Scholarly article on topic 'Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach'

Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach Academic research paper on "Clinical medicine"

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{"Acute pericarditis" / "Recurrent pericarditis" / "Pericardial constriction" / "Pericardial effusion" / Prognosis}

Abstract of research paper on Clinical medicine, author of scientific article — George Lazaros, Massimo Imazio, Antonio Brucato, Dimitrios Tousoulis

Abstract Pericardial disorders constitute a relatively common cause of heart disease. Although acute pericarditis, especially the idiopathic forms that are the most prevalent, is considered a benign disease overall, its short- and long-term complications, namely, recurrent pericarditis, cardiac tamponade and constrictive pericarditis, constitute a matter of concern in the medical community. In recent years, several clinical trials contributed to redefining our traditional approach to pericardial diseases. In this review, we provide the most recent evidence concerning diagnosis, treatment modalities and short- and long-term prognosis of the most common pericardial disorders.

Academic research paper on topic "Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach"

Accepted Manuscript

Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach George Lazaros, MD FESC, Massimo Imazio, Antonio Brucato, Dimitrios Tousoulis

PII: S1109-9666(16)30305-0

DOI: 10.1016/j.hjc.2016.11.024

Reference: HJC 86

To appear in: Hellenic Journal of Cardiology

Received Date: 9 August 2015 Accepted Date: 28 April 2016

Please cite this article as: Lazaros G, Imazio M, Brucato A, Tousoulis D, Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach, Hellenic Journal of Cardiology (2016), doi: 10.1016/ j.hjc.2016.11.024.

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Untying the Gordian Knot of Pericardial Diseases. A Pragmatic Approach

GEORGE LAZAROS1, MASSIMO IMAZIO2, ANTONIO BRUCATO3, DIMITRIOS TOUSOULIS1

1Cardiology Department, University of Athens Medical School, Hippokration General Hospital, Athens, Greece, Cardiology Department, Maria Vittoria Hospital and Department of Public Health and Pediatrics, University of Torino, Torino, Italy, Internal Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

Address for correspondence:

George Lazaros, MD FESC

First Cardiology Department,

University of Athens, Hippokration Hospital

114 Vas. Sofias Ave., 115 27 Athens, Greece

Tel: +30 2132088099

Fax: +30 2132088676

E-mail: glaz3 5 @hotmail. com

Abstract

Pericardial disorders constitute a relatively common cause of heart disease. Although acute pericarditis, and especially the idiopathic forms which are the most prevalent, is considered a benign disease overall, it's short and long term complications, namely recurrent pericarditis, cardiac tamponade and constrictive pericarditis constitute a matter of concern in the medical community. In recent years several clinical trials contributed to redefine our traditional approach to pericardial diseases. In this review we provide the most recent evidence concerning diagnosis, treatment modalities and short and long-term prognosis of the most common pericardial disorders.

Key words: Pericardial diseases, acute pericarditis, recurrent pericarditis, pericardial constriction, pericardial effusion, prognosis

Pericardial diseases encompasse a wide spectrum of clinical conditions

ranging from benign and self-limiting forms to life-threatening conditions. , From a practical point of view the main pericardial syndromes include acute and recurrent pericarditis either idiopathic or secondary with or without concomitant pericardial effusion, chronic constrictive pericarditis and isolated pericardial effusion without evidence of ongoing pericardial inflammation.

In recent years, several clinical trials focused on pericardial diseases, enhanced our knowledge in this context and contributed to the development of effective and safe treatments, thus redefining several aspects of our traditional view of pericardial diseases. The present review aims to emphasize on the most important advances in the field of pericardiology and to provide helpful 'tips and tricks' for an efficacious evidenced-based approach of the main pericardial syndromes.

