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Acute Pericarditis
Acute Pericarditis, Review Niraj S Doctor, Ankit B Shah, Neil Coplan, Itzhak Kronzon PII: DOI: Reference:
S0033-0620(16)30138-4 doi: 10.1016/j.pcad.2016.12.001 YPCAD 770
To appear in:
Progress in Cardiovascular Diseases
Please cite this article as: Doctor Niraj S, Shah Ankit B, Coplan Neil, Kronzon Itzhak, Acute Pericarditis, Review, Progress in Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.12.001
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ACCEPTED MANUSCRIPT Short title: Acute Pericarditis
Acute Pericarditis, Review
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Niraj S Doctor, MD, Ankit B shah MD, Neil Coplan MD, FACC, Itzhak Kronzon MD, FASE, FACC, FACP, FESC, FAHA Lenox Hill Heart and Vascular Institute of New York, New York, NY
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Short title: Acute Pericarditis
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Disclosures: There are no relevant financial disclosures, acknowledgments or conflicts of interest.
Corresponding author. Dr.Itzhak Kronzon MD,Tel +12124346119: fax +1 212434 2111. Email: [email protected],[email protected]
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Keywords: Pericarditis, Acute pericarditis, Recurrent Pericarditis
Abbreviations:
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ACS- Acute Coronary Syndrome
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ASA- Acetyl Salicylic Acid CRP- C Reactive Protein
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COPE - COlchicine for acute PEricarditis COPPS - COlchicine for the Prevention of the Post-pericardiotomy Syndrome CORE - COlchicine for REcurrent pericarditis CT – Computerized Tomography CXR- Chest x ray EKG- Electrocardiogram ESC - European Society of Cardiology ESR- Erythrocyte Sedimentation Rate FMF- Familial Mediterranean Fever 1|Page
ACCEPTED MANUSCRIPT HIV- Human Immunodeficiency Virus IVIG- Intravenous Immnoglobulins
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LV- Left Ventricle
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MI – Myocardial Infarction
NSAIDS- Non Steroidal Anti-inflammatory Drug
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PET- Positron Emission Tomography
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MRI- Magnetic Resonance Imagine
SLE- Systemic Lupus Erythematosus
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TRAPS- Tumor necrosis factor Receptor-Associated Periodic Syndrome
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WBC- White Blood Count
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Abstract:
Acute pericarditis is an acute inflammatory disease of the pericardium, which may occur in many
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different disease states (both infectious and non-infectious). Usually the diagnosis is based on
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symptoms (chest pain, shortness of breath), electrocardiographic changes (ST elevation), physical examination (pericardial friction rub) and elevation of cardiac biomarkers. It may occur in isolation or be associated with an underlying inflammatory disorder. In routine clinical practice, acute pericarditis can be associated with myocarditis due to their overlapping etiologies.
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Anatomy and Function of Pericardium:
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The pericardium is an avascular sac composed of a double layer. The outer layer (parietal pericardium) is composed of fibrous tissue while the inner layer (visceral pericardium) is
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composed of mesothelial serous cells. The parietal pericardium is a thick, tough outer sac made
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of collagenous connective tissue. It is attached to the diaphragm, sternum and the cartilage of the ribs. The parietal pericardium separates the heart from other mediastinal structures. The visceral
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pericardium is a thin layer adherent to the epicardial surface of the heart and its epicardial fat. (1-
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12)
The normal pericardial space contains approximately 25-50ml of fluid and serves as a lubricant
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between the visceral and parietal layer. The parietal layer and the fibrous pericardium are two
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inseparable structures. The pericardial fluid is drained via the right lymphatic duct and the thoracic duct into the right pleural space. (10-12)
The pericardium has a protective physical function as a barrier which prevents the spread of infection or malignancy to the heart. It also serves to prevent dilatation of the cardiac chambers and to maintain ventricular compliance. The subatmospheric pressure in the pericardial sac facilitates atrial filling and maintains cardiac pressure.( 13,14). Pericardial fluid works as a lubricant and decreases the friction of the cardiac surfaces during systole and diastole. (15)
Specific terminologies for pericarditis: Table 1 (1, 3):
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ACCEPTED MANUSCRIPT In the medical literature, pericarditis is subdivided into acute, incessant, recurrent/relapsing and
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chronic pericarditis depending on symptoms duration and their re-occurrence.
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Epidemiology:
Patients should be screened and considered for specific etiology and rational management
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according to their epidemiological background (Table 2). For example, in developing countries
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tuberculosis is a major cause. Tuberculosis with HIV infection is common in the sub-Saharan region. In developed countries, idiopathic or pericarditis related to viral infection is more
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common. (16). In contrast, acute pericarditis and myocarditis share many of the same viral
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etiologies as causative agents and myocardial involvement is common in acute pericarditis.
Acute pericarditis is the most common disorder involving the pericardium, but the true incidence
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and prevalence are unknown since low risk patients are usually not admitted to hospitals. (1,3,7,
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16-25) Pericarditis accounts for 5% of emergency department visits for chest pain in the absence of myocardial infarction (MI) (7,15). In one study, the incidence rate of acute pericarditis was
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present in 3.3 per 100,000 of patients admitted to hospital. Patients with pericardiotomy and myocardial infarction related pericarditis were excluded. (19)
In an observational study from an urban area in northern Italy, the incidence of acute pericarditis (viral/idiopathic) was 27.2 cases per 100,000 persons per year (1,3, 24), and the incidence of myocarditis was 4.0 cases per 100,000 population/year (24). Acute pericarditis was recorded in approximately 0.1% of hospitalized patients and around 5% of patients admitted to the emergency department for non-acute MI chest pain (22, 26, 27). In a Finnish Trial, the in
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ACCEPTED MANUSCRIPT hospital mortality rate for acute pericarditis was 1.1% (19). A Swedish registry found an
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incidence rate of 18.0 per 100,000 for pericarditis in the general population (19).
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The mean age of patients with acute pericarditis in clinical series ranges from 41 to 60 years (19). Men have a twofold incidence rate of acute pericarditis compared to women.(19), Females
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have been associated with complications of acute pericarditis, but was not an independent predictor of mortality (1,19). The reasons for the gender differences in pericarditis are unknown,
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but some studies suggested, due to testosterone effect, young men are at higher risk for
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pericarditis and females during the post menoupausal period are more succeptible for acute pericarditis. Table 2, Non Comprehensive list of Etiologies of Acute Pericarditis (1,3)
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Table 2 showed that there are so many different types of etiologies for acute pericarditis, which
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includes infectious and non-infectious causes. Infectious causes includes bacterial, viral, fungal
drugs and trauma.
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and parasitic causes, whereas non infectious causes includes autoimmune, neoplastic, metabolic,
History:
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Clinical Presentation
Patients with acute pericarditis present with sudden onset of chest pain, which is sharp in nature and usually in the precordial/retrosternal area. The pain classically worsens with inspiration and is often positional. Pain often increases with supine position and is relieved with sitting posture and leaning forward. Pericarditis may involve the phrenic nerve which innervates the trapezius muscles, resulting in pain in the back and shoulders.(28). The pain may radiate to neck, left shoulder and jaw. Symptoms can be associated with cough, rhinorrhea, low grade fever and shortness of breath. 5|Page
ACCEPTED MANUSCRIPT Patients with underlying malignancy or autoimmune disorder may present with specific signs and symptoms of their underlying etiology. (3), this may include fever, leukocytosis, fatigue and
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weight loss.(1)
Physical Examination:
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Meticulous history and physical examination are necessary for every patient with suspected
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pericarditis. A pericardial friction rub, which is thought to be result of friction of inflamed visceral and pericardial layer (28), is a “scratchy” or “squeaky” high pitched sound best heard
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with the diaphragm of stethoscope at the left sternal border at the end of expiration with the patient leaning forward or in the left lateral decubitus position. Pericardial friction rub often
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varies throughout the day, so a patient with suspected acute pericarditis should be examined
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frequently and in multiple positions. (3)
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Classically, a pericardial friction rub has three components, corresponding to (1) atrial systole ( in patient with normal sinus rhythm), (2) ventricular systole, and(3) the rapid filling phase of
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ventricular diastole. However, a triphasic rub is found in only half of patients who have a friction rub. A biphasic rub heard in one third and a monophasic rub in the remainder of patients(28, 29). In contrast to a pleural rub, a pericardial friction rub is audible throughout the entire respiratory cycle while pleural rub is absent when respiration is stopped.
