Etiology of pericardial disease

INTRODUCTION — The pericardium is a fibroelastic sac made up of visceral and parietal layers separated by a (potential) space, the pericardial cavity. In healthy individuals, the pericardial cavity contains 15 to 50 mL of an ultrafiltrate of plasma. Pericardial diseases are relatively common in clinical practice and may have different presentations either as isolated disease or as a manifestation of a systemic disorder.

Although the etiology is varied and complex, the pericardium has a relatively non-specific response to these different causes with inflammation of the pericardial layers and possible increased production of pericardial fluid. Chronic inflammation with fibrosis and calcification can lead to a rigid, usually thickened and calcified pericardium, with possible progression to pericardial constriction. In some cases, the clinical presentation of acute pericardial inflammation predominates, and the presence of excess pericardial fluid is clinically unimportant. In other cases, the effusion and its clinical consequences (ie, cardiac tamponade and constrictive pericarditis) are of primary importance.

Diseases of the pericardium present clinically in one of several ways [1,2]:

●Acute and recurrent pericarditis

●Pericardial effusion without major hemodynamic compromise

●Cardiac tamponade

●Constrictive pericarditis

●Effusive-constrictive pericarditis

This topic will provide a brief overview of the major causes of pericardial disease. Details of the specific pericardial disorders are discussed separately. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Pericardial effusion: Approach to diagnosis" and "Constrictive pericarditis: Diagnostic evaluation".)

CLASSIFICATION — The etiology of pericardial diseases is best considered by using a modification of the time-honored pathologic classification of disease into inflammatory, neoplastic, vascular, congenital, and idiopathic causes (table 1) [3-5]. The major causes include:

●Infectious

•Viral, including human immunodeficiency virus (HIV) and coronavirus disease 2019 (COVID-19)

•Bacterial, fungal (purulent)

•Others (Rickettsia, Chlamydia, Borrelia, Mycoplasma, Treponema, Ureaplasma, Nocardia, Tropheryma)

●Radiation

●Post cardiac injury syndrome

•Post-myocardial infarction

•Post-pericardiotomy

•Post-traumatic (including iatrogenic)

●Drugs and toxins

●Metabolic (uremia, dialysis-associated, myxedema, ovarian hyperstimulation syndrome)

●Malignancy (especially lung and breast cancer, Hodgkin lymphoma, and mesothelioma)

●Collagen vascular disease

●Idiopathic or immune-mediated [6,7]

Pericardial disease may also be a component of other, systemic disorders, including inflammatory bowel disease and familial Mediterranean fever. Aortic dissection or left ventricular free wall rupture should also be considered in patients with unstable hemodynamics and pericardial effusion.

Most of the etiologies of pericardial disease listed above can cause both "dry" pericarditis (that is, pericardial inflammation with minimal or no effusion) and pericardial effusive disease with or without inflammation.

SPECTRUM OF CLINICAL PRESENTATION — The frequency of the specific causes of pericardial disease varies in published reports, depending in part upon geography, the patient population, and how the diagnosis was established.

Acute pericarditis — Acute pericarditis can present in a variety of ways, depending on the underlying etiology (table 2) [8-12]. Patients with an infectious etiology may present with signs and symptoms of systemic infection such as fever and leukocytosis. Viral etiologies in particular may be preceded by "flu-like" respiratory or gastrointestinal symptoms. Patients with a known autoimmune disorder or malignancy may present with signs or symptoms specific to their underlying disorder.

The major clinical manifestations of acute pericarditis include [2,5,13]:

●Chest pain – Typically sharp and pleuritic, improved by sitting up and leaning forward.

●Pericardial friction rub – A superficial scratchy or squeaking sound best heard with the diaphragm of the stethoscope over the left sternal border.

●Electrocardiogram (ECG) changes – New widespread ST elevation or PR depression.

●Pericardial effusion.

At least two of these features should be present to make the diagnosis. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Clinical features'.)

