Pericarditis

Etiology

The 2015 European Society of Cardiology (ESC) guidelines for diagnosing and managing pericardial diseases categorize the causes of acute pericarditis into 2 main groups—infectious and noninfectious.[9]

Infectious Causes of Pericarditis

Viruses are the most common infectious agents causing pericarditis, including coxsackieviruses A and B, echovirus, adenoviruses, parvovirus B19, HIV, influenza, and several herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV).[9][10] Bacterial pericarditis occurs infrequently in in developed countries; however, tuberculosis remains widespread in developing regions and is the most common cause of pericarditis in endemic areas.[11] This is particularly true for HIV-positive patients, among whom the infection rate continues to rise.[12] Less commonly, bacteria such as Coxiella burnetii, Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus, and Streptococcus can cause pericarditis, with life-threatening cases of purulent cardiac tamponade documented in the literature.[13] 

In rare instances, fungal organisms such as Histoplasma, Coccidioides, Candida, and Blastomyces or parasitic species such as Echinococcus and Toxoplasma can also cause pericarditis.[14] When these pathogens are identified, an underlying immunocompromised state should be strongly considered, as many fungi and parasites—particularly Histoplasma and Toxoplasma—are opportunistic infections, and they have been described as predominant in HIV-positive patients.

Noninfectious Causes of Pericarditis

Noninfectious causes of pericarditis are varied and include malignancy (often secondary to metastatic disease), connective tissue disorders (such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Behçet's disease), and metabolic conditions (such as uremia and myxedema).[7][9]

Additional Causes of Pericarditis

Trauma can also lead to pericarditis, which may present as an early onset following injury or, more commonly, as a delayed inflammatory reaction.[15] Dressler Syndrome, also known as "late post-myocardial infarction syndrome," is a well-recognized post-cardiac injury syndrome characterized by pericarditis following acute coronary syndrome, with a delayed inflammatory response typically occurring several weeks after the initial event.[2][5][16] Notably, it is believed that Dressler syndrome occurs secondary to the formation of anti-myocardial antibodies as a delayed autoimmune response, leading to pericarditis symptoms in the late post-myocardial infarction stage.[17] When first described, Dressler syndrome was estimated to occur in 5% to 7% of myocardial infarction cases; however, it has become uncommon due to advancements in the management of acute coronary syndrome, which have led to early revascularization and a reduced burden of myocardial injury. Other post-cardiac injury syndromes can also arise following percutaneous intervention, cardiac surgery, or blunt trauma.[16]

Multiple medications have been implicated in drug-induced pericarditis, although its incidence remains rare. Historically, certain drugs such as procainamide, hydralazine, and isoniazid have been associated with medication-induced SLE, leading to serositis and pericardial involvement manifesting as pericarditis.[18] More recently, checkpoint inhibitors such as ipilimumab and nivolumab have been increasingly recognized as causes of cardiac toxicity, including myocarditis and pericarditis. The 2 most prominent classes of medications are monoclonal antibodies targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) along with its ligand PD-L1. These therapies have seen numerous advancements in oncology and are likely to be implicated in more cases of cardiac toxicity as their clinical use continues to rise.[19]

Miscellaneous conditions, such as amyloidosis and sarcoidosis, should also be considered, particularly when pericarditis is accompanied by suggestive systemic findings.[20] However, in up to 90% of cases, no clear etiology is identified, leading to a diagnosis of idiopathic acute pericarditis. This form is the most commonly encountered in clinical practice, and extensive testing is rarely necessary unless there is specific clinical suspicion.

Epidemiology

Acute pericarditis is a prevalent form of pericardial disease and a common cause of chest pain. This condition often occurs in trauma patients, those with uremia, and individuals with malignant diseases, with a higher incidence in men.[21]

Pathophysiology

The pericardium serves several functions, including anchoring the heart within the thoracic cavity, forming a barrier against extrinsic infections, and facilitating dynamic interaction between cardiac chambers.[2] Notably, the pericardium is not necessary for survival, as cases have been reported of congenital complete absence of the pericardium, which has been incidentally discovered in asymptomatic individuals.[22] Despite potential concerns about increased cardiac mobility and displacement within the chest cavity, studies show these patients have comparable left ventricular ejection fraction and life expectancy to the general population.[23]

