Pericarditis


Antonio Brucato° , Massimo Imazio*, Silvia Maestroni °

Medicina Interna, Ospedali Riuniti, Bergamo°

Dipartimento di Cardiologia, Ospedale Maria Vittoria, Torino*

albrucato@ospedaliriuniti.bergamo.it

massimo_imazio@yahoo.it

This topic last updated: April 17, 2010

 

SUMMARY

CLASSIFICATION OF PERICARDIAL DISEASE

ACUTE PERICARDITIS: DEFINITION

ACUTE PERICARDITIS: CLINICAL FEATURES

ACUTE PERICARDITIS: ETIOLOGY

SCREENING TESTS

RECURRENT ACUTE PERICARDITIS

THERAPY*

THERAPY OF DIFFICULT RECURRENCES

THERAPY OF REFRACTORY CASES

THERAPY IN PARTICULAR SETTINGS

PREGNANCY AND REPRODUCTIVE ISSUES*

CONSTRICTIVE PERICARDITIS

ROLE OF PERICARDIOTOMY AND PERICARDIECTOMY

LONG TERM OUTCOME

 

Items with the asterisk* might be indicated also as separate articles in the site

 

SUMMARY

Pericarditis is an acute inflammatory disease of pericardium. It is characterized by typical chest pain, pericardial rub, widespread saddle-shaped or concave upward ST segment elevation on electrocardiography, pericardial effusion, fever, a high erythrocyte sedimentation rate (ERS) and a high C-reactive protein (CRP).

The chest pain typically is retrosternal in location, sudden in onset, and exacerbated by inspiration. It is often worse when the patient is supine and improves when he or she sits upright and leans forward.

Etiology remains unknown (“idiopathic” pericarditis) in 80-90% of the cases occurring in immunocompetent patients from developed countries. An infectious or systemic etiology cannot usually be identified in these cases using standard laboratory techniques in the real world. Tuberculosis is found in approximately 5% of cases , neoplasms in 5%, and rheumatic autoimmune disease in 5% of cases .

The commonest viral infections causing pericarditis include Coxsackievirus A and B, Echovirus, Adenovirus, Parvovirus B19, Human Herpes Virus 6. In developed countries, tuberculous pericarditis may be found especially among imigrants from areas with a high prevalence of tuberculosis, and HIV-infected patients. On the contrary, tuberculous pericarditis is the commonest etiology in developing countries, such as Africa, where is often associated with HIV-infection.

Pericarditis may be a component of a multiserositis in systemic autoimmune disease; it may also be due to trauma, surgical interventions, interventional invasive procedures, such as pacemaker implantation, or myocardial infarction.

Aspirin (ASA) or non steroid anti-inflammatory drugs (NSAID) are the mainstay of treatment.

A common mistake is to use too low doses, and a full anti-inflammatory dose should be prescribed (i.e. aspirin 2 to 4 g/day, ibuprofen 1200-1800mg/day, indomethacin 75 to 150mg). Administrations of ASA/NSAID should be well distributed in the day, since the length of action of a single dose of ASA, ibuprofen or indomethacin is approximately 8 hours. This therapy is generally able to control also the most severe and painful attacks.

Evidence of inflammation is important to guide the therapy and C-reactive protein should be tested at baseline and during follow-up.

Colchicine is useful for the treatment of recurrent pericarditis, where it approximately halves the frequency of the recurrences; low-dose should be used (0.5-1.2 mg daily).

Corticosteroids use should be strongly restricted in acute pericarditis. Treatment with high doses of prednisone (1 mg/kg daily) resulted in severe steroid-related adverse effects. Lower doses of prednisone (0.25-0.5 mg/kg daily) are commonly used to treat serositis in patients with autoimmune diseases, such as systemic lupus erythemathosus or Sjogren’s syndrome and these therapeutic schemes might be reasonably applied also in recurrent pericarditis, when really necessary. Guidelines recommend osteoporosis prevention with calcium-vitamin D and biphosphonates whenever using corticosteroids, an issue often forgotten in clinical practice.

 

The most troublesome complication for the acute pericarditis is recurrent pericarditis (20-30% of cases).

The long term outcome of idiopathic recurrent pericarditis is good, with no evolution in constrictive pericarditis Although recurrences are a common cause of concern, a recent analysis of all published cases of idiopathic recurrent pericarditis has shown no evolution in constrictive pericarditis even after a long-term follow up; reassurance is important for these patients. The risk of constriction is not related to the number of recurrences but to the etiology of pericarditis (e.g. tuberculosis; post-radiation therapy).

 

M. Imazio, DH. Spodick, A. Brucato, R. Trinchero, Y. Adler. Controversial Issues in the Management of Pericardial Diseases. Circulation 2010; 121;916-928

 

CLASSIFICATION OF PERICARDIAL DISEASE

The spectrum of pericardial diseases includes:

-acute pericarditis

-recurrent pericarditis

-constrictive pericarditis

-symptomatic chronic pericardial effusion with normal erythrocyte sedimentation rate (ERS), and normal C-reactive protein (CRP).

-asymptomatic pericardial effusion, often detected occasionally.

 

ACUTE PERICARDITIS

 

ACUTE PERICARDITIS: DEFINITION

Acute pericarditis accounts for 5% of presentations at Emergency Departments due to non-acute myocardial infarction. Its incidence in Italy is approximately 18/100.000.

It is generally an acute inflammatory disease, which recurs in 20-40% of patients, and is characterized by typical chest pain, pericardial friction rub, suggestive ECG changes (typically widespread ST segment elevation, PR depression), new or worsening pericardial effusion, high ERS and high CRP (in most cases).

It does not include other conditions such as symptomatic pericardial effusion with normal CRP, or asymptomatic pericardial effusion.

ACUTE PERICARDITIS: CLINICAL FEATURES

A prodrome of fever (usually< 38°C), malaise, and myalgia is common, but some patients may not be febrile. Major symptoms are retrosternal or left precordial chest pain, non-productive cough, and shortness of breath.

The chest pain of acute pericarditis typically is retrosternal in location, sudden in onset, and pleuritic in nature, in that it is exacerbated by inspiration. It is often worse when the patient is supine and improves when he or she sits upright and leans forward. As in myocardial infarction, the pain often radiates to the neck, arms, or left shoulder. If the pain radiates to one or both trapezius muscle ridges, it is probably due to pericarditis, since the phrenic nerve (which innervates these muscles) traverses the pericardium.

During physical examination, about 85% percent of patients with pericarditis have an audible friction rub during the course of their disease. The friction rub corresponds temporally to movement of the heart within the pericardial sac. Typically, the rub is a high-pitched scratchy or squeaky sound best heard at the left sternal border at end expiration with the patient leaning forward.

The presence of systemic arterial hypotension, tachycardia, elevated jugular venous pressure, and pulsus paradoxus (a decrease in systolic arterial pressure of more than 10 mmHg with inspiration) suggests cardiac tamponade.

Tamponade, a potentially lethal complication of pericarditis, is reported in about 15 percent with idiopathic pericarditis (usually at its onset) but in as many as 60 percent of those with neoplastic, tuberculous, or purulent pericarditis. These findings should prompt immediate echocardiography, and the physician should consider obtaining pericardial fluid for analysis.