Sixty percent of patients with acute pericarditis present with a small pericardial effusion seen on echocardiography (3). Jugular venous distention, arterial hypotension, and pulsus paradoxus.( a decrease in arterial systolic pressure of more than 10 mm Hg with inspiration) are suggestive of
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ACCEPTED MANUSCRIPT cardiac tamponade. Pericardial tamponade , a potentially lethal complication of pericarditis, is
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present in 15% of patients of acute idiopathic pericarditis. (30,31)
Electrocardiographic changes:
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The classical EKG changes in acute pericarditis are diffuse ST segment elevation and upright deviation of the PR segment, with ST segment depression in lead aVR. In contrast to acute
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coronary syndrome, concave ST segment elevation occurs in acute pericarditis while convex ST
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segment elevation occurs in ACS (Figure 1,2). EKG changes in acute pericarditis, specifically ST segment elevation develop due to acute inflammation of the myocardium, is thought to be
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due to an injury current in response to inflammation of myopericarditis (as the pericardium is an avascular structure). ST segment and classical EKG changes are not present in the case of uremic
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pericarditis where the myocardium is not involved. (3,32-36)
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EKG Evolution in Pericarditis (Over the days to weeks): Table 3
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The so called “Spodick sign” (down sloping TP segments) is seen in 80% of the patients with acute pericarditis. It is not usually observed in patients with acute coronary syndrome or early repolarization. (37)
Pathologic Q waves and prolonged QT segments are seen in coronary syndrome but not in pericarditis. (38) QRS and QT prolongation with reciprocal changes occurs in acute coronary syndrome but not in pericarditis.(39)
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ACCEPTED MANUSCRIPT The time of presentation and medical treatment may mask the classical EKG patterns. In a
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delayed presentation, only diffuse T wave inversion or normalized EKG can be found.
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The classical EKG evolution includes four stages of changes : Stage I is diffuse ST elevation( concave upward) with PR segement depression which usually lasted for hours to days, then stage
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2 usually develops in the first week of illness in which normalization of ST and PR segments occurs. In stage 3, ST segments become isoelectric with diffuse T wave inversions and last or
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Imaging and Laboratory Findings:
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stage 4, normalization of the EKG or indefinite persistent of T wave inversion occurs.
CXR: The Chest X ray is usually normal in acute pericarditis, unless there is a large pericardial
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effusion which can increase the cardiothoracic ratio. As per European Society of Cardiology
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guidelines for pericardial diseases (1), having a chest x ray is a class I indication in patients
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suspected of having acute pericarditis.
Echocardiography (Figure 3): As per European Society of Cardiology guidelines for pericardial
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diseases 2015, routine transthoracic echocardiography is recommended in all patients with acute pericarditis (Class I, level C). Echocardiography is a crucial imaging technique for detection of pericardial fluid and its hemodynamic effects on the heart if cardiac tamponade or constrictive physiology are suspected. It is also helpful to differentiate from acute myocardial ischemia by excluding wall motion abnormality.
Computerized Tomography and Magnetic resonance Imaging (1, 40): Cardiac CT or MRI should be considered as a further imaging modality in patients with underlying etiologies like neoplasm, renal disease, tuberculosis or systemic inflammatory disease. On CT scan, pericardial thickness
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ACCEPTED MANUSCRIPT >2 mm suggests acute pericarditis.(40) .In patients with myopericarditis, MRI shows late
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gadolinium enhancement in the pericardium
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Positron emission tomography and Computerized Tomography: Cardiac PET scans should be considered for the evaluation of inflammatory pericarditis. Abnormal FDG uptake is seen more
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in tuberculous than in idiopathic pericarditis. (1)
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Biomarkers:
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Routine laboratory tests such as Complete Blood Count with differential count, complete metabolic panel and liver function tests and detailed biomarkers evaluation should be done
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according to the epidemiological area and underlying etiology.
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White Blood Count, C Reactive Protein/UsCRP and Erythrocyte Sedimentation Rate are almost always elevated in acute pericarditis. These are the markers for inflammation (3). C Reactive
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Protein level should be obtained in patients with suspected pericarditis and should be monitored
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for information on disease activity.(1)
In most of patients with acute idiopathic/viral pericarditis, routine viral titers or antibody tests are of low yield. Also routine antinuclear antibody test or rheumatoid factor testing should be only ordered if concomitant symptoms suggest underlying autoimmune disease.
The troponin level can be minimally elevated in patients with acute pericarditis and is a marker of inflammation. Usually the troponin level returns to normal in 1-2 weeks, but sustained elevations may suggest a concomitant myocarditis. (1,3)
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ACCEPTED MANUSCRIPT Considering all clinical evaluation there are proposed diagnostic criteria for acute pericarditis. Proposed Diagnostic Criteria: Table 4 (1, 3As discussed above, The major clinical diagnostic
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criteria includes: pericardial chest pain, pericardial friction rubs, new global ST elevation with
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PR segment depression, new or worsening pericardial effusion, also additional imaging and
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inflammatory markers should be checked.
Specific Causes for Acute Pericarditis
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Idiopathic Pericarditis:
Infectious Causes of Pericarditis:
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Idiopathic pericarditis occurs seasonally, typically in the spring and fall and is clinically difficult to separate from viral pericarditis (41)
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Viral Infection is the most common cause of acute pericarditis. It occurs with seasonal
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coxsackie virus B (42)
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epidemics. The most common viral infections associated with acute pericarditis is influenza and
Acute pericarditis secondary to bacterial infection occurs through direct spread from lung
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infection, traumatic injury, blood seeding from bacterial infection, endocarditis, myocardial abscess or post cardiac surgery, and often leads to purulent pericarditis ( 43). Previously pneumococus was the most predominant organism, but currently gram positive organisms (such as staphylococcus) and gram negative organisms are more common causative organisms.
Inflammation:
Acute pericarditis may be related to systemic inflammatory diseases (such as Rheumatoid arthritis and Systemic Lupus Erythematosus). Acute pericarditis usually occurs with advanced
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ACCEPTED MANUSCRIPT destructive rheumatoid arthritis. In patients with SLE, pericarditis is usually associated with
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flare-ups.(44)
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Uremia:
The prevalence of uremic pericarditis is reduced with early recognition of the disease and
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advancement of treatment with dialysis. With dialysis, the incidence of acute uremic pericarditis
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decreased but still occurs after the onset of dialysis in 8-12% of cases (45)
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Myocardial disease:
Acute pericarditis in patients with myocardial infarction, suggests a larger infarction, LV
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dysfunction and chances of higher mortality rate. In the pre-thrombolytic era, pericarditis related
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to myocardial infarction has ranged from 7-23%. With current aggressive interventional treatment of myocardial infarction (including thrombolytic therapy and primary
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angioplasty/stenting) the incidence of pericarditis has been reduced to 5-8%. (46,47)
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Pericarditis associated with Dressler syndrome. Pericarditis usually occurs after 2-3 weeks post myocardial infarction. Precise etiology of the syndrome is unknown but is postulated to be an autoimmune mediated disease and is associated with myocardial antigens. Anticoagulation therapy should be avoided in patients with Dressler syndrome due to risk of hemorrhagic pericarditis.
Radiation Pericarditis: Cardiac disease, including pericardial disease, may occur after radiation therapy to the chest. Radiation induced heart disease has been recognized since the late 1960’s (49). The majority of
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ACCEPTED MANUSCRIPT patients developed radiation induced cardiac disease when they received radiotherapy adjunctive to chemotherapy for cancer treatment for disorders such as lymphoma, esophageal cancer,
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thymoma, lung and breast cancer. (1, 2, 48-50)
Morphological changes after radiation therapy are most pronounced in the parietal pericardium,
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and lead to fibrosis which replaces the adipose tissue. This fibrosis leads to constriction as a late
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sequel.
Acute pericarditis can be seen during the course of radiation, secondary to necrosis and
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inflammation of tumor as early sequel and due to delayed fibrous thickening and adhesions after several months to years after radiation therapy. Patients are at risk of developing radiation-
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induced heart disease even after 10 years of their radiation therapy (1,2) . Forty % of cancer
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survivors with radiation-related cardiac disease developed the problem even 10 years after their radiation therapy. Other manifestations like pericardial effusion (with or without tamponade),
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pericardial constriction (4-20%), effusive constrictive pericarditis, radiation induced
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cardiomyopathy, valvular heart disease (1% at 10 years), coronary artery disease, carotid artery disease may be seen as late sequela. With the use of new technologies and mantle radiation specifically ‘Sub Cranial Block’ the incidence of radiation induced cardiac disease has decreased from 20% to 2.5%. (1, 49,50)
Auto Inflammatory disease and Pericarditis:
Auto inflammatory disease is a group of diseases which preliminary affect the innate immunity. This includes Familial Mediterranean fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), in both disorders pericardial involvement occurs in the late stage of 12 | P a g e
ACCEPTED MANUSCRIPT disease. FMF is an autosomal recessive disorder which occurs due to mutation of MEFV gene. TRAPS is an autosomal dominant disease which results from mutation of TNFRSF1A gene.
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TRAPS and FMF can cause recurrent pericarditis with positive family history of pericarditis.