The parietal layer’s rich innervation makes it highly sensitive to inflammation caused by infectious, autoimmune, or traumatic insults, often resulting in severe retrosternal chest pain, as seen in acute pericarditis.[1] This explains why over 90% of patients with pericarditis present with chest discomfort.[3] In cases of pericardial effusion, increased pericardial compliance allows the sac to dilate over time in response to slowly accumulating fluid, preventing compression of the cardiac chambers.[2] Consequently, the rate of fluid accumulation—and the resulting pressure changes—often has a greater impact than the volume in determining the hemodynamic effects on the heart. As a result, a relatively small pericardial effusion can lead to life-threatening tamponade if it accumulates rapidly, while a gradual process, such as malignancy, may allow a large pericardial effusion to develop over weeks before causing constrictive physiology in the cardiac chambers.[24]

History and Physical

Pericarditis is classified based on duration. Acute pericarditis lasts less than 4 to 6 weeks, incessant pericarditis persists beyond 4 to 6 weeks but resolves within 3 months, and chronic pericarditis extends beyond 3 months. Recurrent pericarditis refers to a new episode that occurs following a symptom-free interval of 4 to 6 weeks between episodes.[23]

Acute pericarditis accounts for approximately 5% of non-ischemic chest pain presentations in emergency departments and 0.1% of inpatient admissions.[23] The classical presentation involves central, severe chest pain that is pleuritic (which worsens with deep inspiration) and positional (which improves with sitting up and leaning forward). The pain may radiate to the trapezius ridges if the phrenic nerve is inflamed as it passes through the pericardium.[23][25] When myocarditis is also present, the pain may be less specific, with symptoms of heart failure, such as shortness of breath, potentially accompanying the presentation.[26]

Pericardial pain can be distinguished from ischemic pain, which typically worsens with exertion or emotional stress and improves with rest or nitroglycerin. Ischemic pain is generally non-positional, non-pleuritic, and non-reproducible with palpation. However, atypical presentations of ischemic pain are common, making clinical differentiation challenging.[27] Pleuritic chest pain that does not improve with sitting up and is accompanied by respiratory symptoms, such as cough or sputum production, is more likely secondary to pulmonary disease. In contrast, lower chest pain that improves with leaning forward, is non-pleuritic, and occurs alongside food intake should raise suspicion for abdominal conditions, such as esophagitis or acute pancreatitis.

Evaluation

The differential diagnosis for chest pain should include angina due to stable ischemic heart disease or acute coronary syndrome, subendocardial ischemia associated with aortic stenosis or hypertrophic cardiomyopathy, aortic dissection, myocarditis, pleurisy secondary to pulmonary embolism or pneumonia, costochondritis, esophageal spasm, peptic ulcer disease, or referred pain from another organ, such as acute cholecystitis. In the acute setting, ruling out life-threatening causes is critical before considering the diagnosis of acute pericarditis, especially in cases of uncertainty.[28]

Auscultation typically reveals a left parasternal pericardial friction rub, characterized by a rasping, scratchy triphasic sound that corresponds to friction between the pericardial layers during atrial systole, ventricular systole, and early ventricular diastole. This friction rub is reported to be present at some point during the illness in 35% to 85% of cases.[29] However, it can be challenging to elicit during an examination. The physician should listen to multiple precordial locations in various positions, including the lateral decubitus position at end-expiration, using the diaphragm to enhance the likelihood of detection. Listening to precordial movements more than once is essential, as pericardial friction rubs can appear and disappear intermittently. They may be discernible only at initial presentation or can become louder and more noticeable as an existing pericardial effusion resolves, facilitating friction between the visceral and parietal layers.

When present, particularly as a triphasic sound, a pericardial friction rub is highly specific for diagnosing acute pericarditis. However, one component may sometimes be absent, resulting in a biphasic sound. This should not be confused with a pleural rub, which may produce a similar sound but is related to respiration rather than the cardiac cycle.[30] Asking the patient to hold their breath while auscultating can help differentiate between the 2 rubs. Even in the absence of a pericardial friction rub, the diagnosis of acute pericarditis should still be considered if clinical suspicion is strong, as its absence does not rule out the diagnosis.