The 12-lead electrocardiogram in patient with acute pericarditis classically shows widespread upward concave ST-segment elevation in PR-segment depression. The electrocardiographic abnormalities may evolve through four phases: diffuse ST-segment elevation and PR-segment depression (stage I); normalization of the ST and PR segments (stage II); widespread T-wave inversions (stage III); and normalization of the T waves (stage IV).

Chest radiography is performed primarily to rule out abnormalities in the mediastinum or lung fields that may be responsible for the pericarditis. The appearance of cardiomegaly with sharp margins ("water bottle" silhouette) indicates a substantial pericardial effusion (more than 250 ml). Pericardial effusions may be present in one third of cases.

Blood exams: the white-cell count, erythrocyte sedimentation rate, and serum C-reactive protein usually are elevated in patients with acute pericarditis, even if these tests don’t insight into the cause of the disease or indications regarding which therapy is called for.

Pericarditis is often accompanied by some degree of myocarditis. Plasma troponin concentrations are elevated in some patients with pericarditis, a findings that is thought to be caused by subepicardial inflammation (thus myopericarditis rather than simple pericarditis). An elevated troponin concentration does not predict an adverse outcome, although a prolonged elevation (generally more than 2 weeks) suggests associated myocarditis, which has a worse prognosis.

Pericarditis is sometimes accompanied by alteration of liver function with elevation of transaminases. We observed it in about 9% of acute pericarditis. This alteration occurs before beginning anti-inflammatory drugs, probably due to viral infection; it does not contraindicate anti-inflammatory drugs or colchicine.

Transthoracic echocardiography is recommended in patients with suspected pericarditis, since the presence of an effusion helps to confirm the diagnosis, and clinical or echocardiographic evidence of tamponade indicates the need for pericardiocentesis.

The size of effusions can be graded as: small (echo-free space in diastole of less than 10 mm), moderate (at least ≥ 10 mm), large (≥ 20 mm). In parasternal long axis view pericardial fluid reflects at the posterior atrioventricular groove, while pleural fluid continues under the left atrium, posterior to the descending aorta.

Cardiac tamponade is the decompensated phase of cardiac compression caused by effusion accumulation and the increased intrapericardial pressure. The volume of fluid causing tamponade varies inversly with both parietal pericardial stiffness and thickness (150-2000ml). Dyspnoea, dysphagia, hoarseness (recurrent laryngeal nerve), hiccups (phrenic nerve), or nausea (diaphragm) can occur. Heart sounds are distant.

Importantly, effusion size is an overall predictor of prognosis: large effusions generally indicate more serious disease.

Two-dimensional echocardiography also provides information about the nature of the fluid, suggesting the presence of fibrin, clot, tumour, air, and calicium.

Thorax and abdomen computer tomography (CT) or cardiac magnetic resonance imaging (MRI) may be useful for the detection of tumoral mass and lymphoadenopathies (generally lung or breast cancer or lympomas or pericardial mesothelioma) or in suggesting possible tuberculosis. In women physical examination of breast and mammography may be useful.

A pericardiocentesis, a pericardial biopsy or pericardioscopy may be reserved to complicated cases.

Important conditions that may cause chest pain similar to that of pericarditis include myocardial infarction, pulmonary embolism, pleuritis and aortic dissecation.

 

R. A Lange, L. D. Hillis. Acute pericarditis. N Engl J Med 2004; 351: 2195-202

B. Maisch, Chairperson, P. Seferovic, A. Ristic, R. Erbel, R. Rienmuller et al. Guidelines on the diagnosis and management of pericardial diseases. European Heart Journal 2004; 1-28

 

ACUTE PERICARDITIS: ETIOLOGY

Anything may cause pericarditis, but an etiological search is often inconclusive in clinical practice. Using a systematic battery of serological tests Levy identified an infectious etiology in approximately 20% of cases.

 

Etiology of acute pericarditis

Infectious:

·         Viral (most common: Echovirus and Coxsackievirus (usual), Influenza, EBV, CMV, Adenovirus, Varicella, Rubella, Mumps, HBV, HCV, HIV, Parvovirus B19 and Human Herpes Virus 6

·         Bacterial (most common: tuberculous, Coxiella burnetii, other very rare bacterial may include Pneumo-, Meningo-, Gonococcosis, Haemophilus, Staphylococci, Chlamydia, Mycoplasma, Legionella, Leptospira, Listeria)

·       Fungal (rare: Histoplasma more likely in immunocompetent patients, Aspergillosis, Blastomycosis, Candida more likely in immunosuppressed host)

·         Parasitary (very rare: Echinococcus, Toxoplasma)

Non-infectious:

·         Autoimmune:

Ø      Pericardial injury syndromes (Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Post-traumatic pericarditis)

Ø      Pericarditis in systemic autoimmune diseases (more common in Sjögren syndrome, systemic lupus erythematosus, rheumathoid arthritis, systemic sclerosis, systemic vasculitides, Behçet syndrome, and familial Mediterranean fever)

Ø      Autoreactive (other presumed to have an autoimmune aetiology after exclusion of infectious and neoplastic causes)

·         Neoplastic: Primary tumours (rare, above all pericardial mesothelioma), Secondary metastatic tumours (common, above all lung and breast cancer, lymphoma)

·         Metabolic (common: uremia, myxedema, other rare)

·         Traumatic (rare):

Ø      Direct injury (penetrating thoracic injury, esophageal perforation)

Ø     Indirect injury (non-penetrating thoracic injury, radiation injury)

·       Other (rare: i.e. drug-related)

 

Major published surveys of unselected, consecutive cases with acute pericarditis in developed countries.

 

 

Permanyer-Miralda G.

et al. (n= 231)

1977-83

Zayas R.

et al. (n= 100)

1991-3

Imazio M.

et al. (n=453)

1996-2004

Setting

Western Europe

Western Europe

Western Europe

Idiopathic

199 (86.0%)

78 (78.0%)

377 (83.2%)

 

 

 

 

 Neoplastic

13 (5.6%)

7 (7.0%)

23 (5.1%)

 Tuberculosis

9 (3.9%)

4 (4.0%)

17 (3.8%)

 Autoimmune

4 (1.7%)

3 (3.0%)

33 (7.3%)

 Purulent

2 (0.9%)

1 (1.0%)

3 (0.7%)

 

The most frequently involved viruses were Echo-virus and Coxsackie virus, with the rare involvement of influenza, EBV, adenovirus, varicella, rubella, mumps, HBV, HCV, HIV, parvovirus B19 and human herpes virus 6.

The most common bacteria were Mycobacterium tuberculosis (4-5%) and Coxiella burnetii (5-7%), with rare involvement of Streptococcus pneumoniae, Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus, Staphyloccus, Chlamydia, Mycoplasma, Legionella, Leptospira and Listeria; Histoplasma fungi were more likely in immunocompetent patients, and Aspergillosis, Blastomycosis and Candida more likely in the immunosuppressed; a parasitic etiology was very rare and involved Echinococcus or Toxoplasma.

