Complicated Pericarditis: Understanding risk factors and pathophysiology to inform imaging and treatment

Topic(s):  Pericardial Disease

Authors:  Paul C. Cremer, Arnav Kumar, Apostolos Kontzias, Carmela D. Tan, E. Rene Rodriguez, Massimo Imazio, Allan L. Klein

Commented by: Antonio Brucato and Silvia Maestroni, Internal Medicine, Ospedale Papa Giovanni XXIII; Bergamo, Italy

Background

Rarely a review paper is covered in this section, but this review was so interesting that we made an exception. Although most patients with acute pericarditis will have resolution, some will develop incessant, recurrent, chronic, or constrictive pericarditis. Many of these patients experience a debilitating chronic disease, and are referred in this review to as having complicated pericarditis.

Aim of the study

To assess:

• Which patients are at risk for complicated disease after acute pericarditis,
• Which patients with complicated pericarditis benefit from multimodality imaging
• What is the pathological progression of pericarditis, and how is autoinflammatory pericarditis distinct from autoimmune pericarditis
• What are the established treatments for pericarditis, and what are the emerging therapies for patients with complicated disease.

Summary

Clinical entities and identifying the patient at risk for complicated pericarditis

Diagnosis of pericarditis requires at least 2 of the following criteria: precordial chest pain that is worse with inspiration and when supine, characteristic ST-segment elevation and PR deviation on ECG, a pericardial friction rub, and a pericardial effusion that is more than trivial (1). In practice diagnosis is made when chest pain is associated  with either ECG changes (50-60% of cases) , pericardial effusion (60%) , or a friction rub (30%) (2-4).

Complicated pericarditis is defined as one of  the following clinical entities:

• incessant (pericarditis that persists for more than 4 to 6 weeks),
• chronic (presence of symptoms for >3 months),
• recurrent (a relapse occurring after a period in which the patient is free of symptoms for at least 4 to 6 weeks) (2),
• constrictive pericarditis.

In the United States and Western Europe, most episodes of pericarditis (80% to 90%) are so-called “idiopathic” and are often presumed to be post-viral (5).

Death in patients hospitalized for acute pericarditis is uncommon (1%), and mortality is most often not related to pericarditis (6);  1% to 2% of patients will have pericardial tamponade during the first acute attack.

After an episode of acute pericarditis, the probability of developing incessant pericarditis or a first recurrence within 18 months is generally 15% to 30% (7,8). In patients who have had an initial recurrence, additional recurrence occurs in 25% to 50% (9,10).

A separate question relates to the risk of developing a first episode of pericarditis after cardiac injury. In the current era of early reperfusion for acute MI, late pericarditis (Dressler’s syndrome) is uncommon (<0.5%) (11,12). Early pericarditis after ST-segment elevation MI has also decreased (approximately 4%), although it is more common in patients who present after at least 6 h of symptoms (14%) and in patients with percutaneous coronary intervention failure (23%) (12). After pericardiotomy, pericarditis is more common, with a likely incidence between 10% and 25% (13,14). An additional risk of pericarditis is the development of constrictive pathophysiology. The development of constrictive pericarditis that will require surgery after an episode of acute idiopathic pericarditis is rare (1%) (15). However, constrictive pericarditis that responds to anti-inflammatory therapy is likely more common (16), although its incidence is unknown.

A direct complication includes extension of the inflammation in the myocardium. When the inflammation predominantly involves the pericardium, it is termed myopericarditis, in distinction to perimyocarditis, in which myocardial inflammation supersedes the pericarditis. Clinically, both syndromes require an abnormal troponin level. In perimyocarditis, patients will also have focal or globally reduced left ventricular systolic function (17). Myocardial involvement occurs in approximately 15% of patients with acute pericarditis, and risk factors include younger age, male sex, fever, arrhythmia, and ST-segment elevation on ECG. Of note, myopericarditis generally has a benign course and is not associated with an increased risk of recurrent pericarditis or pericardial tamponade. Moreover, most patients with left ventricular dysfunction will have recovery (17,18).