More than half of patients with acute pericarditis exhibit characteristic electrocardiogram (ECG) changes that evolve through 4 stages over several weeks, showing significant temporal variability, as mentioned below (see Image. Electrocardiographic Findings in Acute Pericarditis).[31]

• Stage I typically presents with diffuse, concave ST-segment elevation, accompanied by reciprocal ST depression in the lead AVR. This stage may also feature PR segment elevation in lead AVR (and possibly V1), which can effectively differentiate acute pericarditis from myocardial infarction.[32] Although localized pericarditis can present with ST elevations in specific leads, diffuse changes on the ECG are more commonly observed.
• Stage II typically occurs within the first week and shows normalization of ST and PR segment changes.
• Stage III is characterized by widespread T-wave inversions.
• Stage IV involves the eventual normalization of T waves.

The initial ST elevation in pericarditis should not be confused with an acute injury pattern, where ST elevation appears in a localized distribution and is concave down, unlike the concave-up pattern seen in pericarditis. Acute injury patterns are also typically associated with reciprocal ST depressions in multiple leads (not limited to AVR, as in pericarditis), and Q waves often emerge in the same distribution—or develop shortly thereafter—as part of the natural progression of acute or subacute myocardial infarction. The differential diagnosis for ST elevations should include early repolarization abnormalities commonly observed in healthy individuals. These abnormalities are characterized by an elevated J-point, often presenting as an initial slur at the beginning of the ST segment. While they may appear in several leads, they are typically not diffuse.[33]

Clinically, acute pericarditis is indicated by a characteristic description of chest pain and the presence of a pericardial friction rub upon auscultation. However, laboratory studies, ECG, and echocardiography are often necessary to confirm the diagnosis. According to the 2015 ESC guidelines, a diagnosis of acute pericarditis requires the presence of at least 2 out of 4 criteria, as mentioned below.

• Pericardial chest pain
• Pericardial rubs
• New widespread ST elevation or PR depression on ECG
• New or worsening pericardial effusion.

Supporting findings may include elevated inflammatory biomarkers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and leukocytosis) and evidence of pericardial inflammation on advanced imaging, such as cardiac computed tomography (CT) and cardiovascular magnetic resonance imaging (MRI). While pericardial effusion is often present, it is not required for a definitive diagnosis of acute pericarditis.[32]

Certain clues may help identify the underlying cause of pericarditis. Viral pericarditis is often associated with a flu-like prodrome, such as fever or upper respiratory symptoms. Autoimmune and inflammatory etiologies may present with systemic manifestations, such as polyarthritis in rheumatoid arthritis, skin and kidney manifestations in SLE, or asterixis and encephalopathy in uremia.[34][35] A history of prior pericardial injury, such as cardiac surgery or blunt trauma, should also be considered, as symptoms may emerge days to weeks after the initial event.[32]

Treatment / Management

All patients with suspected acute pericarditis should undergo an ECG, echocardiogram, and chest x-ray. Myocardial inflammatory and injury markers, such as ESR, CRP, and troponins, should also be measured (Class I, LOE C).[34][36][37] In regions where tuberculosis is not a concern, the initial workup is often sufficient, as most cases respond promptly to empiric treatment.[36] However, additional testing may be warranted if a specific cause is suspected and should be tailored to the suspected etiology.(B2)

First-level tests, including a complete blood count, basic metabolic panel, liver function tests, and thyroid-stimulating hormone levels, are recommended if further evaluation is pursued, as they may suggest specific etiologies such as uremia or infection. Blood cultures, viral seromarkers, and tuberculosis testing—such as purified protein derivative (PPD) or interferon-γ release assay (IGRAs)—may also be indicated in select patients. HIV testing, using antibody/antigen tests or nucleic acid testing, should be performed if an opportunistic infection is identified, given the strong correlation between immunocompromised states and fungal or tuberculosis infections.[36] Additional workups may include testing for antinuclear antibodies or conducting targeted investigations for suspected systemic diseases, such as sarcoidosis.

The 2015 ESC guidelines recommend CT or MRI as Class I options for second-line testing.[36][38] Cardiac CT may reveal thickened pericardial layers and pericardial fluid accumulation, with calcification often prominent in cases of constrictive pericarditis. However, cardiac CT is unsuitable for assessing hemodynamic compromise in cardiac tamponade, as echocardiography is more effective for this purpose. Additionally, cardiac CT carries an increased radiation risk. Cardiac MRI provides detailed information, including late gadolinium enhancement within the pericardial layers or myocardium in cases of myopericarditis. This imaging technique can also detect intra-myocardial strands associated with fibrinous pericardial effusion and is highly effective for evaluating myocardial function and identifying suspicious pericardial masses.[39]