European investigators have conducted extensive studies based on pericardioscopy, multiple epicardial biopsies, and polymerasis chain reaction (PCR), and reported a higher prevalence of infection or reinfection than other investigators, particularly viral (Coxsackie A and B1-4, Echo virus 8, mumps, EBV, CMV, varicella, rubella, HIV, Parvo B19); bacterial (Pneumococcus, Meningococcus, Hemophilus, Treponema pallidum, Borreliosis, Chlamydia, Tubercolosis); fungal (Candida, Histoplasma) and parasitic infections (Entameba histolitica, Echinococcus, Toxoplasma).

On the other hand, some authors suggest that such intensive etiological searches may not be warranted as they do not affect therapy or prognosis in most cases.

An infectious or systemic etiology cannot usually be identified using standard laborator techniques without molecular tests and, in the real world, the most common specific etiologies reported in published clinical series are tubercolosis 5% (3.9-4.7%), neoplastic pericarditis 5% (4.7-7%), rheumatic autoimmune disease 5% (1.7-10.2%); idiopathic and/or viral acute pericarditis are found in 80-90% of the cases occurring in immunocompetent patients from developed countries.

Specific features at presentation may be associated with a higher risk of a specific etiology (non-viral and non-idiopathic pericarditis) and complications. These features, also reported as poor prognostic predictors, include: fever> 38°C, subacute onset (symptoms developing during a period of several days or weeks), immunodepression, trauma, oral anticoagulant therapy, myopericarditis (pericarditis with clinical or serologic evidence of myocardial involvement), severe pericardial effusion and cardiac tamponade, the failure of aspirin or nonsteroidal antiinflammatory drugs (NSAID). It has been suggested to restrict the etiological search to those patients with at least one poor prognostic predictor, or when etiology can be suspected on the basis of the history and clinical presentation. Patients without these high risk features can be considered at low risk and can be empirically treated with aspirin or a NSAID.

 

M. Imazio, DH. Spodick, A. Brucato, R. Trinchero, Y. Adler. Controversial Issues in the Management of Pericardial Diseases. Circulation 2010; 121;916-928

Levy Py, Habib G, Collart F et al. Etiological diagnosis of pericardial effusion. Future Microbiol 2006; 1: 229-239.

Maish B, Seferovic PM, Ristic AD et al. Guidelines on the diagnosis and management of pericardial disease. Eur Heart J 2004; 25: 1-28.

Imazio M, Cecchi E, Demichelis B et al. Indicators of poor prognosis of acute pericarditis. Circulation 2007; 115: 2739-2744.

 

VIRAL OR IDIOPATHIC PERICARDITIS

Most cases of acute pericarditis and up to one third of recurrent cases are due to virale infections.

It is a common belief that the commonest viral infections causing pericarditis include Coxsackievirus A and B, Echovirus and Adenovirus. Serology and other cultural studies (i.e. throat and rectal swabs) are not reliable and diagnostic; even a fourfold rise in serum antibody levels, or evidence of specific anti-viral IgM is suggestive but not diagnostic.

Since a precise diagnostic definition is not necessary and does not alter management, most cases are labelled as idiopathic in clinical practice.

 

TUBERCOLOSIS PERICARDITIS

This specific etiology has a frequency of about 5% of all unselected cases of pericarditis. In developed countries tuberculous pericarditis may be found especially among imigrants from areas with a high prevalence of tuberculosis, and HIV-infected patients. On the contrary, tuberculous pericarditis is the commonest etiology in developing countries, such as Africa, where is often associated with HIV-infection.

Accurate and early diagnosis is important becouse tuberculous pericarditis is a dangerous disease with a high mortality if untreated, with constrictive pericarditis occuring in 30-50% of cases. In the past, pericarditis were often treated with an antitubercular empirical treatment but there is no justification for this in areas where tubercolosis is not endemic.

Concerning the diagnosis of tubercolosis, tuberculin skin test is not always helpful: the response may be affected by the individual immune response, HIV infection, prior bacille Calmette-Guerin vaccination and use of steroids.

A sensitive enzyme-linked immunospot (ELISPOT) may provide more accurate results even if is sensible only for Mycobacterium tuberculosis and not for Mycobacterium bovis.

Another test is QuantiFERON test: it is used for latent tuberculosis infection and tuberculosis disease. Elispot and QuantiFERON tests and other similar tests detect interferon gamma in rsponse to contact with tubercle bacille (TB) antigens; the sensitivity and specificity of interferon-γ (IFN) values > 200 pg/L are both 100%.

A definite diagnosis of tuberculous pericarditis is based on the demonstration of TB in pericardial fluid or biopsy, even if pericardial fluid cultures are positive for TB in only 50% of cases, and or the presence of caseous granulomas in the pericardium. Another method is the evaluation of adenosine deaminase activity in pericardial fluid, with a sensitivity and specificity of 94% and 68% for values of ³ 30 u/L.

Chest CT scan may show typical changes in mediastinal lymph nodes and sparing of hilar lymph nodes.

Concerning the therapy, various antituberculous drug combinations have been applied. Only patients with proven or very lkely TBC pericarditis should be treated. The use of steroids remains controversial.

If, in spite of combination therapy, constriction develops pericardiectomy is indicated.

 

Mayosi BM, Burgess LJ, Boubell AF. Tuberculous pericarditis.Circulation 2005; 112: 3608-16.

Lesley J, Burges S, Med M et al. The use of adenosine deaminase and IFN gamma as diagnostic tool for tuberculous pericarditis. Chest 2002; 122: 900-905.

 

BACTERIAL PERICARDITIS

Purulent pericarditis is very rare in adults, but always fatal if untreated. Mortality rate in treated patients is 40%, mostly due to cardiac tamponade, toxicity, and constriction. It is usually a complication of an infection originating elsewhere in the body, arising by contiguous spread or haematogenous dissemination.

Sagrista-Sauleda J, Barrabes JA, Permanyer-Miralda G et al. purulent pericarditis: review of a 20-year experience in a general hospital. J Am Coll Cardiol 1993; 22: 1661-5

 

THE POST-CARDIAC INJURY SYNDROME: POSTPERICARDIOTOMY SYNDROME

Post-pericardial injury syndrome develops within days to months after cardiac, pericardial injury or both. Unlike post-myocardial infarction syndrome, post-cardiac injury syndrome acutely provokes a greater antiheart antibody response, probably related to more extensive release of antigenic material. Pericardial effusion also occurs after orthotopic heart transplantation. Cardiac tamponade after open heart surgery is more common following valve surgery (73%) than coronary artery bypass grafting alone (24%) and may be related to the preoperative use of anticoagulants. Constrictive pericarditis may also occur after cardiac surgery.

Kuvin JT, Harati NA, Pandian NG et al. Postoperative cardiac tamponade in the modern surgical era. Ann Thorac Surg 2002; 74: 1148-53.

 

TRAUMATIC PERICARDITIS

Direct pericardial injury can be induced by chest trauma, surgery, invasive procedures (e.g. pacemaker implantation). 

 

POSTINFARCTION PERICARDITIS

There are two forms of postinfarction pericarditis: an early form (epistenocardic pericarditis) and a delayed form (Dressler's syndrome).

Epistenocardiac pericarditis, caused by direct exudation, occurs in 5-20% of transmural myocardial infarctions but is clinically discovered rarely. Dressler's syndrome occurs from one week to sveral months after clinical onset of myocardial infarction with symptoms and manifestations similar to the post-cardiac injury syndrome.