Pericardial effusion — Patients with a hemodynamically significant pericardial effusion leading to cardiac tamponade usually present with signs and symptoms related to impaired cardiac function (ie, dyspnea, elevated jugular venous pressure, hypotension and impaired perfusion). However, in the absence of cardiac tamponade, most patients with a pericardial effusion have no symptoms specific to the effusion, but may have symptoms related to the underlying cause (eg, fever in the setting of pericarditis, etc). Thus, pericardial effusions are often discovered incidentally during evaluation of other cardiopulmonary diseases, and are typically diagnosed by echocardiography. (See "Pericardial effusion: Approach to diagnosis" and "Cardiac tamponade".)

Several case series have reported estimates of the frequency of specific causes of pericardial effusion (table 3) [14-18]. Not surprisingly, the distribution of causes varies with demographics and diagnostic strategies. For example, polymerase chain reaction (PCR) is more sensitive for the detection of infection than cultures; therefore, a study employing PCR will likely have an increased incidence of infectious etiologies. The increased incidence of iatrogenic effusions in the more contemporary series (table 3) reflects the growing number of invasive cardiovascular procedures being performed.

Hemorrhagic pericardial effusion — Patients with hemorrhagic pericardial effusions have a different distribution of causes than those with serous effusions, although there is considerable overlap. Malignancy should always be considered, and tuberculosis is a frequent cause of hemorrhagic effusion in areas in which this infection is common. (See "Pericardial disease associated with cancer: Clinical presentation and diagnosis" and "Tuberculous pericarditis".)

A series from the United States evaluated 96 cases of hemorrhagic pericardial effusion complicated by tamponade and requiring pericardiocentesis. The following causes were identified [19]:

●Malignancy – 26 percent

●Percutaneous interventional procedures – 18 percent

●Post-pericardiotomy syndrome – 13 percent

●Complications of myocardial infarction (free wall rupture, thrombolysis) – 11 percent

●Idiopathic – 10 percent

●Other causes (including uremia, aortic dissection, trauma, etc) – 22 percent

Because efforts to diagnose viral infections were not undertaken, the frequency of hemorrhagic effusions in viral pericarditis was not addressed.

Symptomatic pericardial effusion — The distribution of causes of large symptomatic pericardial effusions was evaluated in a review of 173 consecutive patients undergoing pericardiocentesis [20]. Symptomatic was defined as cardiorespiratory symptoms (eg, dyspnea), signs (eg, tachycardia), echocardiographic features of right heart compromise, or if pericardiocentesis was deemed therapeutically indicated by the clinician.

The following distribution of causes was noted:

●Malignancy – 33 percent (45 of the 58 patients previously known to have a malignancy)

●Chronic-idiopathic – 14 percent

●Acute pericarditis – 12 percent

●Trauma – 12 percent

●Uremia – 6 percent

●Post-pericardiotomy – 5 percent

●Indeterminate – 8 percent

●Other causes (including infection, collagen vascular disease, radiation, heart failure, etc) – 10 percent

Constrictive pericarditis — Patients with constrictive pericarditis typically present with symptoms related to fluid overload (ranging from peripheral edema to anasarca), symptoms related to diminished cardiac output in response to exertion (eg, fatigability and dyspnea on exertion) or at rest, or both. Patients typically present months to years after an initial insult involving the pericardium, although the majority of patients with prior involvement of the pericardium do not develop constrictive pericarditis. While the diagnosis of constrictive pericarditis is often made by echocardiography and cardiac magnetic resonance, patients commonly undergo cardiac catheterization to confirm the diagnosis. (See "Constrictive pericarditis: Diagnostic evaluation".)