Emergent pericardiocentesis is recommended for patients presenting with cardiac tamponade.[40] Pericardiocentesis may also be performed electively in cases of moderate-to-large pericardial effusion without immediate hemodynamic compromise, with a chest tube left in place for several days or until drainage ceases. Diagnostic pericardiocentesis is also indicated when an infectious cause of acute pericarditis is suspected, even with a small effusion. Bacterial, fungal, and tuberculosis studies on pericardial fluid should include basic chemistry, polymerase chain reaction (PCR), and fluid cultures. Blood cultures should also be obtained when appropriate.[40] Purulent effusions, although rare, are associated with high mortality and should be treated aggressively. Urgent drainage is necessary, followed by intra-pericardial thrombolysis in cases of loculated effusions (Class IIa, LOE C). The aspirate may appear overtly purulent, and a low pericardial-to-serum glucose ratio of less than 0.3, along with neutrophilic predominance (mean cell count of 2.8/μL, with 92% neutrophils), helps differentiate it from mycobacterial or neoplastic pericarditis.[41](A1)

An exudative pericardial effusion warrants empiric anti-tuberculosis treatment in regions where tuberculosis is endemic, even while cultures are pending. If a positive diagnosis of tuberculosis is confirmed, medical therapy for at least 6 months is recommended (Class I, LOE C). Pericardiectomy should be considered if there is no improvement in symptoms after 4 to 8 weeks of therapy (Class I, LOE C).[42] Pericardial thickening is present in most cases of tuberculosis pericarditis. Before effective medical treatment was available, effusive pericarditis would progress to constrictive pericarditis in up to half of all cases. Studies have shown that the addition of high-dose adjunctive prednisolone can reduce the incidence of constrictive pericarditis, but it may also increase the risk of HIV-associated malignancies.[43] Consequently, adjunctive steroids may be considered in HIV-negative patients but should be avoided in HIV-positive patients, as per ESC guidelines (Class IIb, LOE C).[41](A1)

Pericardial fluid analysis with cytology is recommended to confirm malignant pericardial disease (Class I, LOE B). Additional testing may include pericardial biopsy and tumor marker assessments, such as carcinoembryonic antigen and CA-19 (Class IIa, LOE B). However, evidence supporting their accuracy in distinguishing malignant effusions is limited.[44] If a definitive diagnosis of viral pericarditis is sought, a comprehensive histological, cytological, and molecular analysis should be performed on the obtained pericardial fluid and any pericardial biopsy. However, routine viral serological testing is not recommended, except for HIV and hepatitis C (HCV).[41](B2)

The incidence of uremic pericarditis has significantly declined with the introduction of dialysis.[45] In this subpopulation, pleuritic chest pain is less prevalent, and ECG changes are often absent. Chronically, these patients are more likely to develop pericardial effusions, though these are not frequently associated with acute cardiac tamponade. If pericardiocentesis is performed, the aspirate is often bloody in this patient population.[46](B3)

Cardiac catheterization may be considered to assess for diastolic pressure equalization and respiratory interventricular dependence if constrictive pericarditis is suspected. However, it is not recommended solely for diagnosing acute pericarditis.[46](B3)

Treatment for acute pericarditis begins with addressing the underlying cause. Patients with uremic pericarditis should receive more frequent dialysis, while those with malignancy or tuberculosis require therapy targeted at the primary disease. For tuberculosis, the standard treatment involves a quadruple antibiotic regimen (rifampicin, isoniazid, pyrazinamide, and ethambutol) for at least 2 months, followed by isoniazid and rifampicin for a total of 6 months. This may be combined with adjunctive high-dose prednisolone, as previously discussed.[42](A1)

Most patients will have idiopathic acute pericarditis, which can be safely managed on an outpatient basis with medical therapy alone. Activity restrictions beyond a sedentary lifestyle are advised until symptoms resolve or cardiac enzyme levels normalize.[47] Patients exhibiting markers of poor prognosis or those who do not respond to therapy within 1 week should be admitted for further evaluation. These markers include fever (>38 °C), a subacute or recurrent presentation, the presence of a large pericardial effusion (>20 mm in thickness), or echocardiographic signs of cardiac tamponade physiology, such as right ventricular diastolic collapse, a transmitral flow respirophasic variation of more than 25% throughout the respiratory cycle, and a dilated inferior vena cava with inspiratory collapse of less than 50%, indicating elevated right atrial filling pressures.[47][48] Minor risk markers include immunosuppression, trauma, or myopericarditis, where patients exhibit troponin elevation alongside elevated inflammatory markers.