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Periodic fever and poor response to colchicine can be seen in these diseases. (51,52)
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Treatment:
Treatment for acute pericarditis should be aimed at the underlying etiology and the absence or
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presence of other underlying disease. It is always clinically important to exclude underlying
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bacterial infection, systemic diseases and malignancy. In the presence of systemic disease appropriate treatment for underlying etiology should be implemented. Also epidemiological
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background (specifically high or low tuberculosis prevalence) should be considered (
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1,3,23,53,54)
Most of the acute pericarditis cases are probably related to viral infection, and do not have a
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specific etiology ascertained. The disease in these patients usually follows a benign clinical
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course, and treatment can be outpatient based. For isolated viral/idiopathic pericarditis in the absence of specific underlying etiology, the mainstay of therapy is aspirin and Non Steroidal Anti-inflammatory Drug (Ibuprofen specifically). Anti-inflammatory agents provide faster relief of symptoms and reduction of further recurrence and usually require only follow- up of patient within one week as an out-patient. (1, 3, 7, 34, 22,55-60)
Patients with high risk features (including fever 38c or 100.4 F, history of immunosuppression, history of trauma, failure to respond within 7 days to treatment with NSAIDS, on oral anticoagulation therapy, have suspected myopericarditis, or severe pericardial effusion by
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ACCEPTED MANUSCRIPT echocardiography - effusion with diastolic free space ≥ 20 mm wide or cardiac tamponade)
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should be hospitalized for further management. (1, 3, 7, 22,53,61)
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Proposed triage of Pericarditis: Table 5 (1) As per ESC guideline proposed triage criteria, for patients presenting with clinical
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manifestation of suspected acute pericarditis: after initial physical examination, CXR, EKG, if any predictors of poor prognosis, such as fever >38 C, subacute in onset, large
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pericardial effusion, cardiac tamponade or lack of response to aspirin or NSAIDS after one week of therapy, the patient should be considered as a high risk case with warrented
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hospitalization and further diagnostic and therapeutic workup. Those patients without any
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followed as an out patient.
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major or minor predictors of poor prognosis and responding to NSAID should be
Physical activity and restriction:
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As per the recent pericardial guideline published by ESC 2015, patients with acute pericarditis
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should be advised to restrict physical activity (other than ordinary sedentary life) until resolution of symptoms and normalization of CRP (61). For athletes, it is recommended to return to competitive sports only after symptoms and diagnostic tests are normalized (including CRP, EKG, echocardiogram), but at least 3 months of exercise restriction should be considered. ( 1,61,62)
Medical therapy: Choice of medical treatment should be based on etiology and concomitant disease, previous history of drug reaction, epidemiological data and physician expertise (1,3, 63).
Non steroidal anti inflammatory drugs (NSAIDS):
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ACCEPTED MANUSCRIPT The goals of therapy for acute pericarditis is relief of symptoms, decrease in inflammation, and
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prevention of recurrences.
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Aspirin or NSAIDS are the mainstay of therapy. The treatment duration should be based on the resolution of symptoms and normalization of CRP (3,63,64). As per ESC 2015 guidelines,
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Aspirin or ibuprofen should be used. Results of multiple cohorts and one randomized cohort study (21, 65, 66) suggest that NSAIDS are effective in approximately 70-80% of
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viral/idiopathic pericarditis. (1), Patients who fail to respond or have worsening of symptoms
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should be further evaluated for other etiologies. The usual recommended dose of Aspirin is 7501000 mg every 8 hours for 1-2 weeks and then decrease dose by 250-500 mg every 1-2 weeks.
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The dose for Ibuprofen is 600 mg every 8 hours for 1-2 weeks and then decrease by 200-400 mg
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every 1-2 weeks. (67)
In patients with history of acute myocardial infarction and pericarditis, aspirin is the drug of
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choice. NSAIDS should be avoided as it may hamper healing and scar formation (68). Also,
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Aspirin is the drug of choice for a patient who requires concomitant other anti platelet therapy.
Proton pump inhibitor like omeprazole and pantoprazole should be given to patients with a history of gastric ulcer, high dose of NSAIDS, long periods of NSAIDS and concurrent use of ASA for treatment with corticosteroids. (15)
In FMF and TRAPS, ASA and NSAIDS are the mainstay of therapy, the same as with idiopathic viral pericarditis. In FMF colchicine is the drug of choice. In refractory cases of FMF long term corticosteroids and immunosuppression drugs should be used. (51,52)
Corticosteroids: 15 | P a g e
ACCEPTED MANUSCRIPT Acute pericarditis responds dramatically to corticosteroid therapy, but early use of steroids is associated with relapsing and recurrence of pericarditis (1, 3,15, 69). Prednisone use was an
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independent risk factor for the subsequent development of recurrence (21). Corticosteroid
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therapy given in the index attack may favor the occurrence of recurrences probably because of its deleterious effect on viral replication. Frequent and prolonged administration may lead to serious
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complications (1,3,21,28,70-71).
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As per ESC guideline 2015, corticosteroids should be considered as second line therapy in
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patients who are clearly refractory to NSAIDS and colchicine in whom specific cause of pericarditis which responds to other therapy has been excluded. (1,3) Specifically, steroids may
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be required in patients with systemic inflammatory disease, uremia, or have a contraindication to use Aspirin/NSAIDS. Corticosteroid should be used with colchicine. Prednisone dose should be
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0.2-0.5 mg/kg/day. The initial dose should be maintained until resolution of symptoms and
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Colchicine:
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normalization of CRP is achieved, and then tapering should be initiated. (1,3, 34, 63, 64,72)
In observational trials, colchicine has showed effective reduction of symptoms and prevention of recurrence. Colchicine should be given with aspirin and NSAIDS or corticosteroids to prevent recurrence. The ESC 2015 guideline suggests 0.5 mg once daily for patients (less than 70 Kg weight) or 0.5 mg twice a day for patients (more than 70 kg weight) for 3 months. Initial dose should be maintained till resolution of symptoms and normalization of biomarker and then tapering should be considered ( 15,73,74) Note, in US colchicine dosage is 0.6 mg rather than 0.5 mg
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ACCEPTED MANUSCRIPT In a randomized double blind study of colchicine versus placebo (in addition to standard antiinflammatory therapy for treatment of first episode of acute pericarditis), colchicine reduced the
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rate of symptom persistence at 72 hours (19.2% vs 40.0%), the number of recurrences per
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patient, and the hospitalization rate (5% vs 14.2%). Colchicine also decreased the remission rate
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at 1 week. (20).
In the open label COPE trial (COlchicine for acute PEricarditis) for first episode of acute
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pericarditis, colchicine was able to reduce the symptoms at 72 hours and subsequent recurrence
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rate by three fold at 18 months (10.7% vs 32.3%). The number of patients with a first episode of acute pericarditis who need to be treated to prevent a recurrence was only 5. (21)
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As per COPPS and COPPS-2 trials (COlchicine for the Prevention of the Post-pericardiotomy
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Syndrome), colchicine is safe and efficacious in the prevention of the post- pericardiotomy
effusion.( 75, 76)
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syndrome but not for post operative atrial fibrillation, post operative pericardial or pleural
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Gastrointestinal side effects occur in up to 10% of cases, although they are mild and may resolve with dose reduction. In the COPE trial, approximately 8% of patients discontinued colchicine secondary to diarrhea. (3,21)
Colchicine undergoes extensive hepatic metabolism by Cytochrome P450 (CYP) 3A4. Drugs such as statins, macrolides and cyclosporine, which also interact with cytochrome 450, increase the levels of colchicine and its toxicity. (3,15)
Other concerns are bone marrow suppression, hepatotoxicity and myotoxicity, specifically when used with statins (15). Side effects include blood dyscrasiasand gastrointenstinal motility 17 | P a g e
ACCEPTED MANUSCRIPT disorder. Colchicine should be avoided in patients with renal insufficiency (as it can result in
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worsening renal function), pregnant patients and those with hypersensitivity to colchicine (3).
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Recurrent Pericarditis:
Recurrent pericarditis is one of the most challenging complications of pericarditis. (3,77). There
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are two forms of recurrent pericarditis, 1) Incessant type and 2) recurrent/relapsing pericarditis.
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Incessant pericarditis symptoms last for weeks or months ( more than 4-6 weeks but less than 3 months). Chronic pericarditis generally refers to symptoms which remain more than 3 months
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despite of treatment. It is usually associated with pericardial effusion (1,3,78).
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Recurrent or relapsing pericarditis refers to complete resolution of symptoms for 4-6 weeks or longer with treatment and subsequently recurrence of the symptoms.( 1, 3,20,67,78). The
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diagnosis of recurrence/relapsing has the same diagnostic criteria, which includes history and
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physical examination, EKG and biomarkers.
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Recurrent pericarditis occurs in 15-30% of acute pericarditis cases (62, 20,21,69).In patients, who presented with first episode of recurrent pericarditis after conventional therapy, addition of colchicine to conventional therapy reduced recurrence rate at 18 months ( 24% vs 50.6%) (69)
Etiology for Recurrence/Relapsing pericarditis:
In most of the cases, recurrent pericarditis is an autoimmune or immune mediated process. The etiology cannot be identified if patients are immunocompetent (1,71). The reasons for many cases of recurrent pericarditis are inadequate treatment with anti inflammatory medications.
