Etiologies of pericarditis

Article written and reviewed by Dr Luca Moretti

The etiologies of pericarditis include infections, immune-mediated diseases, neoplasms, metabolic disorders, and injury caused by procedures, drugs, or radiation. These conditions may produce initially similar manifestations, but differ in the likelihood of recurrence, risk of constriction, and need for specific treatment. Recognizing pericardial inflammation and identifying its cause are therefore two distinct steps: typical pain, a friction rub, or a finding on magnetic resonance imaging may support the syndromic diagnosis without establishing which process caused it.

In practice, idiopathic pericarditis is an operational diagnosis after an evaluation proportionate to risk, whereas the definition of viral pericarditis requires attention to the degree to which infection is documented. The two categories are often grouped together in studies, but they are not biologically synonymous. In settings with a high prevalence of tuberculosis, in immunosuppression, or in oncologic series, the distribution of causes changes substantially and cannot be inferred from series of otherwise healthy outpatients.

Etiologic reasoning must proceed together with assessment of urgency. Tamponade, suspected purulent infection, and myocardial involvement require immediate decisions; in uncomplicated episodes, by contrast, selective investigation may be more useful than an extensive indiscriminate panel. The quality of the assessment depends on linking clinical context, objective findings, and therapeutic consequences, while explicitly distinguishing among a proven cause, a probable cause, and a cause that remains unknown.

Causal classification and the significance of the epidemiologic context

The first distinction separates infectious causes from noninfectious causes, but this alone does not describe the entire mechanism of disease. An infection may directly damage tissues, trigger an immune response that persists after its resolution, or coexist with an independent condition. The timing of onset in relation to infection and the site at which the microorganism is documented modify the interpretation. A positive respiratory swab demonstrates infection in that compartment; attributing pericarditis requires additional correlation and does not automatically imply invasion of pericardial tissue.

Among infectious forms, viruses are frequently presumed in immunocompetent patients with a favorable course. bacterial pericarditis includes very different presentations: pyogenic infections may progress rapidly to an infected collection and sepsis, whereas tuberculous pericarditis may present with effusion, systemic disease, or progressive constriction. The definition of purulent pericarditis describes the suppurative contents and severity of the process, without replacing identification of the pathogen. Fungi and parasites are less common and become relevant mainly in relation to immunosuppression, exposures, and geographic origin.

The pretest probability is established before tests are ordered. Tuberculosis contacts, stays in endemic areas, HIV infection, transplantation, chemotherapy, and immunosuppressive therapy change the weight assigned to different hypotheses. Previous cardiac surgery makes a post-cardiac injury syndrome plausible, but also increases the relevance of infected or hemorrhagic collections. Context therefore points toward several possibilities, not toward an automatic label. The absence of obvious epidemiologic factors lowers some probabilities without eliminating them, especially when prolonged fever, weight loss, or lack of response occurs.

The immune-mediated forms include systemic autoimmune diseases and autoinflammatory processes. In the first group, pericardial involvement may accompany lupus, rheumatoid arthritis, and other conditions; in the second, activation of innate immunity may predominate even without specific autoantibodies. A proportion of recurrent idiopathic forms has features compatible with this mechanism. However, not every recurrence corresponds to a monogenic disease, and not every positive antibody test proves a connective tissue disease. Classification must remain anchored to the overall phenotype and to the criteria for the suspected systemic disease.

The secondary noninfectious causes include uremia, neoplastic infiltration, radiotherapy, drug reactions, and cardiac injury. Overlap is also possible here: in a patient with cancer, an effusion may be due to the tumor, treatment, an infection, or a condition unrelated to the neoplasm. In renal failure, fluid overload and pericardial inflammation are not equivalent. The presence of a predisposing disease makes a cause plausible, but does not eliminate the need to demonstrate that it explains the current presentation.