Effusive constrictive pericarditis — Pericardial pathology consistent with constrictive pericarditis with a concomitant effusion is called effusive constrictive pericarditis. Most cases of effusive constrictive pericarditis are idiopathic, reflecting the frequency of idiopathic pericardial disease in general. Effusive constrictive pericarditis is relatively uncommon (similar to constrictive pericarditis). The diagnosis of effusive constrictive pericarditis often becomes apparent following pericardiocentesis in patients initially considered to have uncomplicated cardiac tamponade. In such cases, the right atrial pressure remains elevated after removal of the pericardial effusion due to underlying constriction. In a study of 205 patients undergoing pericardiocentesis at Mayo Clinic, effusive constrictive pericarditis was diagnosed in 33 (16 percent); the etiology was procedure-related hemopericardium in 11 (33 percent), idiopathic in 9 (27 percent), post-cardiac surgery in 6 (18 percent), post-viral pericarditis in 3 (9 percent), malignancy in 2 (6 percent), and other in 2 (6 percent) [21]. (See "Constrictive pericarditis: Diagnostic evaluation".)

ESTABLISHING THE DIAGNOSIS — The yield of a full diagnostic evaluation is much lower in patients presenting primarily with acute pericarditis without a significant pericardial effusion than in those who present with a significant pericardial effusion. In two series with a total of 331 patients with acute pericarditis, a specific diagnosis was established in only 16 percent [8,9]. The most common were neoplasia (6 percent), tuberculosis (4 percent), nontuberculous infection (2 percent), and collagen vascular disease (2 percent).

In patients with acute pericarditis in whom no cause is identified (idiopathic pericarditis), the etiology is frequently presumed to be viral or immune-mediated [6,7], but evidence for this is usually not sought because of the expense involved, the inaccessibility of pericardial tissue/fluid, the time delay and inaccuracy of viral titers, and the general lack of impact of this information on management. It is possible that many cases in which an identifiable cause exists are labeled "idiopathic pericarditis" as a result of an insufficiently rigorous diagnostic evaluation. However, a complex and exhaustive testing strategy is typically not justified in such patients given the limited implications for clinical management. One clinically important exception to this approach is the absence of a prompt and adequate response to standard treatment, in which case more aggressive efforts at establishing a diagnosis are warranted.

Epicardial/pericardial biopsy using pericardioscopy has improved the diagnostic yield, but it is not widely available. It may be useful for relapsing cardiac tamponade, suspected bacterial or neoplastic pericarditis, worsening pericarditis without a definitive diagnosis despite medical treatment, and symptomatic moderate to large pericardial effusions [2,22].

INFECTION — Virtually any infectious organism can infect the pericardium (table 1). While most infectious causes of pericardial disease result in a typical acute presentation (ie, acute pericarditis or pericardial effusion), some organisms, especially bacteria and fungi, can cause a purulent inflammatory exudate. (See "Purulent pericarditis".)

The frequency of specific pathogens in infectious pericardial disease has been changing in recent decades and continues to vary with geography. Tuberculous pericarditis has become much less common in developed countries, while HIV infection remains an important cause of pericardial disease in the developing world.

The clinical manifestations are often confined to the pericardium, as in viral pericarditis, but extrapericardial infection may be a prominent component of the clinical picture, as in pneumonia or empyema with associated pericardial involvement. In some cases, particularly with tuberculous or fungal infection, an infectious pericarditis can result in chronic constrictive pericarditis. (See "Tuberculous pericarditis" and "Constrictive pericarditis: Diagnostic evaluation".)

Viral — Though the most common viral infections causing pericarditis are reported to be coxsackievirus (types A and B) and echovirus, most of these data come from children diagnosed by serologic testing in the 1960s. More recent data suggest that adult patients are more commonly infected with cytomegalovirus and herpes viruses as well as HIV (table 1) [15,23]. There are many viruses that have been associated with transient pericardial inflammation, which resolves without sequelae. Pericarditis, usually with myocarditis, has also been described as an infrequent complication of smallpox vaccination. (See "Myopericarditis", section on 'Vaccinia-associated myopericarditis'.)