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ACCEPTED MANUSCRIPT Recurrent pericarditis relapse rates are higher in patients on steroid therapy in comparison with those not treated with steroids. The mean numbers of relapses were 8.3% on steroids vs 4.5% not
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on steroids on overall four years of follow up. (71,79)
Therapy for Recurrent pericarditis:
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Therapeutic algorithm for acute and recurrent pericarditis: Table 6 (1)
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Physical Activity: (1,61,62) The recommendation regarding reduced physical activity remains
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same as with acute pericarditis.
Medical Therapy: Treatment of recurrent pericarditis is aimed at preventing recurrence of
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symptoms with focus on underlying etiology. ASA or NSAIDS are mainstay of treatment, and
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colchicine should be considered in addition to standard therapy. Colchicine treatment should be weight based and duration should be at least for 6 months. ( 1,67,69,71,80,81,82). Patients
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treated with colchicine usually respond within 18 hours of treatment and in 75-80% of patients
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joint inflammation subsides within 48 hours. (67,69). The main reason for discontinuation of colchicines is diarrhea ( 7% in CORE Trial) and was promptly reversed after drug withdrawal.(69)
In patients with incomplete resolution of symptoms despite the use of ASA/NSAIDS and colchicine, corticosteroids at low to moderate doses should be added (1).If corticosteroids are used, tapering should be slow and over 2-6 weeks of interval.
Alternative treatments like IVIG ( Immuno modulatory and anti viral), azathioprine, anakinra ( a recombinant IL-1B receptor antagonist), TNF ( anti tumor necrosis factor agents) like
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ACCEPTED MANUSCRIPT cyclophosphomide, cyclosporine, methotrexate, hydroxychloroquine may be considered in the case of proven infection negative, corticosteroids dependent, recurrent pericarditis not responsive
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to colchicine. Such treatments are supported by weak evidence and lack of strong based trials.
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(1,3,83,84,85)
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Pericardiectomy:
Surgical pericardiectomy is an effective last resort for patients with relapsing pericarditis in
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whom adequate medical therapy failed. Surgical pericardiectomy has been proposed for relief of
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symptoms in patients with relapsing pericarditis. However, pericardiectomy does not always result in the end of recurrences.(1,3,15,71).
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Interventional technique and surgical therapy:
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Interventional and surgical therapies should be considered in patients with cardiac tamponade, hemodynamically significant moderate to large pericardial effusion, in symptomatic patients who
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are refractory to medical therapy, effusive constrictive or constrictive pericarditis, or suspicion of
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neoplastic or bacterial etiology ( HIV,TB), Bacterial cultures can be useful to evaluate the possible underlying etiology in patients with recurrent/relapsing pericarditis with high suspicion for bacterial infections. (1,3)
Prognosis:
Most cases of relapsing/recurrent pericarditis are viral or immunological in etiology (73). In study of a total of 230 patients with idiopathic recurrent pericarditis after follow-up for 61 months, complication rate was 3.5% of cardiac tamponade which usually occurs in early course of disease. Constrictive pericarditis and LV dysfunction are rarely reported in patients with
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ACCEPTED MANUSCRIPT idiopathic recurrent pericarditis. Thus complications are related to underlying etiologies and not
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related to recurrences. (1,71,86,87)
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Overall long term prognosis is good with rare complication. Side effects of medicines, glucocorticoids dependence in patients with relapsing and recurrent pericarditis may affect the
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quality of life (1,86,87)
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Conclusion:
Acute pericarditis is a common disease in routine clinical practice. A careful clinical history,
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physical examination, and application of diagnostic criteria are needed to make an accurate
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diagnosis, exclude concomitant disease and properly triage patients. Therapy for acute pericarditis should be guided according to the underlying etiology. For common forms of
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pericarditis such as idiopathic and viral pericarditis, NSAIDS or aspirin with addition of
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colchicine remains the mainstay of therapy. This will usually result in reduction of symptoms and prevent the rate of recurrence of disease. Patients with hemodynamic compromise or who
therapy.
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are resistant to therapy may require prompt hospitalization and initiation of more aggressive
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79.. Raatikka M, Pelkonem PM, Karjalainen J, Jokinen E. Recurrent pericarditis in children and adolescents. J Am Coll Cardiol 2003;42:759–764. 28 | P a g e
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80. Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, Trinchero R, Spodick DH, Adler Y; CORP (COlchicine for Recurrent Pericarditis) Investigators. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med. 2011 Oct 4;155(7):409-14
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84. Moretti M, Buiatti A, Merlo M, Massa L, Fabris E, Pinamonti B, Sinagra G. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol 2013;112:1493–1498.
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85. Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, D’Alessandro M, Picco P, Martini A, Gattorno M. Long term efficacy of interleukin-1 receptor antagonist (anakinra) in steroid dependent and colchicine-resistant recurrent pericarditis. J Pediatr 2014;164:1425–1431.
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86. Imazio M, Brucato A, Markel G, Cemin R, Trinchero R, Spodick DH, Adler Y. Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome. Am J Cardiol. 2011 Aug 15;108(4):575-9. 87. Brucato A, Brambilla G, Moreo A, Alberti A, Munforti C, Ghirardello A, Doria A, Shinar Y, Livneh A, Adler Y, Shoenfeld Y, Mauri F, Palmieri G, Spodick DH. Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol. 2006 Jul 15;98(2):267-71.
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Acute Pericarditis- First attack of pericardial inflammation with acute onset of symptoms which usually last for 4-6 weeks with treatment and symptoms resolves in 4-6 weeks.
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Incessant- Symptoms last for >4-6 weeks but < 3 months without remission
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Recurrent/Relapsing – After complete resolution of symptoms for 4-6 weeks with treatment and, if symptoms recurs. Chronic Pericarditis lasting more than 3 months
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Infectious Causes Bacterial
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Gram positive and Gram negative species (streptococci, staphylococcus, pneumococcus),Mycobacterium tuberculosis. Less common – Legionella, Norcardia, Actinobacillus,Rickettsia, Borrelia burgdoferi ( Lyme disease), Listeria, laptospira, chlamydophila psittaci, treponema pallidum ( Syphilis), coxiella burnettii, meningococus species, hemophilus species, mycoplasma species Histoplasma, blastomyces, coccidiosis, aspergillus,candida Toxoplasma, entomoeba, echinococcus Coxsackie viruses, echoviruses, adenovirus, influenza A & B viruses, enterovirus, mumps virus, Epstein barr virus, HIV, Herpes simplex virus, type I varicella zoster virus ( VZV), Measles, para influenza viruses type II, RSV, CMV, Hepatitis A,B & C, Parvovirus B 19.
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Parasitic infection Idiopathic/Viral causes
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Non infectious Autoimmune
Neoplastic causes Metabolic causes Miscellaneous Drugs
Trauma, Iatrogenic
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Systemic lupus erythematous, Sjogren syndrome, rheumatoid arthritis, scleroderma, vasculitideseosinophilic granulomatosis ( Churg-Strauss syndrome), Takayasu disease, Behcet syndrome, scarcoidosis, familial Mediterranean fever, inflammatory bowel disease, Still disease, mixed connective tissue disorder , Reiter syndrome, Wegners granulomatosis, ankylosing spondylitis, giant cell arteritis, dermatomyocitis, serum sickness Primary ( mesothelioma), secondary (lung ,breast, etc) Uremia, Myxoedema, cholesterol pericarditis Amyloidosis, aortic dissection, radiation induced(indirect injury) Daunorubicin, doxorubicin, cyclophosphamide,5 flurouracil,amiodarone, cyclosporine, mesalazine, clozapine, methysergide, anti tumor necrosis factor, hydralazine, procainamide, methyldopa, phenytoin, Isoniazide, Reserpine Coronary interventions, permanent pacemaker/ICD implantation, radiofrequency
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The American Journal of Medicine, Volume 127, Issue 5, May 2014, Page e17 The American Journal of Medicine, Volume 127, Issue 5, May 2014, Page e1xDavid H. Spodick Search for articles by this author
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Address for reprints: David H. Spodick, MD, Lemuel Shattuck Hospital, 170 Morton St., Boston, Mass. 02130.
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ACCEPTED MANUSCRIPT Table 3: EKG Evolution in Pericarditis (Over the days to weeks):
2) After ST segment and PR segment normalization
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3) ST Segment isoelectric with diffuse T wave inversions
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1) Acute Phase : ST Segment elevation concave upward with PR segment depression
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4) Persistent T wave inversion or Normalization of EKG.
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1) Pericardial chest pain
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3) New global ST Elevation with PR depression
Additional Supporting Findings
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4) Pericardial effusion ( New or worsening)
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1) Inflammatory markers Elevation ( ESR, CRP,
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Leukocytosis)
2) Evidence of pericardial Inflammation by Imaging modality ( CT/MRI)
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Table 5: Proposed triage of Pericarditis
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Reprinted from European Heart Journal, oxford university press. (1) Y Adler, P Charron, M Imazio et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. 2921-2964,with permission from Oxford University Press.
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Table 6: Therapeutic algorithm for acute and recurrent pericarditis
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Reprinted from European Heart Journal, oxford university press. (1) Y Adler, P Charron, M Imazio et al.2015 ESC Guidelines for the diagnosis and management of pericardial diseases. 2921-2964, with permission from Oxford University Press.