Published percentages also reflect selection of the case series. Studies of patients undergoing drainage enroll more large effusions, neoplasms, and specific infections than outpatient series of chest pain. Surgical series concentrate constriction and advanced structural disease. Applying these frequencies to every new case of pericarditis leads to overestimation or underestimation of risk. Epidemiology is useful when population, definition, and level of care are comparable with the case being evaluated.

From cause to injury: pathogenesis and pathophysiologic consequences

The pericardium responds to different stimuli through a relatively limited number of inflammatory pathways. Activation of resident cells and endothelium increases permeability and leukocyte recruitment; proteins and cells accumulate in the cavity, while fibrin and edema alter the serosal surfaces. These events explain why different causes may produce similar pain, friction rub, and effusion. Similarity of the final response, however, does not imply identity of the initial mechanism and does not justify applying the same immunosuppression to every etiology.

In infections, injury may depend on microbial replication, toxins, necrosis, and the host response. Purulent forms generate a neutrophil-rich exudate that may organize into loculations and make simple drainage incomplete. Tuberculosis combines granulomatous inflammation with varying degrees of exudation and remodeling. In forms attributed to viruses, the relative importance of local infection and immune activation varies and is often not measurable in clinical practice. Detection of viral genetic material must be interpreted considering the compartment, latency, and the possibility of blood contamination.

The sterile response may be triggered by cardiac injury or maintained by immune circuits. The NLRP3 inflammasome and interleukin-1 signaling contribute to inflammation in some phenotypes, but do not represent a universal diagnostic marker. The efficacy of interleukin-1 antagonists in selected populations with recurrent pericarditis supports the relevance of this pathway without proving that all pericarditis has the same origin. In systemic autoimmunity, adaptive immunity, autoantibodies, and organ inflammation may act together with innate mechanisms.

The consequences of an effusion depend on the pressure-volume relationship, not only on its echocardiographic size. A rapidly accumulating collection may compromise filling before reaching a large volume; slow distension allows greater adaptation. The cause influences the rate of accumulation, contents, and distribution, while volume status and intracardiac pressures modify the clinical expression. Tamponade is therefore a hemodynamic syndrome to be recognized regardless of whether the collection is idiopathic, neoplastic, or infectious.

Fibroadhesive repair represents another possible pathway of injury. Persistent fibrin, fibroblast activity, and matrix deposition may limit sliding of the pericardial layers and cardiac expansion. Risk is particularly associated with bacterial causes, including tuberculosis and purulent infections, whereas it remains low in uncomplicated idiopathic forms. Constriction may also be temporarily sustained by edema and inflammation, with the possibility of regression. Symptom duration alone or the presence of thickening does not prove irreversible fibrosis.

Myocardial involvement changes the clinical problem. Elevated troponin, ventricular dysfunction, or arrhythmias require determination of whether the syndrome is limited to the pericardium or includes clinically significant myocarditis. A preserved ejection fraction does not exclude myocardial injury, whereas elevated troponin may also have ischemic or systemic causes. Multimodality characterization helps distinguish these mechanisms and prevents every abnormality from being interpreted as a simple extension of benign pericarditis.

History, clinical manifestations, and risk selection

The timeline is often the first element capable of organizing the hypotheses. It is necessary to establish when pain, fever, and dyspnea appeared, whether there was a symptom-free interval, and which treatments preceded the investigations. A subacute onset with progressive malaise raises different questions from a recent episode that is typically positional and rapidly responsive. The relationship with a procedure, a new therapy, or an infection must be documented with dates and course, because temporal sequence alone does not prove causality.

The history must explore exposures and systemic conditions with targeted questions. Persistent fever, night sweats, and weight loss point toward infection or neoplasia; arthralgia, rash, Raynaud phenomenon, ulcers, and renal abnormalities may support an immunologic disease. Stereotyped febrile episodes, serositis at other sites, and family history suggest an autoinflammatory workup. The absence of these elements at the first episode does not prevent them from appearing later, making etiologic reassessment necessary during follow-up.