The risks of later developing complicated pericarditis can be categorized as either patient- or treatment-related. In regard to treatment, early use of corticosteroids has been consistently associated with recurrence (19,20), and relapse is especially hastened with high-dose short courses. Colchicine has reduced recurrences of pericarditis by 50% and has become a mainstay of treatment (84%). Too rapid tapering of drugs, automatic and independent from symptoms and C-reactive protein (CRP) is a deleterious and preventable risk factor for recurrence. In particular, high doses of corticosteroids followed by brisk tapering can lead often to relapse (21). In regard to patient-related factors, at 1 week after acute pericarditis, an incomplete response to nonsteroidal anti-inflammatory agents (NSAIDs) and a persistently elevated CRP are both associated with risk of recurrence (20). Of note, other patient-related factors, including younger age, female sex, and pericardial effusion, have not been associated with recurrent pericarditis (20).

The risks for developing constrictive pericarditis seems related to the etiology: low (1%) for idiopathic and presumed viral pericarditis; intermediate (2–5%) for autoimmune, immunemediated and neoplastic aetiologies; and high (20–30%) for bacterial aetiologies, especially with tuberculosis and purulent pericarditis (15).

The value of multimodality imaging in complicated pericarditis

Patients with complicated pericarditis may benefit from imaging, primarily directed at 2 questions. First, does the patient still have significant pericardial inflammation? Second, does the patient have constrictive pathophysiology? In general, compared with echocardiography, cardiac magnetic resonance (CMR) has a predominant role in the evaluation of pericardial inflammation. For constriction, CMR is typically an adjuvant test when echocardiographic data are ambiguous.

CMR offers  the unique imaging capability to detect pericardial inflammation by assessment of pericardial thickening, edema by STIR-T2w imaging, edema and/or fibrosis by late gadolinium enhancement (LGE), and presence of pericardial effusion and constrictive physiology. On the other hand CT is particularly well-suited to define the extent of pericardial calcification, helping with surgical planning prior to pericardiectomy (22).

Echocardiographic features of constriction include respirophasic septal shift, annulus reversus or paradoxus on tissue Doppler imaging, significant respiratory variation in tricuspid and mitral inflow, preserved global longitudinal strain, a dilated inferior vena cava, and prominent diastolic expiratory flow reversal in hepatic veins (23-27). If a patient has all of these findings, the diagnosis of constrictive pericarditis is secure. Yet, few patients demonstrate all of these features (28). Therefore, CMR is likely best reserved for patients with suggestive, but inconclusive evidence of constrictive pericarditis on echocardiography. With CMR, the constrictive physiology is reflected in ventricular coupling during real-time cine imaging with free breathing (29-30). During early inspiration in patients with constrictive pericarditis, the septum shifts toward the left ventricle. An increased relative septal excursion has been shown as a very specific finding for constrictive pericarditis (29-30). In practice, though, this technique may be limited if a patient can take only shallow breaths, not generating adequate negative intrathoracic pressure. Conversely, with a particularly vigorous inspiration, mild septal excursion may be evident in a patient without constrictive pericarditis, thus decreasing specificity.

Other caveats that must be considered are the following ones. Concerning pericardial thickening, on CMR, normal pericardial thickness is <4 mm (31). However, anatomic studies suggest that the normal parietal pericardium is thinner, approximately <1 mm or less. Given these limitations, reporting a pericardial thickness of 3 mm as normal and a thickness of 4 mm as abnormal is clearly fraught with error. Overall the imprecision of the measurement of pericardial thickening should be emphasized, especially in patients with seemingly normal or slightly increased pericardial thickness.

A potential advantage of CMR is the ability to assess pericardial edema; in T2-weighted short-tau inverted recovery (STIR) fast spin-echo sequences (STIR-T2w), pericardial edema will appear bright. Occasionally, these edema-weighted images are helpful, but their clinical effect is often limited for 2 reasons. First, patients with dramatically increased pericardial signals on T2-STIR images typically have a clear severe pericarditis on the basis of history, examination, and inflammatory markers. Therefore, this finding does not usually inform the diagnosis. Second, in a patient who also has a pericardial effusion, the interpretation of superimposed pericardial edema is difficult because both will appear bright on T2-STIR images: in practice, a comment on pericardial edema in a patient with a pericardial effusion is difficult to report with confidence.