Spodick DH. post-myocardial infarction syndrome (Dressler's syndrome). ACC Curr J Rev 1995; 4: 35-7.

 

NEOPLASTIC PERICARDITIS

Primary tumours of the pericardium are 40 times less common than the metastatic ones and mesothelioma is the most common of the primary tumours.

The most common secondary malignant tumours are lung cancer, breast cancer, malignant melanoma, lymphomas, and leukemias.

Of note, in patient with documented malignant disease, pericardial effusion is often due to radiation therapy or cardio toxic chemotherapy.

 

PERICARDITIS IN SYSTEMIC AUTOIMMUNE DISEASE

Pericarditis is also a component of a multiserositis in systemic autoimmune disease: rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis/ dermatomyositis, mixed connective tissue disease, seronegative spondyloarthropathies, systemic and hypersensitivity vasculitides, familial Mediterranean fever, Behcet syndrome, Wegener granulomatosis and sarcoidosis.

Pericarditis can occur during the active phase of the systemic disease or may be subclinical with a silent pericardial effusion.

In many case the diagnosis of a connective disease is already known at the time of the diagnosis of pericarditis, but during a follow up of patients with apparent idiopathic pericarditis we made a new diagnosis of primary Sjogren's Syndrome  in 9% of the cases, and of rheumatoid arthritis in 2% of the cases. All patients with Sjogren's syndrome were positive for anti-Ro/SSA and/or anti-La/SSB antibodies, the minor salivary biopsy was diagnostic. It is noteworthy that pericarditis represented the dominant clinical manifestation.

 

Brucato A, Brambilla G, Adler Y, Spodick DH, Canesi B. Therapy of recurrent acute pericarditis: a rheumatological solution? Clin Exp Rheumatol 2006; 24: 45-50.

 

PERICARDITIS IN RENAL FAILURE

Renal failure is a common cause of pericardial disease, producing large pericardial effusions in up to 20% of patients. Two forms have been described: 1) uremic pericarditis, in patient with advances renal failure. It results from inflammation of the visceral and parietal pericardium and correlates with the degree of azotemia. 2) Dialysis-associated pericarditis, in up to 13% of patients on maintenance haemodialysis. The clinical features may include fever and pleuritic chest pain but many patients are asymptomatic.

NSAIDs are often controindicated in renal failure while colchicine can be used at low dosage.

 

SCREENING TESTS

Screening tests might  include:

-Blood exams: ERS, CRP, white blood cell count, creatinine, ALT, AST, uric acid, thyroid-stimulating hormone (TSH)

-Autoimmunity exams:  anti-nuclear antibody (ANA),  anti- ENA, anti-DNA

-Chest radiography

-Electrocardiogram

-Echocardiogram

-Tuberculin skin test and cultures for tuberculosis

-in selected cases: chest CT and/or cardiac RMI.

- in selected cases: IgM for Coxsachie, Echo, Parvovirus, HHV6, HBV, HCV, HIV.

  

RECURRENT ACUTE PERICARDITIS

The most troublesome complication for the acute pericarditis is recurrence, which is estimated to occur in approximately 30% of unselected cases with viral, presumed viral or idiopathic pericarditis. A higher recurrence rate should be expected in patients who have already experienced recurrences (30-50%). Although recurrences are a common cause of concern for the fear of a possible evolution towards constriction, a recent analysis of all published cases with idiopathic recurrent pericarditis has shown no cases of constrictive pericarditis even after a long-term follow up. The risk of constriction is not related to the number of recurrences but to the etiology of pericarditis. Patients with specific etiology (i.e. tuberculous pericarditis, postradiation pericardtis) have a substantial risk of constriction, while this risk is approximately 0% for idiopathic recurrent pericarditis.

The distinction between acute recurrent pericarditis, usually idiopathic and benign, and chronic or incessant pericarditis eventually evolving in constrictive pericarditis might be difficult. In idiopathic recurrent pericarditis the clinical picture is characterized by attacks of pain, fever, with increased CRP, that resolve, with normalization of CRP and disappearance of symptoms, but then recur after a free interval. On the other hand chronic pericarditis directly evolving in constrictive pericarditis has an incessant course, with pain and fever at the beginning, while peripheral congestion develops in weeks/months, becoming the dominant clinical features.

Recurrent pericarditis is generally idiopathic (i.e. the cause remains unknown, as is common in most diseases), other mechanisms suggested to explain recurrence include: insufficient dose or/and insufficient treatment duration of antiphlogistics or corticoids in an autoimmune pericardial disease, reinfection, exacerbation of connective tissue disease. The recurrent pericarditis is a disease of suspected immune-mediated pathogenesis. This is suggested by the presence of pro-cytokines in the pericardial fluid, the presence of anti-heart antibodies in the sera of these patients and the good response to anti-inflammatory or immunosuppressive therapy. It may also represent an autoinflammatory condition similar to Familial Mediterranean Fever.

 

Imazio M, Bobbio M, Cecchi E et al. Colchicine as first-choice therapy recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch. Intern. Med. 2005; 165: 1987-1991.

Imazio M, Brucato A, Adler Y et al. Prognosis of idiopathic recurrent pericarditis as determined from previously published reports. Am J. Cardiol. 2007; 100: 1026-1028.

 

THERAPY OF ACUTE PERICARDITIS

ASPIRIN OR NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID)

They are the mainstay of treatment. The selection of the specific NSAID should be based on physician experience and the patient’s previous history (eg, an NSAID that was effective in previous attacks should be the favourite choice) and comorbidities; eg, aspirin is the favoured choice in patients with ischemic heart disease or when the patient is already on aspirin or needs antiplatelet treatment, whereas indomethacin and other NSAIDs should be avoided in patients with coronary artery diseases.

A common mistake is to use too low doses, and a full anti-inflammatory dose should be prescribed (i.e. aspirin 2 to 4 g/day, ibuprofen 1200-1800mg/day, indomethacin 75 to 150mg). Aspirin may be the preferred choice in patients who already are or need treatment with an antiplatelet agent (i.e. patients with ischemic heart disease). ASA or NSAID may be given intravenously (e.g. ASA 2-4 g/day or indomethacin 50 mg in saline 500 ml twice daily), eventually adding low dose tramadol or other analgesics to control the pain. Administrations of ASA/NSAID should be well distributed in the day, since the length of action of a single dose of ASA, ibuprofen or indomethacin is approximately 8 hours. This therapy is generally able to control also the most severe and painful attacks.

Evidence of inflammation is important to guide the therapy and C-reactive protein should be tested at baseline and during follow-up. Although there are no specific guidelines on the best length of treatment, it seems reasonable to individualize not only the treatment choice, but also the treatment length. The aim of the antinflammatory drugs is to extinguish inflammation and control symptoms. C-reactive protein may be an useful marker of the inflammation. The attack dose can be maintained till normalization of the C-reactive protein (usually within 7 to 21 days), then gradual tapering of the drug can be considered.

In the less severe cases ASA/NSAID may be gradually tapered from high to medium-low doses (e.g. ASA 1500mg, ibuprofen 1200mg, indomethacin 75 mg/day) after 1-4 weeks, then continued at that dosage till normalization of CRP, that may occur in 2-6 weeks and then gradually discontinued. Total length of therapy might be 2-8 weeks. A gradual tapering should be advised.