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Figure 1: Acute Pericarditis, Concave ST-T abnormality
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Figure 2: Acute coronary syndrome, Convex ST-T abnormality
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Figure 3: Echocardiogram Acute pericarditis with small pericardial effusion (Arrow)
Niraj Doctor Email: [email protected] Itzhak Kronzon Email: [email protected] 39 | P a g e
S0033-0620(16)30138-4 doi: 10.1016/j.pcad.2016.12.001 YPCAD 770
To appear in:
Progress in Cardiovascular Diseases
Please cite this article as: Doctor Niraj S, Shah Ankit B, Coplan Neil, Kronzon Itzhak, Acute Pericarditis, Review, Progress in Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.12.001
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ACCEPTED MANUSCRIPT Short title: Acute Pericarditis
Acute Pericarditis, Review
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Niraj S Doctor, MD, Ankit B shah MD, Neil Coplan MD, FACC, Itzhak Kronzon MD, FASE, FACC, FACP, FESC, FAHA Lenox Hill Heart and Vascular Institute of New York, New York, NY
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Short title: Acute Pericarditis
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Disclosures: There are no relevant financial disclosures, acknowledgments or conflicts of interest.
Corresponding author. Dr.Itzhak Kronzon MD,Tel +12124346119: fax +1 212434 2111. Email: [email protected],[email protected]
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Keywords: Pericarditis, Acute pericarditis, Recurrent Pericarditis
Abbreviations:
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ACS- Acute Coronary Syndrome
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ASA- Acetyl Salicylic Acid CRP- C Reactive Protein
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COPE - COlchicine for acute PEricarditis COPPS - COlchicine for the Prevention of the Post-pericardiotomy Syndrome CORE - COlchicine for REcurrent pericarditis CT – Computerized Tomography CXR- Chest x ray EKG- Electrocardiogram ESC - European Society of Cardiology ESR- Erythrocyte Sedimentation Rate FMF- Familial Mediterranean Fever 1|Page
ACCEPTED MANUSCRIPT HIV- Human Immunodeficiency Virus IVIG- Intravenous Immnoglobulins
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LV- Left Ventricle
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MI – Myocardial Infarction
NSAIDS- Non Steroidal Anti-inflammatory Drug
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PET- Positron Emission Tomography
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MRI- Magnetic Resonance Imagine
SLE- Systemic Lupus Erythematosus
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TRAPS- Tumor necrosis factor Receptor-Associated Periodic Syndrome
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WBC- White Blood Count
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Abstract:
Acute pericarditis is an acute inflammatory disease of the pericardium, which may occur in many
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different disease states (both infectious and non-infectious). Usually the diagnosis is based on
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symptoms (chest pain, shortness of breath), electrocardiographic changes (ST elevation), physical examination (pericardial friction rub) and elevation of cardiac biomarkers. It may occur in isolation or be associated with an underlying inflammatory disorder. In routine clinical practice, acute pericarditis can be associated with myocarditis due to their overlapping etiologies.
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Anatomy and Function of Pericardium:
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The pericardium is an avascular sac composed of a double layer. The outer layer (parietal pericardium) is composed of fibrous tissue while the inner layer (visceral pericardium) is
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composed of mesothelial serous cells. The parietal pericardium is a thick, tough outer sac made
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of collagenous connective tissue. It is attached to the diaphragm, sternum and the cartilage of the ribs. The parietal pericardium separates the heart from other mediastinal structures. The visceral
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pericardium is a thin layer adherent to the epicardial surface of the heart and its epicardial fat. (1-
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12)
The normal pericardial space contains approximately 25-50ml of fluid and serves as a lubricant
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between the visceral and parietal layer. The parietal layer and the fibrous pericardium are two
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inseparable structures. The pericardial fluid is drained via the right lymphatic duct and the thoracic duct into the right pleural space. (10-12)
The pericardium has a protective physical function as a barrier which prevents the spread of infection or malignancy to the heart. It also serves to prevent dilatation of the cardiac chambers and to maintain ventricular compliance. The subatmospheric pressure in the pericardial sac facilitates atrial filling and maintains cardiac pressure.( 13,14). Pericardial fluid works as a lubricant and decreases the friction of the cardiac surfaces during systole and diastole. (15)
Specific terminologies for pericarditis: Table 1 (1, 3):
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ACCEPTED MANUSCRIPT In the medical literature, pericarditis is subdivided into acute, incessant, recurrent/relapsing and
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chronic pericarditis depending on symptoms duration and their re-occurrence.
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Epidemiology:
Patients should be screened and considered for specific etiology and rational management
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according to their epidemiological background (Table 2). For example, in developing countries
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tuberculosis is a major cause. Tuberculosis with HIV infection is common in the sub-Saharan region. In developed countries, idiopathic or pericarditis related to viral infection is more
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common. (16). In contrast, acute pericarditis and myocarditis share many of the same viral
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etiologies as causative agents and myocardial involvement is common in acute pericarditis.
Acute pericarditis is the most common disorder involving the pericardium, but the true incidence
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and prevalence are unknown since low risk patients are usually not admitted to hospitals. (1,3,7,
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16-25) Pericarditis accounts for 5% of emergency department visits for chest pain in the absence of myocardial infarction (MI) (7,15). In one study, the incidence rate of acute pericarditis was
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present in 3.3 per 100,000 of patients admitted to hospital. Patients with pericardiotomy and myocardial infarction related pericarditis were excluded. (19)
In an observational study from an urban area in northern Italy, the incidence of acute pericarditis (viral/idiopathic) was 27.2 cases per 100,000 persons per year (1,3, 24), and the incidence of myocarditis was 4.0 cases per 100,000 population/year (24). Acute pericarditis was recorded in approximately 0.1% of hospitalized patients and around 5% of patients admitted to the emergency department for non-acute MI chest pain (22, 26, 27). In a Finnish Trial, the in
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ACCEPTED MANUSCRIPT hospital mortality rate for acute pericarditis was 1.1% (19). A Swedish registry found an
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incidence rate of 18.0 per 100,000 for pericarditis in the general population (19).
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The mean age of patients with acute pericarditis in clinical series ranges from 41 to 60 years (19). Men have a twofold incidence rate of acute pericarditis compared to women.(19), Females
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have been associated with complications of acute pericarditis, but was not an independent predictor of mortality (1,19). The reasons for the gender differences in pericarditis are unknown,
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but some studies suggested, due to testosterone effect, young men are at higher risk for
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pericarditis and females during the post menoupausal period are more succeptible for acute pericarditis. Table 2, Non Comprehensive list of Etiologies of Acute Pericarditis (1,3)
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Table 2 showed that there are so many different types of etiologies for acute pericarditis, which
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includes infectious and non-infectious causes. Infectious causes includes bacterial, viral, fungal
drugs and trauma.
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and parasitic causes, whereas non infectious causes includes autoimmune, neoplastic, metabolic,
History:
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Clinical Presentation
Patients with acute pericarditis present with sudden onset of chest pain, which is sharp in nature and usually in the precordial/retrosternal area. The pain classically worsens with inspiration and is often positional. Pain often increases with supine position and is relieved with sitting posture and leaning forward. Pericarditis may involve the phrenic nerve which innervates the trapezius muscles, resulting in pain in the back and shoulders.(28). The pain may radiate to neck, left shoulder and jaw. Symptoms can be associated with cough, rhinorrhea, low grade fever and shortness of breath. 5|Page
ACCEPTED MANUSCRIPT Patients with underlying malignancy or autoimmune disorder may present with specific signs and symptoms of their underlying etiology. (3), this may include fever, leukocytosis, fatigue and
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weight loss.(1)
Physical Examination:
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Meticulous history and physical examination are necessary for every patient with suspected
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pericarditis. A pericardial friction rub, which is thought to be result of friction of inflamed visceral and pericardial layer (28), is a “scratchy” or “squeaky” high pitched sound best heard
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with the diaphragm of stethoscope at the left sternal border at the end of expiration with the patient leaning forward or in the left lateral decubitus position. Pericardial friction rub often
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varies throughout the day, so a patient with suspected acute pericarditis should be examined
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frequently and in multiple positions. (3)
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Classically, a pericardial friction rub has three components, corresponding to (1) atrial systole ( in patient with normal sinus rhythm), (2) ventricular systole, and(3) the rapid filling phase of
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ventricular diastole. However, a triphasic rub is found in only half of patients who have a friction rub. A biphasic rub heard in one third and a monophasic rub in the remainder of patients(28, 29). In contrast to a pleural rub, a pericardial friction rub is audible throughout the entire respiratory cycle while pleural rub is absent when respiration is stopped.