With severe pericarditis, the inflammation can also extend into the surrounding epicardial fat. This epicarditis may be seen on CMR with increased delayed enhancement of the pericardium and epicardial fat. However, the kinetics of gadolinium egress from the pericardium are unclear. Therefore, the optimal timing for imaging, especially in different stages of pericarditis, is not defined. Notably, delayed enhancement has a different meaning for myocardium and pericardium; in myocardial diseases, delayed enhancement reflects the degree of myocardial fibrosis (32). Conversely, in pericardial disease, delayed enhancement may reflect both fibrosis and neovascularisation due to inflammation: as pericarditis leads to increasing neovascularisation, delayed enhancement of the pericardium also increases. Overall the relationship between histology and pericardial delayed enhancement is not well defined, because histological correlation is typically performed from samples obtained during pericardiectomy, generally performed for constrictive pericarditis, so the validity of these data in other inflammatory pericardial diseases is limited. Consequently, CMR seems most appropriate in 2 scenarios. The first applies to a patient in whom the presence of active pericardial inflammation is uncertain. The second applies to a patient with constrictive pericarditis in whom the severity of active pericarditis is unclear. Therefore, in a patient who has chest pain and a history of pericarditis, delayed pericardial enhancement may favour continued or intensified anti-inflammatory treatment. If CMR does not show delayed pericardial enhancement, then tapering of medications may continue, and other diagnoses may be considered.

CMR also has the potential to affect management in patients with constrictive pericarditis when the degree of active pericardial inflammation is uncertain. In 2 small observational studies, increased pericardial delayed enhancement was associated with reversible constrictive pericarditis (33,34). As this inflammation resolves with anti-inflammatory therapy, the constriction may also resolve, and pericardiectomy may be unnecessary or premature.

Pathogenesis of recurrent pericarditis

Similarities exist between recurrent pericarditis and autoinflammatory diseases, including familial Mediterranean fever (FMF) and tumor necrosis factor–associated periodic syndrome (TRAPS) (35). These syndromes are characterized by seemingly unprovoked attacks of multisystem inflammation with serositis, systemic symptoms and strikingly elevated CRP, and are triggered by innate immunity perturbations in the absence of antigen specific T cells or autoantibodies.

To better understand the pathophysiology of autoinflammatory disease, research has focused on the pivotal role of the inflammasome, that is an enzymatic complex that at the end activates IL1, a potent inflammatory cytokine (36). Colchicine mechanism of action was originally associated mainly to inhibition of neutrophils by binding to tubulin, but now we know that colchicine also inhibits the inflammosome. Furthermore the therapeutic role of anakinra, an anti-IL1 agent, has become increasingly clear (37), and IL1 is the final product of the activation of the inflammosome. This emerging focus on the inflammasome has also highlighted an important distinction in patients with complicated pericardial disease: those with a tendency toward inappropriate autoinflammation versus those with predominant autoimmune disease.

Established and novel treatment for pericardial inflammation

Over 25 years ago, NSAIDs were shown to be effective in a randomized trial of patients with post-pericardiotomy syndrome (38). Aspirin or an NSAID, in conjunction with gastroprotection, is now routinely given for rapid control of symptoms (2), although a randomized trial of NSAIDs in post-viral pericarditis has never been performed. Initially, an attack dose is recommended every 8 h to alleviate symptoms, and usually continues until CRP has normalized (4,20). Intravenous therapy may be very useful, when available, in hospitalized patients (2). Tapering typically begins after the patient is quiescent in terms of symptoms and inflammatory markers (5).

More recently, when added to an NSAID, colchicine has also become an established first-line therapy for pericarditis (2), halving the recurrences (Class IA).

Given the rapid resolution of symptoms and pericardial effusions, corticosteroids were once commonly used to treat pericarditis. Unfortunately, unopposed corticosteroids increase the risk of recurrence and prolong the course of disease (2). In particular, high doses at an equivalence of 1.0 to 1.5 mg/kg/day of prednisone are associated with severe side effects in 25% of patients. Furthermore, brisk tapering can lead to relapse (21). Conversely, when the combination of colchicine and an NSAID is ineffective, low-dose corticosteroids may prevent further recurrences (2).