In more severe cases a similar schedule may be used, but tapering is slower. In these cases it is important not discontinue the therapy till normalization of CRP and stable disappearance of symptoms. Total length of therapy might be in these cases 4-16 weeks.

However, patients with a suspected specific etiology or high risk features should be admitted to hospital, and a comprehensive etiological search should be performed. A targeted therapy should directed to the specific cause, when it has been identified.

Dose adjustments are recommended for children and the elderly especially for specific drugs.

Drug

Antiinflammatory doses

Contraindications

Aspirin

Children:

Oral: Initial: 60-90 mg/kg/day in divided doses; usual maintenance: 80-100 mg/kg/day divided every 6-8 hours;

Adults:

Oral: Initial: 2-4 g/day in divided doses; usual maintenance: 1-2 g/day

Hypersensitivity to salicylates, any component, or other NSAIDs; bleeding disorders; hepatic failure

ibuprofen

Children:

Oral: 30-50 mg/kg/24 hours divided every 8 hours; start at lower end of dosing range and titrate upward (maximum: 2.4 g/day)

Adults:

Oral: 400-800 mg/dose 3-4 times/day (maximum: 3.2 g/day)

Hypersensitivity to ibuprofen, aspirin, other NSAIDs, or any component of the formulation; perioperative pain in the setting of coronary artery bypass graft (CABG) surgery

Ibuprofen lysine is contraindicated in preterm infants

Indomethacin

Oral:

Children ≥2 years: 1-2 mg/kg/day in 2-4 divided doses; maximum dose: 4 mg/kg/day; do not exceed 150-200 mg/day


Adults:

25-50 mg/dose 2-3 times/day; maximum dose: 150 mg/day;

Hypersensitivity to indomethacin,  aspirin, or other NSAIDs; patients with the "aspirin triad" [asthma, rhinitis (with or without nasal polyps), and aspirin intolerance] (fatal asthmatic and anaphylactoid reactions may occur in these patients); perioperative pain in the setting of coronary artery bypass graft (CABG)

Contraindicated in preterm infants

Casella di testo: Warnings: do not use aspirin in children and teenagers who have or who are recovering from chickenpox or flu symptoms (due to the association with Reye’s syndrome); when using aspirin, changes in behaviour (along with nausea and vomiting) may be early sign of Reye’s syndrome. Precautions: Aspirin- Use with caution in patients with impaired renal function, erosive gastritis, peptic ulcer, gout, platelet and bleeding disorders. NSAID- Use with caution in patients with cardiac dysfunction, hypertension, renal or hepatic impairment, epilepsy, patients receiving anticoagulants and for treatment of Juvenile Rheumatoid Arthritis JRA in children (fatal hepatitis has been reported; monitor children closely; assess liver function periodically)
 
 

  

1s

 

 

 

 

M. Imazio, A. Brucato, R. Trinchero, D. Spodick and Y. Adler. Individualized therapy for pericarditis. Expert Rev. Cardiovasc. Ther. 2009; 7(8);  965-975.

 

COLCHICINE

Colchicine has been studied and prescribed for the treatment and prevention of gouty attacks and also for other inflammatory conditions (i.e. serositis in Familial Mediterranean Fever- FMF). More recently the use of colchicine has been proposed for the treatment and prevention of pericarditis, following the successful use of the drug in the treatment and prevention of polyserositis related to Familial Mediterranean Fever.

A number of studies have been published supporting the use of colchicine in recurrent cases with a variable success rate. Colchicine is also recommended by homeopathic medicine (Materia Medica of homeopathic medicine. Phatak SR, B. Jain Publishers).

The stronger evidence base to support the use of the drug, above all for primary or secondary prevention of recurrences, comes from the first 2 open-label randomized trials in which colchicine at least halved the recurrence rate.  In the COlchicine for PEricarditis (COPE) trial, colchicine (0.5 to 1 mg daily for 3 months) as an adjunct to conventional treatment significantly decreased the recurrence rate (at 18 months 10.7% and 32.3%, respectively; P=0.004; number needed to treat, 5.0) and symptom persistence at 72 hours (11.7% and 36.7%; P=0.003) in 120 patients with a first episode of acute pericarditis. In this study, colchicine was discontinued in 5 patients (8.3%) because of diarrhea.

In the COlchicine for Recurrent Pericarditis (CORE) trial, colchicine (0.5 to 1 mg daily for 6 months) as an adjunct to conventional treatment for recurrent pericarditis significantly decreased the recurrence rate (at 18 months, 24.0% versus 50.6%, respectively; P=0.022; number needed to treat, 4.0) and symptom persistence at 72 hours (9.5% versus 31.0%, respectively; P=0.029) in 84 patients with recurrent pericarditis. In both CORE and COPE, a maintenance dose of 0.5 mg BID was adopted and reduced to 0.5 mg daily in patients <70 kg; thus, lower doses may be equally efficacious but with a possible lower rate of side effects.

Treatment was for 3 months in the first episode (COPE) and 6 months in recurrent pericarditis (CORE). In recurrent more severe cases, some authors advocate a longer use of the drug: up to 12 to 24 months after the last recurrence, tailored to the individual patient and with gradual tapering, considering that recurrences have been described after colchicine discontinuation.

Doseà 0,5-1mg/day. In the United States colchicine is usually prescribed as 0.6 mg once or twice a day rather than 0.5 mg once or twice a day.

Pharmacological effects à Most of them appear to be related to the capacity of colchicine to inhibit the process of microtubule self-assembly by binding ß-tubulin with the formation of tubulin-colchicine complexes, thus interfering with several cellular functions (such as chemotaxis, degranulation, phagocytosis). In pericarditis, a sustained anti-inflammatory effect may be beneficial in autoimmune (autoreactive) forms.

Wide interindividual colchicine bioavailability may explain different individual susceptibility to the effects of the drug. Lower plasma levels have been detected in non-responders patients with familial Mediterranean fever. Individual differences in colchicine plasma levels may reflect differences in the intestinal absorption, which is dependent on different expression of P-glycoprotein and CYP3A4 .

Side effectsà

At doses of 1 to 2 mg per day, colchicine is safe even when given continuously over decades.

Gastrointestinal symptoms (up to 10-15% of cases): nausea, vomiting, diarrhoea, abdominal pain; usually they limit drug compliance and are a common cause of drug withdrawal, although generally mild; they may resolve with dose reduction. Weight-adjusted doses, such as in the COPE and CORE trials (only 0.5 mg daily if weight is less than 70 kg), may halve these side effects. Other rare side effects include anorexia, elevation of transaminases and reversible alopecia. In less than 1% of cases other side effects are reported including agranulocytosis, aplastic anaemia, bone marrow suppression, hepatotoxicity, and myotoxicity. Although azoospermia has been reported as a rare possible side effect (<1%), no interference of colchicine treatment was recorded in either growth rate or fertility after a cumulative 15 years of follow-up in patients with Familial Mediterranean Fever (see reproductive issues).