The treatment history includes prescribed drugs, cancer immunotherapies, changes in dialysis, and recent procedures. For a suspected drug reaction, latency, a plausible mechanism, the course after withdrawal, and alternative diagnoses matter; intentional rechallenge is generally not necessary to achieve certainty. In patients with cancer, pain and elevated troponin during treatment with immune checkpoint inhibitors require attention to concomitant myocarditis. In patients who have received radiation, injury may also involve myocardium, coronary arteries, and valves, with implications for diagnosis and recovery.

The physical examination looks for both pericardial signs and clues to the cause. A friction rub is suggestive but intermittent, and its absence does not exclude disease. Blood pressure, heart rate, perfusion, jugular venous distension, and pulsus paradoxus contribute to hemodynamic assessment. Lymph nodes, skin lesions, arthritis, signs of infection, and hepatic congestion may guide the workup. Ascites or edema should not automatically be attributed to hepatic or renal disease before considering a pericardial obstacle to filling.

The high-risk features include fever above 38 °C, subacute onset, large effusion, tamponade, and lack of response to initial anti-inflammatory therapy. Immunosuppression, trauma, anticoagulant treatment, and myocardial involvement add further elements to assess. These findings do not identify a specific cause, but make a simple idiopathic attribution less secure and may require hospitalization and more extensive investigation. Clinical thresholds must be integrated with comorbidities, feasibility of monitoring, and the course over the first few days.

Risk stratification keeps urgency and etiologic probability distinct. Tamponade must be treated before all results are available; drainage can simultaneously provide diagnostic material. Conversely, a stable patient without risk features may be followed with close reassessment, without invasive tests performed solely to assign a name to the process. A favorable response supports the chosen pathway, but should be accompanied by confirmation of remission and must not become retrospective proof of a viral origin.

Initial investigations and construction of the etiologic diagnosis

Evaluation begins by confirming the syndrome. ECG, echocardiography, inflammatory markers, and biomarkers of myocardial injury answer different questions: the ECG looks for compatible changes and ischemic alternatives; echocardiography quantifies fluid and assesses its effects; C-reactive protein provides information about systemic inflammatory activity; troponin indicates myocardial injury that requires interpretation. None of these tests alone identifies the etiology. Even magnetic resonance imaging showing edema and late enhancement demonstrates tissue characteristics, not a specific causative agent.

The basic diagnostic workup generally includes a complete blood count, renal function, and electrolytes, with additional testing guided by the presentation. Leukocytosis may be infectious, inflammatory, or drug-related; renal function is relevant both to etiologic reasoning and to the choice of medications and contrast. Chest radiography may show pulmonary disease, pleural effusion, or an enlarged cardiac silhouette, whereas CT is more informative when the question concerns neoplasia, lymph nodes, complex collections, or associated thoracic disease. Each test should be selected according to the clinical question.

Features that justify a targeted etiologic workup

• High-risk presentation, instability, or a clinically significant effusion with an indication for drainage.
• Persistent fever, sepsis, suspected tuberculosis, or immunosuppression.
• Known neoplasia, suspicious radiologic findings, or unexplained constitutional symptoms.
• Manifestations compatible with autoimmune, autoinflammatory, or metabolic disease.
• Atypical course, lack of response, recurrences with new findings, or progression toward constriction.

The microbiologic investigations must consider the site and timing of sampling. Blood cultures are important when systemic or purulent infection is suspected and, when possible, should be obtained before antibiotics without delaying urgent treatment. Tuberculosis requires an approach integrating epidemiology, extrapericardial sites, and tests on available material. Immunologic tests of exposure do not demonstrate pericardial localization. Broad viral serology has low causal yield and does not replace clinical assessment; targeted tests for systemic infections are ordered when they may change management or treatment.