Sixty percent of patients with acute pericarditis present with a small pericardial effusion seen on echocardiography (3). Jugular venous distention, arterial hypotension, and pulsus paradoxus.( a decrease in arterial systolic pressure of more than 10 mm Hg with inspiration) are suggestive of
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ACCEPTED MANUSCRIPT cardiac tamponade. Pericardial tamponade , a potentially lethal complication of pericarditis, is
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present in 15% of patients of acute idiopathic pericarditis. (30,31)
Electrocardiographic changes:
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The classical EKG changes in acute pericarditis are diffuse ST segment elevation and upright deviation of the PR segment, with ST segment depression in lead aVR. In contrast to acute
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coronary syndrome, concave ST segment elevation occurs in acute pericarditis while convex ST
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segment elevation occurs in ACS (Figure 1,2). EKG changes in acute pericarditis, specifically ST segment elevation develop due to acute inflammation of the myocardium, is thought to be
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due to an injury current in response to inflammation of myopericarditis (as the pericardium is an avascular structure). ST segment and classical EKG changes are not present in the case of uremic
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pericarditis where the myocardium is not involved. (3,32-36)
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EKG Evolution in Pericarditis (Over the days to weeks): Table 3
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The so called “Spodick sign” (down sloping TP segments) is seen in 80% of the patients with acute pericarditis. It is not usually observed in patients with acute coronary syndrome or early repolarization. (37)
Pathologic Q waves and prolonged QT segments are seen in coronary syndrome but not in pericarditis. (38) QRS and QT prolongation with reciprocal changes occurs in acute coronary syndrome but not in pericarditis.(39)
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ACCEPTED MANUSCRIPT The time of presentation and medical treatment may mask the classical EKG patterns. In a
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delayed presentation, only diffuse T wave inversion or normalized EKG can be found.
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The classical EKG evolution includes four stages of changes : Stage I is diffuse ST elevation( concave upward) with PR segement depression which usually lasted for hours to days, then stage
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2 usually develops in the first week of illness in which normalization of ST and PR segments occurs. In stage 3, ST segments become isoelectric with diffuse T wave inversions and last or
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Imaging and Laboratory Findings:
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stage 4, normalization of the EKG or indefinite persistent of T wave inversion occurs.
CXR: The Chest X ray is usually normal in acute pericarditis, unless there is a large pericardial
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effusion which can increase the cardiothoracic ratio. As per European Society of Cardiology
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guidelines for pericardial diseases (1), having a chest x ray is a class I indication in patients
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suspected of having acute pericarditis.
Echocardiography (Figure 3): As per European Society of Cardiology guidelines for pericardial
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diseases 2015, routine transthoracic echocardiography is recommended in all patients with acute pericarditis (Class I, level C). Echocardiography is a crucial imaging technique for detection of pericardial fluid and its hemodynamic effects on the heart if cardiac tamponade or constrictive physiology are suspected. It is also helpful to differentiate from acute myocardial ischemia by excluding wall motion abnormality.
Computerized Tomography and Magnetic resonance Imaging (1, 40): Cardiac CT or MRI should be considered as a further imaging modality in patients with underlying etiologies like neoplasm, renal disease, tuberculosis or systemic inflammatory disease. On CT scan, pericardial thickness
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ACCEPTED MANUSCRIPT >2 mm suggests acute pericarditis.(40) .In patients with myopericarditis, MRI shows late
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gadolinium enhancement in the pericardium
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Positron emission tomography and Computerized Tomography: Cardiac PET scans should be considered for the evaluation of inflammatory pericarditis. Abnormal FDG uptake is seen more
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in tuberculous than in idiopathic pericarditis. (1)
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Biomarkers:
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Routine laboratory tests such as Complete Blood Count with differential count, complete metabolic panel and liver function tests and detailed biomarkers evaluation should be done
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according to the epidemiological area and underlying etiology.
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White Blood Count, C Reactive Protein/UsCRP and Erythrocyte Sedimentation Rate are almost always elevated in acute pericarditis. These are the markers for inflammation (3). C Reactive
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Protein level should be obtained in patients with suspected pericarditis and should be monitored
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for information on disease activity.(1)
In most of patients with acute idiopathic/viral pericarditis, routine viral titers or antibody tests are of low yield. Also routine antinuclear antibody test or rheumatoid factor testing should be only ordered if concomitant symptoms suggest underlying autoimmune disease.
The troponin level can be minimally elevated in patients with acute pericarditis and is a marker of inflammation. Usually the troponin level returns to normal in 1-2 weeks, but sustained elevations may suggest a concomitant myocarditis. (1,3)
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ACCEPTED MANUSCRIPT Considering all clinical evaluation there are proposed diagnostic criteria for acute pericarditis. Proposed Diagnostic Criteria: Table 4 (1, 3As discussed above, The major clinical diagnostic
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criteria includes: pericardial chest pain, pericardial friction rubs, new global ST elevation with
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PR segment depression, new or worsening pericardial effusion, also additional imaging and
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inflammatory markers should be checked.
Specific Causes for Acute Pericarditis
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Idiopathic Pericarditis:
Infectious Causes of Pericarditis:
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Idiopathic pericarditis occurs seasonally, typically in the spring and fall and is clinically difficult to separate from viral pericarditis (41)
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Viral Infection is the most common cause of acute pericarditis. It occurs with seasonal
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coxsackie virus B (42)
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epidemics. The most common viral infections associated with acute pericarditis is influenza and
Acute pericarditis secondary to bacterial infection occurs through direct spread from lung
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infection, traumatic injury, blood seeding from bacterial infection, endocarditis, myocardial abscess or post cardiac surgery, and often leads to purulent pericarditis ( 43). Previously pneumococus was the most predominant organism, but currently gram positive organisms (such as staphylococcus) and gram negative organisms are more common causative organisms.
Inflammation:
Acute pericarditis may be related to systemic inflammatory diseases (such as Rheumatoid arthritis and Systemic Lupus Erythematosus). Acute pericarditis usually occurs with advanced
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ACCEPTED MANUSCRIPT destructive rheumatoid arthritis. In patients with SLE, pericarditis is usually associated with
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flare-ups.(44)
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Uremia:
The prevalence of uremic pericarditis is reduced with early recognition of the disease and
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advancement of treatment with dialysis. With dialysis, the incidence of acute uremic pericarditis
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decreased but still occurs after the onset of dialysis in 8-12% of cases (45)
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Myocardial disease:
Acute pericarditis in patients with myocardial infarction, suggests a larger infarction, LV
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dysfunction and chances of higher mortality rate. In the pre-thrombolytic era, pericarditis related
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to myocardial infarction has ranged from 7-23%. With current aggressive interventional treatment of myocardial infarction (including thrombolytic therapy and primary
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angioplasty/stenting) the incidence of pericarditis has been reduced to 5-8%. (46,47)
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Pericarditis associated with Dressler syndrome. Pericarditis usually occurs after 2-3 weeks post myocardial infarction. Precise etiology of the syndrome is unknown but is postulated to be an autoimmune mediated disease and is associated with myocardial antigens. Anticoagulation therapy should be avoided in patients with Dressler syndrome due to risk of hemorrhagic pericarditis.
Radiation Pericarditis: Cardiac disease, including pericardial disease, may occur after radiation therapy to the chest. Radiation induced heart disease has been recognized since the late 1960’s (49). The majority of
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ACCEPTED MANUSCRIPT patients developed radiation induced cardiac disease when they received radiotherapy adjunctive to chemotherapy for cancer treatment for disorders such as lymphoma, esophageal cancer,
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thymoma, lung and breast cancer. (1, 2, 48-50)
Morphological changes after radiation therapy are most pronounced in the parietal pericardium,
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and lead to fibrosis which replaces the adipose tissue. This fibrosis leads to constriction as a late
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sequel.
Acute pericarditis can be seen during the course of radiation, secondary to necrosis and
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inflammation of tumor as early sequel and due to delayed fibrous thickening and adhesions after several months to years after radiation therapy. Patients are at risk of developing radiation-
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induced heart disease even after 10 years of their radiation therapy (1,2) . Forty % of cancer
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survivors with radiation-related cardiac disease developed the problem even 10 years after their radiation therapy. Other manifestations like pericardial effusion (with or without tamponade),
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pericardial constriction (4-20%), effusive constrictive pericarditis, radiation induced
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cardiomyopathy, valvular heart disease (1% at 10 years), coronary artery disease, carotid artery disease may be seen as late sequela. With the use of new technologies and mantle radiation specifically ‘Sub Cranial Block’ the incidence of radiation induced cardiac disease has decreased from 20% to 2.5%. (1, 49,50)
Auto Inflammatory disease and Pericarditis:
Auto inflammatory disease is a group of diseases which preliminary affect the innate immunity. This includes Familial Mediterranean fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), in both disorders pericardial involvement occurs in the late stage of 12 | P a g e
ACCEPTED MANUSCRIPT disease. FMF is an autosomal recessive disorder which occurs due to mutation of MEFV gene. TRAPS is an autosomal dominant disease which results from mutation of TNFRSF1A gene.
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TRAPS and FMF can cause recurrent pericarditis with positive family history of pericarditis.