Dose reduction should be considered in patients who develop gastrointestinal symptoms (anorexia, diarrhoea, nausea, vomiting) or weakness related to drug therapy. Dose adjustment is necessary also for patients with renal impairment, debilitated patients, and the elderly. Moreover, monitoring is recommended during therapy with colchicine (blood cell count, transaminase, CK, and renal function test at least at baseline, and after 1 month of treatment).

Setting

Dose adjustment of colchicine

Children:

≤5years

>5years

 

0.5mg/day

1.0 to 1.5mg/day in 2-3 divided doses

Elderly (>70years)

reduce dose by 50%

Renal impairment:

Clcr 35-49 mL/minute

Clcr 10-34 mL/minute

Clcr <10 mL/minute

 

0.5-0.6 mg once daily

0.5-0.6 mg every 2-3 days

Avoid chronic use of colchicine. Use in serious renal impairment is contraindicated by the manufacturer.

Hepatic dysfunction:

Avoid in severe hepatobiliary dysfunction

Duration of therapy à in less severe cases 6 months, but in complicated cases colchicine has been given for 1-2 years after the last attack. At that point colchicine discontinuation is discussed with the patient, explaining that cases of recurrences after colchicine discontinuation have been reported. Discontinuation is better done gradually, e.g. the daily dose is changed to every other day for 1 month, than twice a week for one month, then once a week for one month, and finally completely discontinuated.

 

Imazio M, Brucato A, Trinchero R, Spodick D, Adler Y. Colchicine for pericarditis: hype or hope? Eur Heart J. 2009 Mar;30(5):532-9. Epub 2009 Feb 3.

Imazio M, Bobbio M, Cecchi E. et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med 2005;165: 1987-1991.

Imazio M, Bobbio M, Cecchi E. et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112:2012-2016.

Adler Y, Finkelstei Y, guindo J et al. Colchicine treatment for recurrent pericarditis. A decade of experience. Circulation 1998; 97:2183-2185.

Ben-Chetrit E, Levy M. Colchicine prophylaxis in familial Mediterranean fever: Reappraisal after 15 years. Semin Arthritis Rheum 1991;20:241-246.

 

CORTICOSTEROIDS

Corticosteroids use should be strongly restricted in acute pericarditis.

Although guidelines and reviews suggest limiting the use of these drugs, they are commonly prescribed especially during recurrences because of the fast relief of symptoms. Unfortunately quick tapering and use of inappropriate doses may exacerbate the disease instead of solving it. In fact, a number of retrospective and prospective studies have documented that corticosteroids are an independent risk factor for recurrences either in acute or recurrent pericarditis.

The evidence to support the use of corticosteroids for pericarditis is rather weak.

In a retrospective study on 12 patients with recurrent pericarditis unrelated to any systemic disease a 3-month course of prednisone with high doses (1.0 to 1.5 mg/Kg/day) was started for 1 month and followed by subsequent gradual tapering. When prednisone tapering was started, all patients received a 5-month course with aspirin (1.6 g/day until steroid withdrawal, and then 0.8 g/day). During a mean follow-up of 42 months, treatment with high doses of prednisone resulted in stable remission in all except one patient. In this study the efficacy of prolonged treatment with aspirin cannot be excluded to explain the overall good remission rate. Moreover, three patients (25%) had severe steroid-related adverse effects, two of them were treated with other immunosuppressive treatments (respectively one with azathioprine, and the other with cyclophosphamide).

Lower doses of steroids are commonly used to treat serositis in patients with autoimmune diseases, such as systemic lupus erythemathosus, Sjogren syndrome and these therapeutic schemes might be reasonably applied also in recurrent pericarditis.

A recent retrospective and non-randomized study challenged the common practice of using high doses of corticosteroids. One hundred patients with recurrent pericarditis were assigned to two alternative therapeutic regimens of prednisone: one half was treated with “low doses” of prednisone (0.2-0.5mg/Kg/die) and the other half was treated with prednisone 1.0mg/Kg/die. Baseline demographic and clinical characteristics were well balanced across the groups, each initial dose was maintained for 4 weeks and then slowly tapered. During 5,580 patient-months of follow-up, patients treated with high doses of prednisone had a higher rate of severe side effects (respectively 23.5% vs 2.0%), but also of recurrences (respectively 64.7% vs 32.6%), and disease-related hospitalizations (respectively 31.4% vs 8.2%). On this basis, low doses of corticosteroids should be considered instead of higher doses. Most of the observed side effects were vertebral fractures.

Moreover, corticosteroids may cause hypothalamic pituitary adrenal suppression (acute adrenal insufficiency or adrenal crisis occurs with abrupt withdrawal after long term therapy or with stress) and immunosuppression. Corticosteroids may mask signs of infection, may activate latent opportunistic infections or exacerbate systemic fungal infections. They may cause osteoporosis (at any age), inhibition of bone growth in pediatric patients, acute myopathy, elevated intraocular pressure (especially with prolonged use), cataratta, central nervous system effects (ranging from euphoria to psychosis), diabetes. Rare cases of anaphylactoid reactions have been reported.

Guidelines recommend osteoporosis prevention when using these drugs, an issue often forgotten in clinical practice. Supplementation with calcium and vitamin D (1500mg/day and 800 IU/day, respectively), or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. Moreover bisphosphonates are recommended to prevent bone loss in all men and postmenopausal women, in whom a long-term treatment with glucocorticoids is initiated at a dose≥ 5mg/day of prednisone or equivalent, as well as in men and postmenopausal women receiving long-term glucocorticoids, in whom the Bone Mineral Density T-score at either the lumbar spine or the hip is below normal.

Bisphosphonates should not be prescribed to fertile women considering future pregnancies.

Proton pumps inhibitors are not routinely indicated when corticosteroids are used without NSAID.

 

Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S. et al. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation. 2008; 5;118:667-71.

Marcolongo R, Russo R, Laveder F, Noventa F, Agostini C. Immunosoppressive therapy prevents recurrent pericarditis. J Am Coll Cardiol 1995; 26: 1276-9.

Man BL, Mok CC. Serositis related to systemic lupus erythematosus: prevalence and outcome. Lupus. 2005; 14: 822-6

M Imazio, A Brucato, R Trinchero, D Spodick and Y Adler. Individualized therapy for pericarditis. Expert Rev. Cardiovasc. Ther. 2009; 7 (8): 965-975.

 

THERAPY OF DIFFICULT RECURRENCES

Although recurrences are a common cause of concern for the fear of a possible evolution towards constriction, a recent analysis of all published cases with idiopathic recurrent pericarditis (the commonest form of recurrence) have shown no cases of constrictive pericarditis also after a long-term follow-up.

Then reassurance is important for these patients.

The treatment of these patients is not different to acute pericarditis. Aspirin and NSAID are mainstay, while corticosteroid use should be restricted as much as possible. Colchicine halves the recurrence rate.

 

ASA or NSAID are used according to the same schedule outlined above, at high dosages.

Adding COLCHICINE 0.5-1.2 mg/day is strongly recommended, if tolerated.

 

If the patients is treated only with ASA or NSAID and colchicine, a gradual tapering of ASA/NSAID is attempted, with each tapering done only when CRP is normal and symptoms are absent. In case of recurrence, prompt resumption of an higher dosages of ASA/NSAID is recommended, to avoid under treatment of the attack. In less severe cases ASA/NSAID might be given for 3-6 months, and colchicine for 6 months. Normally ASA/NSAID are stopped first, and colchicine later.