Pericardial effusion is prevalent in patients hospitalized with COVID-19, but is infrequently attributable to pericarditis [24]; it has been associated with myocardial dysfunction and all-cause mortality. (See "COVID-19: Cardiac manifestations in adults".)

Viral infection is less common among patients who present with pericardial effusion without pericarditis, especially if the effusion is large (table 3). An exception to this may be patients with HIV, in whom pericardial effusion seems more prevalent. However, this high frequency may well be decreasing as more and more patients infected with HIV are receiving aggressive therapy. (See "Cardiac and vascular disease in patients with HIV", section on 'Pericardial disease'.)

Bacterial — While any bacterial infection may involve the pericardium (table 1), the most notable organisms include Staphylococcus, Pneumococcus, Streptococcus (rheumatic pancarditis), Haemophilus, and M. tuberculosis. Less common bacteria have the potential to invade the pericardium when the bacterial flora have been altered by prolonged antibiotic use and when the immune system is seriously compromised. (See "Purulent pericarditis" and "Tuberculous pericarditis".)

Other infectious causes — A variety of fungi and parasites are also known to cause pericardial disease (table 1), particularly in endemic areas or in immunocompromised patients.

MALIGNANCY — In two large series, malignancy was responsible for approximately 6 percent of cases of acute pericardial disease (acute pericarditis or tamponade without apparent cause) [8,9]. In addition, malignancy accounts for approximately 15 to 20 percent of moderate to large pericardial effusions (table 3) [14,15]. (See "Pericardial disease associated with cancer: Clinical presentation and diagnosis".)

Virtually any malignant tumor can metastasize to the pericardium, with the most common being lung and breast cancer and Hodgkin lymphoma. Primary tumors of the pericardium are rare and include several different types. In many cases, it is not easy to decide whether pericardial disease is a manifestation of the malignancy itself or of treatment with radiation or chemotherapy. (See "Pericardial disease associated with cancer: Clinical presentation and diagnosis", section on 'Pericardial effusion'.)

POST-CARDIAC INJURY SYNDROMES — Pericarditis with or without a pericardial effusion resulting from injury of the pericardium constitutes the post-cardiac injury syndrome. The principal conditions considered under this rubric are postmyocardial infarction syndrome, post-pericardiotomy syndrome, and posttraumatic pericarditis. (See "Post-cardiac injury syndromes".)

●Post-myocardial infarction syndrome – Pericardial disease, manifested as pericarditis and/or effusion, is a common event following acute myocardial infarction (MI), but has become fairly rare in the era of primary reperfusion therapy. [25-28]. An effusion that occurs early after infarction is related to the acute inflammation associated with the infarct, while immunologic mechanisms are responsible for effusions that occur several weeks to months after the infarct. The acute effusions are usually silent. (See "Pericardial complications of myocardial infarction", section on 'Post-MI pericardial effusion'.)

Left ventricular free wall rupture can also occur after a myocardial infarction. Affected patients have a large hemorrhagic pericardial effusion and tamponade, and the diagnosis is suggested by the development of sudden, profound heart failure and shock. This syndrome is discussed separately. (See "Acute myocardial infarction: Mechanical complications", section on 'Rupture of the left ventricular free wall'.)

●Postpericardiotomy syndrome – Postpericardiotomy syndrome occurs in up to 15 percent of patients following surgery. The presentation and clinical course of the post-pericardiotomy syndrome is comparable to that of acute pericarditis. (See "Post-cardiac injury syndromes", section on 'Clinical features'.)

Pericardial effusion occurring within hours after cardiac surgery is more often associated with pericardial bleeding, is presumably not due to the post-cardiac injury syndrome, and is frequently associated with cardiac tamponade [29]. Post-cardiac surgery tamponade is often atypical and may be associated with left rather than right ventricular compression on echocardiography.

Pericardial effusion also occurs in 9 to 21 percent of patients after cardiac transplantation [30,31].