In patients on corticosteroids, after remission with resolution of symptoms and normalization of CRP is attained, the dose must be slowly tapered. Often, pericarditis recurs at doses of prednisone <15 mg/day. If tolerable, the dose of NSAID or colchicine should be increased, rather than increasing the corticosteroid (2). In difficult situations, this approach may not be possible, and steroid-sparing regimens should be considered.

Among the emerging treatments, 3 promising options include azathioprine, human intravenous immunoglobulin (IVIG), and anakinra.

The largest study of azathioprine in recurrent pericarditis is a single-center retrospective report of 46 patients (39). At a dose of 1.5 to 2.5 mg/kg/day and a mean duration of treatment of over 1 year, azathioprine was associated with stable remission following steroid discontinuation in more than 50% of patients. In particular, azathioprine is a slow-acting drug that may facilitate a gradual tapering of corticosteroids.

In select cases, IVIG may be an effective treatment for refractory pericarditis. In patients with a history of multiple recurrences, especially in the setting of an underlying autoimmune disease, IVIG can act rapidly to improve symptoms during an acute attack (40). Typically, patients receive infusions of 400 to 500 mg/kg/day for 5 days, and if necessary, this regimen can be repeated after 1 month (41). However, despite broader use with a good safety profile in rheumatological diseases, IVIG therapy has been reported in only 30 patients with recurrent pericarditis (40).

Among biological agents, anakinra is increasingly used to treat patients with pericarditis that is refractory to NSAIDs, colchicine, and corticosteroids. An IL-1 receptor antagonist, anakinra is currently approved by the U.S. Food and Drug Administration for the treatment of rheumatoid arthritis. Given the central role of IL-1 in perpetuating an autoinflammatory state, anakinra may have a pathogenic role. Anakinra is administered as a daily subcutaneous injection at 1 to 2 mg/kg/day, up to 100 mg, for at least several months, although the optimal duration is unknown. With this regimen, efficacy has been demonstrated in children and adults, although the number of treated patients is small (42-44). Very recently the first randomized controlled trial with anakinra was published (37). With anakinra, symptoms typically improve rapidly, but unfortunately, recurrence is common after the drug is discontinued. Anakinra is currently reserved for patients with the most debilitating and refractory pericarditis, especially if they are corticosteroid-dependent and colchicine-resistant/intolerant (37).

Conclusion

If treated with appropriate anti-inflammatory therapy, the majority of patients with acute pericarditis will have a benign course. About 15% of patients will have myocardial involvement (so called myopericarditis), a benign entity (8,17,18).

After acute pericarditis, complicated pericarditis will develop in 15% to 30% of patients.

Risks for recurrence include early use of corticosteroids, a lack of response to NSAIDs, and a high CRP (20).

Most cases of recurrent pericarditis with a typical clinical course of severe attacks, with strikingly elevated CRP followed by a prolonged period of quiescence with CRP normalization have probably an autoinflammatory pathogenesis, with unprovoked activation of inflammosome and production of IL1. We now know that colchicine may also inhibits the inflammosome, while anti-IL1 agents may specifically block IL1.

CMR has the potential to provide insight into the progression of pericarditis by imaging pericardial thickness, edema, and inflammation. Currently, the assessment of pericardial inflammation with delayed enhancement imaging is essentially binary. A patient either does or does not have significant pericardial delayed enhancement. The patient with an inflamed pericardium warrants anti-inflammatory therapy or, in the setting of constrictive pericarditis, deferral of pericardiectomy to observe the response to intensified medical therapy.

Comments

This is a well done review of complicated pericarditis, in which the authors take advantages of their huge experience in the field to identify patients at risk of developing complicated pericarditis, to show strengths and weaknesses of CMR, particularly in assessing pericardial inflammation, to speculate on the possible pathogenesis of so-called “idiopathic” pericarditis, and to underline practical tips concerning treatment options. For rare cases really colchicine-resistant or intolerant and corticosteroid- dependent, with a severe inflammatory pattern, systemic symptoms and strikingly elevated CRP, anti –IL1 agents may be very useful.