CORTICOSTEROIDS should not be used, but most of these patients are already on steroids. In these cases ASA/NSAID should be added at high dosages, plus colchicine at low dose (0.5-1.2 mg/day). Calcium and vitamin D should be added as soon as possible, and also bisphosphonates should be strongly considered, except in young fertile women. At this point the patient will be on a complex multidrug therapy, including: ASA or NSAID, colchicine, prednisone, a proton pump inhibitor, calcium and vitamin D, and possibly also a weekly bisphosphonate.

Tapering of drugs

The first drug to taper is the corticosteroid; this should be done quickly till the dosage of 30-25 mg/day of prednisone, and then very slowly, using protocol similar to those used by Rheumatologists in the treatment of Polymyalgia Reumatica.

Prednisone daily dose

Tapering

>50 mg

10 mg/day every 1 to 2 weeks

50-25 mg

5-10 mg/day every 1 to 2 weeks

25-15 mg

2.5 mg/day every 2 to 4 weeks

<15 mg

1.25 to 2.5 mg/day every 2 to 6 weeks

 A critical threshold for recurrences is often the dose of 10-15 mg/day of prednisone, and at this threshold very slow decrements as small as 1.25 to 2.5 mg at intervals of 2 to 6 weeks are useful. Each tapering should be done only with normal CRP and in the absence of symptoms. In case of recurrence every attempt should be done not to increase again the dosage of the corticosteroid, but to maintain the current dosage, that eventually might be split in two administrations (e.g. from 10 mg in the morning to 5 mg in the morning plus 5 mg in the evening, to better control the attack during the night hours) while increasing to the maximal dosages ASA or NSAID, well distributed every eight hours during the day, eventually given them intravenously and adding analgesics. Further tapering of steroids will be attempted e.g. one month later, in absence of symptoms and with normal CRP.

Steroid discontinuation might be done in 2-10 months. During this time ASA/NSAID are used, at low or high dosages according to the clinical condition (e.g rising the dosages during recurrences or in the days in which corticosteroids dose is reduced). After corticosteroid stable discontinuation ASA/NSAID dosages are gradually tapered , e.g. in 1-3 months, while maintaining colchicine.

The last drug to be stopped is colchicine. This can be accomplished in less severe cases in 6 months, but in complicated cases colchicine has been given for 1-2 years after the last attack. At that point colchicine discontinuation is discussed with the patient, explaining that cases of recurrences after colchicine discontinuation have been reported. Discontinuation is better done gradually, e.g. the daily dose is changed to every other day for 1 month, than twice a week for one month, then once a week for one month, and finally completely discontinuated.

We abitually use prednisone, but there are other corticosteroids.
 

Name                         equivalent-prednisone dose (mg)

Idrocortisone                          20       

Prednisone                             5

Metilprednisolone                  4

Deflazacort                            6-7.5

Flucortolone                           4

Betametasone                         0.6

Desametasone                        0.75

 

Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S. et al. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation. 2008; 5;118:667-71.

M. Imazio, A. Brucato, R. Trinchero, D. Spodick and Y. Adler. Individualized therapy for pericarditis. Expert Rev. Cardiovasc. Ther. 2009; 7(8);  965-975.

M. Imazio, DH. Spodick, A. Brucato, R. Trinchero, Y. Adler. Controversial Issues in the Management of Pericardial Diseases. Circulation 2010; 121;916-928

 

THERAPY OF REFRACTORY CASES

Refractory cases should probably not be considered cases that recur after steroid tapering (that is very common), but cases that require unacceptably high chronic dosages of corticosteroids to be controlled (e.g higher than prednisone 15-20 mg daily). In this condition several drugs have been employed (azathioprine, cyclophosphamide, cyclosporine, methotrexate, hydroxychloroquine, intravenous immunoglobulin, anakinra); azathioprine is the preferred choice if tolerated (at the common dosage of 2-3 mg/kg/die), but it should be acknowledged that evidence based data are lacking. The less toxic and less expensive drugs (e.g. azathioprine or methotrexate) should be preferred, tailoring the therapy on the single patient and the physician experience and , importantly, with the patient informed consent.

Brucato A, Brambilla G, Adler Y, Spodick D. Recurrent pericarditis: therapy of refractory cases. Eur Heart J 2005; 26(23):2600-1.

 

THERAPY IN PARTICULAR SETTINGS

IN CHILDREN

Dose adjustments are recommended for children.

NSAID

Ibuprofen Oral: 30-50 mg/kg/24 hours divided every 8 hours; start at lower end of dosing range and titrate upward (maximum: 2.4 g/day)

Indomethacin  Children ≥2 years: 1-2 mg/kg/day in 2-4 divided doses; maximum dose: 4 mg/kg/day; do not exceed 150-200 mg/day

Warnings: do not use aspirin in children and teenagers who have or who are recovering from chickenpox or flu symptoms (due to the association with Reye’s syndrome); when using aspirin, changes in behaviour (along with nausea and vomiting) may be early sign of Reye’s syndrome.

Precautions for treatment of Juvenile Rheumatoid Arthritis JRA in children (fatal hepatitis has been reported; monitor children closely; assess liver function periodically).

COLCHICINE:

It can be used, as in children in Familial Mediterranean Fever

CORTICOSTEROIDS.

If possible, avoid them. If necessary, the dose is 0.05-2 mg/kg/day divided 1-4 times/day.

Precautions: suppression of hypothalamus axis, suppression of linear growth (ie, reduction of growth velocity), reduction of bone mineral density, hypercorticism (Cushing's syndrome), hyperglycemia, or glucosuria may occur. Reduction in growth velocity may occur when corticosteroids are administered to pediatric patients by any route (monitor growth).

 

IN ASSOCIATION WITH ANTICOAGULANTS

There isn’t an encoded protocol. In patients with pericarditis in therapy with anticoagulant drugs we use ibuprofen or nimesulide or corticosteroids al low dosage.

 

PREGNANCY AND REPRODUCTIVE ISSUES

Pericardial involvement is sporadic during pregnancy, and pregnant women do not show any specific predisposition to pericardial diseases. The more common form of pericardial involvement is hydropericardium, usually as a benign mild effusion recorded in about 40% of pregnant women by the third trimester, followed by pericarditis as the more common disease requiring medical therapy.

The general management of acute pericarditis in pregnancy is not different from non-pregnant women, although specific precautions should be followed for specific diagnostic and therapeutic issues during pregnancy. All women planning a pregnancy should take folic acid supplementation, to decrease the risk of neural tube malformations. Therapy should be checked, to evaluate possible changes tailored to the future pregnancy. In particular colchicine is preferentially gradually stopped before conception, eventually substituted with aspirin and/or low-dose prednisone. Importantly, pregnancy should be planned in a phase of disease quiescence. Nowadays the general outcomes of pregnancies in these women can be similar to that expected in the general population when carefully followed by dedicated multidisciplinary teams.

We published the largest survey of pregnant women with pericarditis, including 6 cases. The adopted protocol of treatment includes aspirin at high dosages (1.5-3 g/daily), gradually stopped at 20 weeks of gestation, plus low dosages of prednisone if needed throughout all pregnancy and lactation, with very gradual tapering after delivery. Acetaminophen (paracetamol) is always allowed, both in pregnancy and during breast feeding.