●Posttraumatic pericarditis – Trauma causing pericarditis may be blunt, as with a steering wheel injury, or sharp, as with bullet or knife wounds. Iatrogenic causes include virtually all cardiac invasive diagnostic and therapeutic procedures, and rarely cardiopulmonary resuscitation. (See "Post-cardiac injury syndromes".)

RADIATION — Prior mediastinal radiation is an important cause of pericardial disease. Most cases are secondary to radiation therapy for Hodgkin lymphoma or breast or lung cancer. Less commonly, radiation exposure occurs with thoracic radiation for other conditions (eg, esophageal cancer). However, improved shielding and dose calculation have reduced the incidence of this complication. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Soon after radiation, the patient may develop acute pericarditis with or without effusion [32]. Late onset of pericardial disease is common and is not necessarily preceded by acute pericarditis [33]. The late pericardial disease may consist of effusive constrictive pericarditis or classic constrictive pericarditis. (See "Constrictive pericarditis: Diagnostic evaluation".)

DRUGS AND TOXINS — The list of drugs and toxins that can cause pericardial disease is long (table 4).

●Procainamide, tocainide, hydralazine, isoniazid, methyldopa, and phenytoin, can induce a lupus-like syndrome. (See "Drug-induced lupus".)

●The penicillins may cause a hypersensitivity pericarditis with eosinophilia.

●Minoxidil (among other drugs) may produce an idiosyncratic reaction with pericardial effusion.

●Doxorubicin and daunorubicin are more often associated with a cardiomyopathy, but may cause pericardial disease, as may other chemotherapy agents. Immune mediated and non-immune mediated cytotoxicity with tyrosine kinase inhibitors and immune checkpoint inhibitors have been reported to cause pericardial syndromes [34]. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".)

Asbestos exposure, resulting in asbestosis, can also induce pericardial lesions, commonly in conjunction with pleural and parenchymal lung disease. (See "Asbestos-related pleuropulmonary disease".)

SYSTEMIC DISORDERS — A variety of systemic disorders have pericardial involvement:

●Collagen vascular disease – A number of rheumatic diseases can involve the pericardium. Symptomatic pericarditis can occur with all of these disorders, while pericardial effusion, when present, is usually clinically silent. This is most likely to occur in systemic lupus erythematosus (SLE) and rheumatoid arthritis. In SLE, for example, the pericardium is involved in almost one-half of patients [35]. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults".)

●Uremia and dialysis – Important causes of metabolic pericardial disease are uremia (which causes pericarditis in 6 to 10 percent of patients with advanced renal failure who are not being dialyzed) and dialysis-related pericardial effusion (occurring in approximately 13 percent of patients). Both inadequate dialysis (ie, uremic pericarditis) and fluid overload may contribute to the latter disorder [36,37]. An important clinical feature of uremic pericarditis is that the electrocardiogram does not usually show typical diffuse ST elevation, presumably because epicardial injury is uncommon [37]. The presence of ST-T abnormalities suggests some other cause for the pericarditis.

●Hypothyroidism – Severe hypothyroidism, especially with classic myxedema, may be a cause of pericardial effusion but not usually pericarditis [38]. The effusion is typically slow to accumulate, which frequently results in a large (hundreds of milliliters) effusion, which is rarely hemodynamically significant. (See "Cardiovascular effects of hypothyroidism".)

●Ovarian hyperstimulation syndrome – Severe ovarian hyperstimulation syndrome is a potential complication of gonadotropin therapy for the induction of ovulation. The syndrome includes the combination of underlying ovarian enlargement due to multiple ovarian cysts and an acute fluid shift out of the intravascular space that can lead to ascites and pericardial and pleural effusions. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)

●GI disease – The pericardium can also be involved in gastrointestinal diseases. These include inflammatory bowel disease (ulcerative colitis and Crohn's disease) and Whipple's disease. (See "Whipple's disease".)