The immunologic assessment starts from the phenotype, not from a list of autoantibodies. Low-titer antinuclear antibodies may occur without a connective tissue disease and require contextualization. More specific testing, complement, urinalysis, and specialist assessment are appropriate when coherent manifestations are present. Similarly, genetic testing for autoinflammatory syndromes is selective: early onset, family history, periodic fevers, and multiple serositis increase its usefulness, whereas a variant of uncertain significance does not provide a definitive explanation.

The result of the investigation should express the degree of certainty. A relevant culture or positive cytology may provide direct evidence; a coherent combination of exposure, presentation, and findings may support a probable cause. If the evidence is insufficient, an idiopathic designation remains legitimate provided that the evaluation was appropriate to the risk. It is preferable to describe the residual uncertainty and plan reassessment rather than assign an etiology on the basis of a single nonspecific test.

Fluid, tissue, and subsequent investigations

Pericardial drainage is indicated mainly for therapeutic needs or a clinically relevant etiologic question, not by a desire to obtain material in every case of pericarditis. Tamponade with clinical compromise requires prompt intervention; a suspected purulent collection, some neoplastic effusions, and persistent symptomatic collections may require a planned or urgent procedure depending on the context. Location, loculations, contents, and available expertise guide the choice between pericardiocentesis and a surgical approach. The method chosen should also account for the possibility of incomplete drainage.

The sample should be allocated to relevant tests before the procedure, with containers and transport organized in advance. Cytology, cultures, possible molecular analyses, and other tests are selected on the basis of the clinical suspicion. Hemorrhagic fluid is not synonymous with neoplasia: it may result from procedures, trauma, and other causes. Likewise, a high protein content or lymphocytic predominance does not prove tuberculosis. Biochemical criteria developed for other serous fluids should not be transferred without considering the specificity of the pericardial compartment.

The cytology may document malignant involvement and, with appropriate ancillary studies, help define its origin. Sensitivity depends on tumor type, involvement, and the quality and quantity of the specimen. A negative sample does not exclude all infiltration, especially if imaging and clinical history remain suspicious. Biopsy may be complementary, but it is not automatically superior in every situation and may miss focal lesions. The value of each result derives from integration with the anatomic distribution of disease and with other oncologic investigations.

The pericardial biopsy has a role when the result may change care, when the diagnosis remains unresolved despite adequate testing, or during an intervention that is already indicated. Granulomas, tumor infiltration, necrosis, and the composition of the infiltrate guide interpretation, whereas isolated fibrosis is poorly specific. Stains, cultures, and molecular investigations require planning with the laboratory. The specimen should not be sent entirely in fixative if this prevents necessary microbiologic analyses; handling and aliquots depend on the applicable diagnostic protocol.

multimodality imaging defines aspects that the specimen cannot describe. Magnetic resonance imaging characterizes pericardial and myocardial inflammation, whereas CT shows calcification, masses, and thoracic anatomy in greater detail. Positron emission tomography may have a selective role, but metabolic uptake does not absolutely distinguish infection, sterile inflammation, and tumor. In suspected constriction, functional assessment of filling is essential: increased thickness without consistent physiology is insufficient to explain congestion.

The reassessment over time completes the etiologic investigation. A new recurrence does not necessarily require repeating all previously negative tests, but the appearance of persistent fever, increasing effusion, organ injury, or systemic manifestations justifies review. The point is not to accumulate results, but to verify whether the initial hypothesis continues to explain the entire course. Documentation should make clear which tests were performed, what uncertainties remain, and what conditions would trigger a diagnostic or therapeutic change.

Therapeutic consequences, prognosis, and prevention of complications

The etiologic therapy differs radically among categories. In uncomplicated idiopathic or presumably viral forms, control of inflammation and prevention of recurrences are central to management. Purulent pericarditis requires antibiotics and adequate control of the collection; tuberculosis requires complete antimycobacterial treatment. An anti-inflammatory drug may reduce pain and fever without eradicating infection, so symptomatic improvement should not interrupt a necessary causal workup or treatment.

