute episode, it's usually a treatment duration of only three months. What about interleukin blockers? Yeah, so there's sort of a new class of therapies that are very promising in patients with recurrent paracorditis. And that's the interleukin-1 blockers. And I think these are really appropriate therapies in patients that have colchicine-resistant paracorditis. So the patient that continues to have symptoms of paracorditis and impaired quality of life related to that, despite colchicine treatment, and the patients who have corticosteroid-dependent paracorditis. So the patients who have paracorditis symptoms treated with prednisone but can't come off the prednisone. And really an advantage of the interleukin-1 blockers is that they are a steroid-sparing therapy. The reason we use the interleukin-1 blockers is because we've learned more about the underlying pathobiology of recurrent idiopathic paracorditis, and also paracorditis second to a prior cardiac injury, such as an electrophysiology procedure, coronary intervention, cardiac surgery. Some of those patients, after that cardiac injury, will go on to have recurrent paracorditis. So if we look at those two groups of patients that develop recurrences, it seems like the underlying problem is inappropriate activation of the innate immune response and upregulation of the inflammasome. And the primary driver, the apical cytokine of the innate immune response is interleukin-1. And so with the interleukin-1 blockers, we can quickly control acute flares and prevent recurrence. And now we have randomized trials to really show that these medications are highly efficacious, but really reserved for the patients who are certainly failing in seds and colchicine with recurrences with prior evidence of systemic inflammation as evidenced by an elevated C-reactive protein. Well, is there anything else you would like our listeners to know about pericarditis? I would just say that to think about pericarditis in the right clinical context, as you noted, it's a common cause of non- ischemic chest pain. And we're often seeing patients where the diagnosis has been missed or there's a delay in diagnosis. And also, which we've emphasized, as part of the evaluation check to see reactive protein, I often see patients who've been seen in outpatient clinics or urgent cares, where they're given a diagnosis of pericarditis, but a CRP hasn't been checked. And it's really helpful, one, for the diagnosis, and two, as we've talked about the prognostic implications and treatment implications of CRP elevation. In regards to treatment, we talked about the importance of NSAIDs and colchicine, but also emphasized what not to do, and that's to initially treat with corticosteroids. We know that in particular short courses of high dose prednisone increase the risk of recurrence. So the last thing we want to see is a patient present with acute pericarditis and an initial treatment is a Medrol dose pack. So I think that's the other practical point that I would emphasize. Thank you, Dr. Cremer, for joining us today to talk about pericarditis. This episode was produced by Shelley Steffens at the JAMA Network. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio, alloneword.com. Thanks for listening.