●Immunoglobulin G4-related disease – This fibroinflammatory disease characterized by elevated serum levels of IgG4 and multiorgan involvement was reported as a cause of constrictive pericarditis [39].

IDIOPATHIC — In many cases, the etiology of pericardial disease cannot be determined.

●In patients with acute pericarditis, a cause is identified in only about 16 percent, based on two large series [8,9]. The etiology in the remaining patients is frequently presumed to be viral, but evidence for this is often not sought because of the expense involved, the inaccessibility of pericardial tissue/fluid, and the time delay and inaccuracy of viral titers. (See "Acute pericarditis: Clinical presentation and diagnosis".)

●By comparison, a specific etiology can be established in many patients with moderate to large pericardial effusions (table 3). In two series, a diagnosis of idiopathic disease was made in only 7 to 29 percent of patients [14,15]. (See "Pericardial effusion: Approach to diagnosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pericarditis in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Pericarditis (Beyond the Basics)")

SUMMARY

●Causes of pericardial disease – Pericardial disease can be a result of inflammatory, neoplastic, vascular, iatrogenic, and idiopathic causes (table 1). The specific causes of pericardial disease vary depending in part upon geography, the patient population, and how the diagnosis is established. (See 'Classification' above and 'Spectrum of clinical presentation' above.)

•Infection, most commonly viral – Though the most common viral infections causing pericarditis are reported to be coxsackievirus (types A and B) and echovirus, most of these data come from children diagnosed by serologic testing in the 1960s. More recent data suggest that adult patients are more commonly infected with cytomegalovirus and herpes viruses as well as HIV (table 1). (See 'Viral' above.)

•Malignancy – Malignancy (usually due to metastatic spread) is responsible for approximately 6 percent of cases of acute pericardial disease (acute pericarditis or tamponade without apparent cause) as well as 15 to 20 percent of moderate to large pericardial effusions. (See 'Malignancy' above and "Pericardial disease associated with cancer: Clinical presentation and diagnosis".)

•Radiation – Prior mediastinal radiation is an important cause of pericardial disease, with most cases following radiation therapy for Hodgkin lymphoma, breast cancer, or lung cancer. Soon after radiation, the patient may develop acute pericarditis with or without effusion. Late onset of pericardial disease is common and may consist of effusive constrictive pericarditis, classic constrictive pericarditis, or pericardial effusion with or without tamponade. (See 'Radiation' above and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

•Post-cardiac injury syndromes – Both pericarditis and pericardial effusion can occur following an acute myocardial infarction (MI). An effusion that occurs early after MI is related to the acute inflammation associated with the infarct, while immunologic mechanisms are responsible for effusions that occur several weeks to months after the infarct. (See 'Post-cardiac injury syndromes' above and "Pericardial complications of myocardial infarction", section on 'Post-MI pericardial effusion'.)

•Systemic disorders – A number of rheumatic diseases, most commonly systemic lupus erythematosus and rheumatoid arthritis, can involve the pericardium, leading to either pericardial inflammation with pleuritic pain, pericardial effusion with or without cardiac tamponade, and occasionally constrictive pericarditis. (See 'Systemic disorders' above.)

●Evaluating the cause of acute pericarditis – In patients with acute pericarditis in whom no cause is identified (idiopathic pericarditis), the etiology is frequently presumed to be viral, and extensive evaluation for a specific diagnosis is usually not necessary. However, if a prompt and adequate response to standard treatment is not seen, more aggressive efforts at establishing a specific etiology are warranted. (See 'Establishing the diagnosis' above and "Acute pericarditis: Clinical presentation and diagnosis".)

●Causes of pericardial effusion – The distribution of causes of pericardial effusion varies with demographics and diagnostic strategies (table 3). In a patient with nontraumatic hemorrhagic pericardial effusion, malignancy and tuberculosis (particularly in an endemic area) are common. (See 'Pericardial effusion' above and 'Hemorrhagic pericardial effusion' above.)