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Periodic fever and poor response to colchicine can be seen in these diseases. (51,52)
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Treatment:
Treatment for acute pericarditis should be aimed at the underlying etiology and the absence or
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presence of other underlying disease. It is always clinically important to exclude underlying
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bacterial infection, systemic diseases and malignancy. In the presence of systemic disease appropriate treatment for underlying etiology should be implemented. Also epidemiological
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background (specifically high or low tuberculosis prevalence) should be considered (
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1,3,23,53,54)
Most of the acute pericarditis cases are probably related to viral infection, and do not have a
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specific etiology ascertained. The disease in these patients usually follows a benign clinical
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course, and treatment can be outpatient based. For isolated viral/idiopathic pericarditis in the absence of specific underlying etiology, the mainstay of therapy is aspirin and Non Steroidal Anti-inflammatory Drug (Ibuprofen specifically). Anti-inflammatory agents provide faster relief of symptoms and reduction of further recurrence and usually require only follow- up of patient within one week as an out-patient. (1, 3, 7, 34, 22,55-60)
Patients with high risk features (including fever 38c or 100.4 F, history of immunosuppression, history of trauma, failure to respond within 7 days to treatment with NSAIDS, on oral anticoagulation therapy, have suspected myopericarditis, or severe pericardial effusion by
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ACCEPTED MANUSCRIPT echocardiography - effusion with diastolic free space ≥ 20 mm wide or cardiac tamponade)
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should be hospitalized for further management. (1, 3, 7, 22,53,61)
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Proposed triage of Pericarditis: Table 5 (1) As per ESC guideline proposed triage criteria, for patients presenting with clinical
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manifestation of suspected acute pericarditis: after initial physical examination, CXR, EKG, if any predictors of poor prognosis, such as fever >38 C, subacute in onset, large
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pericardial effusion, cardiac tamponade or lack of response to aspirin or NSAIDS after one week of therapy, the patient should be considered as a high risk case with warrented
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hospitalization and further diagnostic and therapeutic workup. Those patients without any
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followed as an out patient.
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major or minor predictors of poor prognosis and responding to NSAID should be
Physical activity and restriction:
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As per the recent pericardial guideline published by ESC 2015, patients with acute pericarditis
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should be advised to restrict physical activity (other than ordinary sedentary life) until resolution of symptoms and normalization of CRP (61). For athletes, it is recommended to return to competitive sports only after symptoms and diagnostic tests are normalized (including CRP, EKG, echocardiogram), but at least 3 months of exercise restriction should be considered. ( 1,61,62)
Medical therapy: Choice of medical treatment should be based on etiology and concomitant disease, previous history of drug reaction, epidemiological data and physician expertise (1,3, 63).
Non steroidal anti inflammatory drugs (NSAIDS):
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ACCEPTED MANUSCRIPT The goals of therapy for acute pericarditis is relief of symptoms, decrease in inflammation, and
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prevention of recurrences.
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Aspirin or NSAIDS are the mainstay of therapy. The treatment duration should be based on the resolution of symptoms and normalization of CRP (3,63,64). As per ESC 2015 guidelines,
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Aspirin or ibuprofen should be used. Results of multiple cohorts and one randomized cohort study (21, 65, 66) suggest that NSAIDS are effective in approximately 70-80% of
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viral/idiopathic pericarditis. (1), Patients who fail to respond or have worsening of symptoms
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should be further evaluated for other etiologies. The usual recommended dose of Aspirin is 7501000 mg every 8 hours for 1-2 weeks and then decrease dose by 250-500 mg every 1-2 weeks.
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The dose for Ibuprofen is 600 mg every 8 hours for 1-2 weeks and then decrease by 200-400 mg
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every 1-2 weeks. (67)
In patients with history of acute myocardial infarction and pericarditis, aspirin is the drug of
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choice. NSAIDS should be avoided as it may hamper healing and scar formation (68). Also,
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Aspirin is the drug of choice for a patient who requires concomitant other anti platelet therapy.
Proton pump inhibitor like omeprazole and pantoprazole should be given to patients with a history of gastric ulcer, high dose of NSAIDS, long periods of NSAIDS and concurrent use of ASA for treatment with corticosteroids. (15)
In FMF and TRAPS, ASA and NSAIDS are the mainstay of therapy, the same as with idiopathic viral pericarditis. In FMF colchicine is the drug of choice. In refractory cases of FMF long term corticosteroids and immunosuppression drugs should be used. (51,52)
Corticosteroids: 15 | P a g e
ACCEPTED MANUSCRIPT Acute pericarditis responds dramatically to corticosteroid therapy, but early use of steroids is associated with relapsing and recurrence of pericarditis (1, 3,15, 69). Prednisone use was an
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independent risk factor for the subsequent development of recurrence (21). Corticosteroid
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therapy given in the index attack may favor the occurrence of recurrences probably because of its deleterious effect on viral replication. Frequent and prolonged administration may lead to serious
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complications (1,3,21,28,70-71).
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As per ESC guideline 2015, corticosteroids should be considered as second line therapy in
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patients who are clearly refractory to NSAIDS and colchicine in whom specific cause of pericarditis which responds to other therapy has been excluded. (1,3) Specifically, steroids may
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be required in patients with systemic inflammatory disease, uremia, or have a contraindication to use Aspirin/NSAIDS. Corticosteroid should be used with colchicine. Prednisone dose should be
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0.2-0.5 mg/kg/day. The initial dose should be maintained until resolution of symptoms and
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Colchicine:
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normalization of CRP is achieved, and then tapering should be initiated. (1,3, 34, 63, 64,72)
In observational trials, colchicine has showed effective reduction of symptoms and prevention of recurrence. Colchicine should be given with aspirin and NSAIDS or corticosteroids to prevent recurrence. The ESC 2015 guideline suggests 0.5 mg once daily for patients (less than 70 Kg weight) or 0.5 mg twice a day for patients (more than 70 kg weight) for 3 months. Initial dose should be maintained till resolution of symptoms and normalization of biomarker and then tapering should be considered ( 15,73,74) Note, in US colchicine dosage is 0.6 mg rather than 0.5 mg
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ACCEPTED MANUSCRIPT In a randomized double blind study of colchicine versus placebo (in addition to standard antiinflammatory therapy for treatment of first episode of acute pericarditis), colchicine reduced the
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rate of symptom persistence at 72 hours (19.2% vs 40.0%), the number of recurrences per
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patient, and the hospitalization rate (5% vs 14.2%). Colchicine also decreased the remission rate
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at 1 week. (20).
In the open label COPE trial (COlchicine for acute PEricarditis) for first episode of acute
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pericarditis, colchicine was able to reduce the symptoms at 72 hours and subsequent recurrence
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rate by three fold at 18 months (10.7% vs 32.3%). The number of patients with a first episode of acute pericarditis who need to be treated to prevent a recurrence was only 5. (21)
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As per COPPS and COPPS-2 trials (COlchicine for the Prevention of the Post-pericardiotomy
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Syndrome), colchicine is safe and efficacious in the prevention of the post- pericardiotomy
effusion.( 75, 76)
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syndrome but not for post operative atrial fibrillation, post operative pericardial or pleural
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Gastrointestinal side effects occur in up to 10% of cases, although they are mild and may resolve with dose reduction. In the COPE trial, approximately 8% of patients discontinued colchicine secondary to diarrhea. (3,21)
Colchicine undergoes extensive hepatic metabolism by Cytochrome P450 (CYP) 3A4. Drugs such as statins, macrolides and cyclosporine, which also interact with cytochrome 450, increase the levels of colchicine and its toxicity. (3,15)
Other concerns are bone marrow suppression, hepatotoxicity and myotoxicity, specifically when used with statins (15). Side effects include blood dyscrasiasand gastrointenstinal motility 17 | P a g e
ACCEPTED MANUSCRIPT disorder. Colchicine should be avoided in patients with renal insufficiency (as it can result in
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worsening renal function), pregnant patients and those with hypersensitivity to colchicine (3).
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Recurrent Pericarditis:
Recurrent pericarditis is one of the most challenging complications of pericarditis. (3,77). There
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are two forms of recurrent pericarditis, 1) Incessant type and 2) recurrent/relapsing pericarditis.
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Incessant pericarditis symptoms last for weeks or months ( more than 4-6 weeks but less than 3 months). Chronic pericarditis generally refers to symptoms which remain more than 3 months
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despite of treatment. It is usually associated with pericardial effusion (1,3,78).
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Recurrent or relapsing pericarditis refers to complete resolution of symptoms for 4-6 weeks or longer with treatment and subsequently recurrence of the symptoms.( 1, 3,20,67,78). The
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diagnosis of recurrence/relapsing has the same diagnostic criteria, which includes history and
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physical examination, EKG and biomarkers.
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Recurrent pericarditis occurs in 15-30% of acute pericarditis cases (62, 20,21,69).In patients, who presented with first episode of recurrent pericarditis after conventional therapy, addition of colchicine to conventional therapy reduced recurrence rate at 18 months ( 24% vs 50.6%) (69)
Etiology for Recurrence/Relapsing pericarditis:
In most of the cases, recurrent pericarditis is an autoimmune or immune mediated process. The etiology cannot be identified if patients are immunocompetent (1,71). The reasons for many cases of recurrent pericarditis are inadequate treatment with anti inflammatory medications.