In most patients, empiric treatment with high-dose anti-inflammatory agents, in addition to colchicine, is recommended. Nonsteroidal anti-inflammatory drug (NSAID) therapy should continue until symptom relief is achieved, which typically occurs within 3 days to 2 weeks. Possible regimens include ibuprofen 600 mg every 8 hours, indomethacin 25 to 50 mg every 8 hours, or naproxen 500 to 1000 mg every 12 hours.[49] Aspirin 500 to 1000 mg every 6 to 8 hours should be used instead of other NSAIDs in patients post-myocardial infarction or those already on antiplatelet therapy (Class I, LOE C). Aspirin is also considered first-line therapy during the first trimester of pregnancy but is contraindicated after 20 weeks of gestation, where paracetamol may be used instead.

The COPE trial randomized 120 patients to receive either conventional therapy with acetylsalicylic acid (ASA, also known as aspirin) or conventional therapy with adjunctive colchicine, following them for 18 months. The colchicine group showed less symptom persistence at 72 hours (11.7% versus 36.7%; P = .003) and significantly fewer recurrent episodes (10.7% versus 32.3%; P = .004) compared to the control group.[50] Several studies have demonstrated that colchicine effectively reduces the recurrence of pericarditis, with further episodes decreased by approximately half.[51] Consequently, adjunctive colchicine therapy is now recommended for most patients with acute pericarditis for a duration of 3 to 6 months. The recommended dosage is 0.6 mg PO BID for patients with a body weight of more than 70 kg and 0.5 mg orally once daily for those with a body weight of less than 70 kg. Colchicine is contraindicated in patients with severe renal impairment (Class III, LOE C).(A1)

Low-to-moderate doses of prednisone (0.2–0.5 mg/kg/d or equivalent) with a slow taper may be considered if NSAIDs or ASA and colchicine are contraindicated. While the latter can often provide rapid clinical improvement, ample evidence suggests that their use increases the risk of recurrent pericarditis after therapy is discontinued.[52] Consequently, corticosteroids are not recommended as first-line therapy for most patients unless an autoimmune etiology for acute pericarditis is identified. The initial dose should be maintained until symptom relief and normalization of CPR, after which it should be tapered down slowly.[52](A1)

Response to therapy is assessed clinically based on symptom relief, although serial CRP measurements can also be helpful. If there is an incomplete response to anti-inflammatory agents (ASA or NSAIDs) with adjunctive colchicine—such as in cases of recurrent pericarditis—the addition of steroids as part of a triple therapy regimen should be considered after ruling out an infectious etiology.[53](B2)

For corticosteroid-dependent recurrent pericarditis, steroid-sparing immunosuppressive agents such as azathioprine, intravenous immunoglobulin (IVIG), or anakinra (an interleukin-1 receptor antagonist) may be considered as third-line therapy.[54] If these options are ineffective, pericardiectomy remains a last resort.[55](B2)

Certain forms of acute pericarditis, such as iatrogenic and uremic pericarditis, have been associated with an increased risk of hemorrhagic pericardial effusion and cardiac tamponade, according to small studies. Therefore, while strong evidence is lacking, stopping anticoagulation when feasible in these patients may be prudent.[46] However, no formal guidelines exist, and recommendations are based solely on expert opinion. Additionally, concomitant use of ASA should be avoided unless there is a strong indication, such as recent stent placement or post-acute coronary syndrome.(B3)

Differential Diagnosis

Differential diagnoses include:

• Pleurisy
• Pneumonia
• Acute myocardial infarction
• Bony pain
• Costochondritis
• Angina

Prognosis

The overall prognosis for acute pericarditis is excellent, with most patients experiencing complete recovery. Up to 30% of patients who are not treated with colchicine may experience recurrent pericarditis. Constrictive pericarditis is exceedingly rare following idiopathic acute pericarditis, occurring in less than 1% of cases. However, the risk of constrictive pericarditis increases with specific etiologies, particularly purulent bacterial or tuberculosis pericarditis, where it may rise to as high as 30%.[56][57] Cardiac tamponade, the most feared acute complication, rarely occurs after idiopathic pericarditis but is more commonly associated with malignancy and infectious causes of pericarditis.[58]