The autoimmune pericarditis is treated within the context of the systemic disease, considering which other organs are involved. The autoinflammatory pericarditis may require a strategy directed at innate immunity, but only after appropriate assessment. Interleukin-1 inhibitors have strong evidence in specific populations with inflammatory recurrences; they are not indiscriminate treatment for every effusion or fibrosis. Before immunomodulation, infectious risk, contraindications, and appropriate monitoring must be addressed.

In uremic pericarditis management of the renal condition and renal replacement therapy is central, with attention to hemodynamics and bleeding risk. The neoplastic pericardial disease requires coordination between fluid control and oncologic treatment, taking overall goals and prognosis into account. Drug- or radiation-induced forms require assessment of injury and therapeutic alternatives. Independently stopping an essential therapy is not equivalent to a considered causal strategy.

The post-cardiac injury syndrome includes immune-inflammatory processes following myocardial or pericardial injury. The temporal relationship and context help identify it, but an effusion after surgery is not always inflammatory. Bleeding, infection, and a simple postoperative collection should be considered before prescribing prolonged treatment. Even when the mechanism is plausible, drug dose and duration depend on documented activity, renal function, gastrointestinal risk, and interactions.

The prognosis is defined on several levels. Immediate risk depends on tamponade, sepsis, and myocardial injury; subsequent risk includes recurrence, constriction, and injury from the underlying disease. In idiopathic forms, recurrences may cause substantial morbidity without implying high mortality or inevitable progression to fibrosis. In specific bacterial infections, structural risk is higher, whereas in neoplasia the outcome may be dominated by the oncologic disease. A single clinical label does not summarize all these dimensions.

Prevention of complications requires treatment of the cause, reassessment of response, and surveillance proportionate to risk. Reduction in C-reactive protein is useful when the marker was elevated, but does not replace assessment of symptoms, effusion, and filling. Persistent congestion after drainage suggests looking for effusive-constrictive physiology or other cardiac causes; failure of functional recovery requires consideration of myocardium, comorbidities, and treatment toxicity. The etiologic pathway therefore remains active until the clinical data have a coherent explanation and disease control is documented.

References
1. Schulz-Menger J et al. 2025 ESC Guidelines for the management of myocarditis and pericarditis. European Heart Journal. 2025;46(40):3952-4041.
2. Wang TKM et al. 2025 Concise Clinical Guidance: An ACC Expert Consensus Statement on the Diagnosis and Management of Pericarditis: A Report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology. 2025;86(25):2691-2719.
3. Klein AL et al. Pericardial Diseases: International Position Statement on New Concepts and Advances in Multimodality Cardiac Imaging. JACC: Cardiovascular Imaging. 2024;17(8):937-988.
4. Adler Y et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC). Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal. 2015;36(42):2921-2964.
5. Roberts WC. Pericardial heart disease: its morphologic features and its causes. Proceedings (Baylor University Medical Center). 2005;18(1):38-55.
6. Mauro AG et al. The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches. JACC: Basic to Translational Science. 2021;6(2):137-150.
7. Imazio M et al. Indicators of poor prognosis of acute pericarditis. Circulation. 2007;115(21):2739-2744.
8. Sagristà-Sauleda J et al. Purulent pericarditis: review of a 20-year experience in a general hospital. Journal of the American College of Cardiology. 1993;22(6):1661-1665.
9. Mayosi BM et al. Tuberculous pericarditis. Circulation. 2005;112(23):3608-3616.
10. Saab J et al. Diagnostic yield of cytopathology in evaluating pericardial effusions: Clinicopathologic analysis of 419 specimens. Cancer Cytopathology. 2017;125(2):128-137.
11. Imazio M et al. Risk of constrictive pericarditis after acute pericarditis. Circulation. 2011;124(11):1270-1275.
12. Spodick DH. Acute cardiac tamponade. New England Journal of Medicine. 2003;349(7):684-690.
13. Klein AL et al. Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis. New England Journal of Medicine. 2021;384(1):31-41.