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ACCEPTED MANUSCRIPT Recurrent pericarditis relapse rates are higher in patients on steroid therapy in comparison with those not treated with steroids. The mean numbers of relapses were 8.3% on steroids vs 4.5% not
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on steroids on overall four years of follow up. (71,79)
Therapy for Recurrent pericarditis:
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Therapeutic algorithm for acute and recurrent pericarditis: Table 6 (1)
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Physical Activity: (1,61,62) The recommendation regarding reduced physical activity remains
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same as with acute pericarditis.
Medical Therapy: Treatment of recurrent pericarditis is aimed at preventing recurrence of
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symptoms with focus on underlying etiology. ASA or NSAIDS are mainstay of treatment, and
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colchicine should be considered in addition to standard therapy. Colchicine treatment should be weight based and duration should be at least for 6 months. ( 1,67,69,71,80,81,82). Patients
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treated with colchicine usually respond within 18 hours of treatment and in 75-80% of patients
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joint inflammation subsides within 48 hours. (67,69). The main reason for discontinuation of colchicines is diarrhea ( 7% in CORE Trial) and was promptly reversed after drug withdrawal.(69)
In patients with incomplete resolution of symptoms despite the use of ASA/NSAIDS and colchicine, corticosteroids at low to moderate doses should be added (1).If corticosteroids are used, tapering should be slow and over 2-6 weeks of interval.
Alternative treatments like IVIG ( Immuno modulatory and anti viral), azathioprine, anakinra ( a recombinant IL-1B receptor antagonist), TNF ( anti tumor necrosis factor agents) like
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ACCEPTED MANUSCRIPT cyclophosphomide, cyclosporine, methotrexate, hydroxychloroquine may be considered in the case of proven infection negative, corticosteroids dependent, recurrent pericarditis not responsive
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to colchicine. Such treatments are supported by weak evidence and lack of strong based trials.
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(1,3,83,84,85)
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Pericardiectomy:
Surgical pericardiectomy is an effective last resort for patients with relapsing pericarditis in
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whom adequate medical therapy failed. Surgical pericardiectomy has been proposed for relief of
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symptoms in patients with relapsing pericarditis. However, pericardiectomy does not always result in the end of recurrences.(1,3,15,71).
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Interventional technique and surgical therapy:
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Interventional and surgical therapies should be considered in patients with cardiac tamponade, hemodynamically significant moderate to large pericardial effusion, in symptomatic patients who
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are refractory to medical therapy, effusive constrictive or constrictive pericarditis, or suspicion of
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neoplastic or bacterial etiology ( HIV,TB), Bacterial cultures can be useful to evaluate the possible underlying etiology in patients with recurrent/relapsing pericarditis with high suspicion for bacterial infections. (1,3)
Prognosis:
Most cases of relapsing/recurrent pericarditis are viral or immunological in etiology (73). In study of a total of 230 patients with idiopathic recurrent pericarditis after follow-up for 61 months, complication rate was 3.5% of cardiac tamponade which usually occurs in early course of disease. Constrictive pericarditis and LV dysfunction are rarely reported in patients with
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ACCEPTED MANUSCRIPT idiopathic recurrent pericarditis. Thus complications are related to underlying etiologies and not
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related to recurrences. (1,71,86,87)
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Overall long term prognosis is good with rare complication. Side effects of medicines, glucocorticoids dependence in patients with relapsing and recurrent pericarditis may affect the
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quality of life (1,86,87)
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Conclusion:
Acute pericarditis is a common disease in routine clinical practice. A careful clinical history,
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physical examination, and application of diagnostic criteria are needed to make an accurate
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diagnosis, exclude concomitant disease and properly triage patients. Therapy for acute pericarditis should be guided according to the underlying etiology. For common forms of
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pericarditis such as idiopathic and viral pericarditis, NSAIDS or aspirin with addition of
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colchicine remains the mainstay of therapy. This will usually result in reduction of symptoms and prevent the rate of recurrence of disease. Patients with hemodynamic compromise or who
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are resistant to therapy may require prompt hospitalization and initiation of more aggressive
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84. Moretti M, Buiatti A, Merlo M, Massa L, Fabris E, Pinamonti B, Sinagra G. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol 2013;112:1493–1498.
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86. Imazio M, Brucato A, Markel G, Cemin R, Trinchero R, Spodick DH, Adler Y. Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome. Am J Cardiol. 2011 Aug 15;108(4):575-9. 87. Brucato A, Brambilla G, Moreo A, Alberti A, Munforti C, Ghirardello A, Doria A, Shinar Y, Livneh A, Adler Y, Shoenfeld Y, Mauri F, Palmieri G, Spodick DH. Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol. 2006 Jul 15;98(2):267-71.
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ACCEPTED MANUSCRIPT Table 1: Specific Terminologies for Pericarditis (1,3)
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Acute Pericarditis- First attack of pericardial inflammation with acute onset of symptoms which usually last for 4-6 weeks with treatment and symptoms resolves in 4-6 weeks.
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Incessant- Symptoms last for >4-6 weeks but < 3 months without remission
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Recurrent/Relapsing – After complete resolution of symptoms for 4-6 weeks with treatment and, if symptoms recurs. Chronic Pericarditis lasting more than 3 months
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Gram positive and Gram negative species (streptococci, staphylococcus, pneumococcus),Mycobacterium tuberculosis. Less common – Legionella, Norcardia, Actinobacillus,Rickettsia, Borrelia burgdoferi ( Lyme disease), Listeria, laptospira, chlamydophila psittaci, treponema pallidum ( Syphilis), coxiella burnettii, meningococus species, hemophilus species, mycoplasma species Histoplasma, blastomyces, coccidiosis, aspergillus,candida Toxoplasma, entomoeba, echinococcus Coxsackie viruses, echoviruses, adenovirus, influenza A & B viruses, enterovirus, mumps virus, Epstein barr virus, HIV, Herpes simplex virus, type I varicella zoster virus ( VZV), Measles, para influenza viruses type II, RSV, CMV, Hepatitis A,B & C, Parvovirus B 19.
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Parasitic infection Idiopathic/Viral causes
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Non infectious Autoimmune
Neoplastic causes Metabolic causes Miscellaneous Drugs
Trauma, Iatrogenic
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Systemic lupus erythematous, Sjogren syndrome, rheumatoid arthritis, scleroderma, vasculitideseosinophilic granulomatosis ( Churg-Strauss syndrome), Takayasu disease, Behcet syndrome, scarcoidosis, familial Mediterranean fever, inflammatory bowel disease, Still disease, mixed connective tissue disorder , Reiter syndrome, Wegners granulomatosis, ankylosing spondylitis, giant cell arteritis, dermatomyocitis, serum sickness Primary ( mesothelioma), secondary (lung ,breast, etc) Uremia, Myxoedema, cholesterol pericarditis Amyloidosis, aortic dissection, radiation induced(indirect injury) Daunorubicin, doxorubicin, cyclophosphamide,5 flurouracil,amiodarone, cyclosporine, mesalazine, clozapine, methysergide, anti tumor necrosis factor, hydralazine, procainamide, methyldopa, phenytoin, Isoniazide, Reserpine Coronary interventions, permanent pacemaker/ICD implantation, radiofrequency
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The American Journal of Medicine, Volume 127, Issue 5, May 2014, Page e17 The American Journal of Medicine, Volume 127, Issue 5, May 2014, Page e1xDavid H. Spodick Search for articles by this author
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Address for reprints: David H. Spodick, MD, Lemuel Shattuck Hospital, 170 Morton St., Boston, Mass. 02130.
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ACCEPTED MANUSCRIPT Table 3: EKG Evolution in Pericarditis (Over the days to weeks):
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3) ST Segment isoelectric with diffuse T wave inversions
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1) Acute Phase : ST Segment elevation concave upward with PR segment depression
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4) Persistent T wave inversion or Normalization of EKG.
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ACCEPTED MANUSCRIPT Table 4: Proposed Diagnostic Criteria (1,3) 2/4 Criteria should be positive
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3) New global ST Elevation with PR depression
Additional Supporting Findings
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4) Pericardial effusion ( New or worsening)
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1) Inflammatory markers Elevation ( ESR, CRP,
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Leukocytosis)
2) Evidence of pericardial Inflammation by Imaging modality ( CT/MRI)
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Table 5: Proposed triage of Pericarditis
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Reprinted from European Heart Journal, oxford university press. (1) Y Adler, P Charron, M Imazio et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. 2921-2964,with permission from Oxford University Press.
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Table 6: Therapeutic algorithm for acute and recurrent pericarditis
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Reprinted from European Heart Journal, oxford university press. (1) Y Adler, P Charron, M Imazio et al.2015 ESC Guidelines for the diagnosis and management of pericardial diseases. 2921-2964, with permission from Oxford University Press.
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Figure 1: Acute Pericarditis, Concave ST-T abnormality
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Figure 2: Acute coronary syndrome, Convex ST-T abnormality
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Figure 3: Echocardiogram Acute pericarditis with small pericardial effusion (Arrow)
Niraj Doctor Email: [email protected] Itzhak Kronzon Email: [email protected] 39 | P a g e