NSAID including high dose aspirin are not teratogenic and can be continued during the first and second trimester. After gestational week 20, all NSAID (except aspirin at less than 100 mg/day) can cause constriction of the ductus arteriosus and impair fetal renal function and should be withdrawn in any case at gestational week 32. Diclofenac, flufenamic acid, ibuprofen, indomethacin, ketorolac, mefenamic acid, naproxen and piroxicam are compatible with breastfeeding, while aspirin at more than 100 mg/day should be used cautiously because of potential adverse effects in the infant. Prednisone, prednisolone and methyl prednisolone may be used during pregnancy, and breastfeeding is allowed with moderate doses of these steroids.

Colchicine is considered contraindicated during pregnancy and lactation, even if most women with Familial Mediterranean Fever (FMF) take this drug during pregnancy and lactation with no reported maternal side effects or harmful effects for fetuses and infants.

 

Concerning female and male infertility, our current knowledge suggests that even prolonged exposure to colchicine has no effects on male or female fertility. In women with FMF colchicine prevents abortions and inhibits peritoneal adhesions and secondary infertility .

Azoospermia is a possible rare adverse event reported in men (<1%), based upon a single case report from the early seventies, in which Merlin described azoospermia in a patient with gout after chronic colchicine treatment. On the other hand in 1961, Yu and Gutman reported their experience with colchicine prophylaxis in 208 men with gout over a mean period of 5 years, and none reported infertility. Similarly fertility and growth rate were not affected by colchicine during a long term follow-up in patients with FMF .

Bremner and Paulsen found no significant effects of colchicine on sperm count, plasma testosterone, luteinising hormone, and follicle stimulating hormone in healthy volunteers after 3-6 months of therapy. In addition, studies on sperm motility have shown that colchicine may affect this function only at high doses that cannot be reached in the clinical setting with recommended doses for pericarditis. On this basis a routine spermiogram is not recommended for every male patient taking colchicine.

Colchicine was found to be excreted in breast milk, but the relatively low concentration of colchicine in breast milk suggests that the amount ingested by the infant is small. Thus, nursing appears to be safe for lactating women with FMF who continue to take colchicine .

 

 

Brucato A, Imazio M, Curri S, Palmieri G, Trinchero R. Medical treatment of pericarditis during pregnancy. Int J Cardiol 2010; in press.

Østensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, Doria A et al. A. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8(3):209.

Ben-Chetrit E, Levy M. Reproductive system in familial Mediterranean fever: an overview. Ann Rheum Dis. 2003;62:916-919.

 

CONSTRICTIVE PERICARDITIS

Constrictive pericarditis is a rare but severely disabling consequence of the chronic inflammation of the pericardium, leading to an impaired filling of the ventricles and reduced ventricular function. Tuberculosis, mediastinal irradiation, and previous cardiac surgical procedures are frequent causes of the disease. Constrictive pericarditis is not a consequence of idiopathic recurrent pericarditis. Transient reversible cases of constrictive pericarditis have been reported in almost 10% of cases with effusive acute idiopathic pericarditis.

Commonly, there is a long delay, even decades, between the initial pericardial inflammation and the onset of constriction. Patients complain about fatigue, peripheral oedema, breathlessness, and abdominal swelling; venous congestion, hepatomegaly, pleural effusions, and ascites may occur.

Differential diagnosis has to include acute dilatation of the heart, pulmonary embolism, right ventricular infarction, pleural effusion, chronic obstructive lung diseases, restrictive cardiomyopathy and liver cirrhosis.

 

Maish B, Seferovic PM, Ristic AD et al. Guidelines on the diagnosis and management of pericardial disease. Eur Heart J 2004; 25: 1-28.

 

ROLE OF PERICARDIOTOMY AND PERICARDIECTOMY

The role of interventional and surgical techniques for the treatment of pericarditis is controversial, with the only exception of constrictive pericarditis.

The 2004 European Society of Cardiology guidelines recommended pericardiectomy for frequent highly symptomatic recurrence resistant to medical treatment. Unfortunately, a precise definition of resistance or treatment failure has not been published.

The only well-established indication for pericardiectomy is chronic persistent constrictive pericarditis. This approach requires the understanding that transient reversible cases of constrictive pericarditis have been reported in almost 10% of cases with effusive acute idiopathic pericarditis, and in patients with a new echocardiographic diagnosis of constrictive pericarditis.

Pericardiotomy can be obtained following a traditional surgical approach (creation of a pericardial window), by thoracoscopy or a percutaneous approach.

 

Haley JH, Tajik AJ, Danielson GK, Schaff HV, Mulvagh SL, Oh JK. Transient constrictive pericarditis: causes and natural history. J Am Coll. Cardiol. 2004; 43 (2): 271-75.

M. Imazio, DH. Spodick, A. Brucato, R. Trinchero, Y. Adler. Controversial Issues in the Management of Pericardial Diseases. Circulation 2010; 121;916-928

 

LONG TERM OUTCOME

Idiopathic recurrent pericarditis

Long term outcome is good for idiopathic recurrent pericarditis. After a systematic review of all publications on recurrent pericarditis from 1966 to 2006, we identified 8 major clinical series including a total number of 230 patients with idiopathic recurrent pericarditis (mean age 46 year, male/female ratio: 0.9).  After a mean follow-up of 61 months the following complication rate was calculated: cardiac tamponade in 3.5%, constrictive pericarditis and left ventricular dysfunction in 0.0%. The overall life prognosis is excellent in idiopathic recurrent pericarditis and complications are uncommon; constrictive pericarditis was never reported in spite of even numerous recurrences. Thus, it is important to reassure patients on their prognosis, explaining the nature of the disease, and the likely course. Therapeutic choices should take into account of the overall good outcome of these patients including less toxic agents.

Other pericardial diseases and constrictive pericarditis

The long term outcome of other form of pericardial diseases, such as chronic effusions, incessant pericarditis and constrictive pericarditis is not well known, and strongly influenced by the cause and the clinical setting.

Concerning constrictive pericarditis, timing of surgery is important. In the absence of evidence that the condition is chronic (e.g., cachexia, atrial fibrillation, hepatic dysfunction, or pericardial calcification), patients with newly diagnosed constrictive pericarditis who are hemodynamically stable may be given a trial of conservative management for 2–3 months before recommending pericardiectomy. On the other hand surgery should be performed before chronic or irreversible damage occurred. Pericardiectomy should be performed by surgeons with considerable experience with this procedure, which may require referral to a center with a special interest in pericardial disease.

Long-term survival after pericardiectomy is inferior to that of an age-matched and sex-matched population. In the Mayo Clinic series, the 5-year and 10-year survival was 78 and 57%, respectively. Idiopathic constrictive pericarditis had the best prognosis (7-year survival 88%) followed by postsurgical and postradiation constriction .

 

Brucato, G. Brambilla, A. Moreo et al. Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol 2006;98: 267-71.

Imazio M., Brucato A., Adler Y.et al. Prognosis of idiopathic recurrent pericarditis as determined from previously published reports Am J Cardiol 2007; 100: 1026-1028

 

 

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