1. Acute pericarditis

The lack of well-established criteria for the diagnosis of acute pericarditis turned out as an important confounding factor in the recent past, causing important methodological divergences between investigations. Unfortunately, the absence of a pathognomonic marker, such as troponins for myocardial necrosis, accounts for this inconvenient. In recent years however, an expert consensus on the diagnosis of acute pericarditis has contributed to overcoming this inconvenience.4 Indeed, acute pericarditis is considered when 2 out of the following criteria are fulfilled: i. retrosternal chest pain sharing several features with ischemic pain which however, worsens in supine position, deep inspiration, cough, swallowing etc., and it is relieved in the upright position and by leaning forward ii. Pericardial friction rub which is pathognomonic for pericarditis but it is unfortunately present in one-third of patients5,

iii. Typical electrocardiographic features with evolution in four stages in 60% of cases (namely diffuse concave ST segment elevation with concomitant PR depression in the first stage, return to baseline of the latter deviations and T wave flattening in the second stage, diffuse T-wave inversion in the third stage, and electrocardiographic normalization in the fourth stage) and iv. New-appearing or worsening pericardial effusion which is observed in 60% of cases (80% mild, and 10% either moderate or large). In the above-mentioned main diagnostic criteria 2 more variables have been additionally included, this time as supportive findings. The first is CRP elevation which however, apart from being found normal in in ~22% of cases at presentation , has the additional limitation of low overall specificity. The second is thickening and late gadolinium enhancement at the pericardial level in the cardiac MRI (cMR), which

is indicative of pericardial inflammation. , , It is stressed that both MRI and computed tomography are considered as a second line option in the diagnostic work-up process of pericardial diseases, and should be performed when the rest of the findings are inconclusive.2

The causes of acute pericarditis include infectious and non-infectious forms and are summarized in

Table 1.4 With

respect to the diagnostic approach, local epidemiology should be always taken into account. For example tuberculous pericarditis which is a rare condition in the Western word, it is the most common cause of acute pericarditis (~70-80%) in the sub-Saharan Africa.4 Identification of the causative infective agent in viral forms is not necessary in every day practice since it does not add any therapeutic or prognostic information.10 Although troponins do not seem to have a prognostic impact on acute pericarditis they should be evaluated to exclude myopericarditis.4

Hospitalization in acute pericarditis should be restricted only to high risk patients (high risk of non-viral, non-idiopathic etiology and complications during follow-up), who should be investigated and treated accordingly. Major criteria validated by multivariate analysis include large pericardial effusion (>2cm in diastole) with or without tamponade, fever >38oC, subtle presentation over the course of several days, and lack of responsiveness to the non-steroidal anti-inflammatory treatment within 1 week of therapy.4 Minor clinical poor prognostic criteria include myopericarditis, immunodepression, traumatic pericarditis and oral anticoagulant therapy. Patients with one or more of the above mentioned criteria should be hospitalized and subjected to an extensive etiologic search.4

Restriction of physical activity should be recommended in all patients with acute pericarditis. However, this recommendation applies till complete clinical remission along with CRP normalization. Competitive sports are allowed at least 3 months after the index episode.11

As far as medical treatment is concerned the combination of aspirin-NSAIDs

with colchicine 0.5mg twice daily (or 0.5mg once daily if <70Kg) for 3 months is the

2,11,12

mainstay approach. , , Aspirin and ibuprofen are the medications most frequently administered worldwide. Although they are highly effective in controlling symptoms, both of them do not seem to affect the natural history and complication rates of acute pericarditis.1 Particular attention should be paid in using the highest tolerable doses of each medication and reassure a continuous anti-inflammatory coverage throughout the day (e.g. each dose given every 8 hours for ibuprofen and aspirin).11 The optimal treatment length and the need for dose tapering have not been tested in clinical trials and similarly, no head to head comparisons between anti-inflammatory agents have been performed. However, it is well-established that the full-dose regimen should be

offered at least until normalization of CRP values. Thus, CRP monitoring is extremely helpful in individualizing the duration of treatment. Although of doubtful benefit

several experts recommend dose tapering of NSAIDs after initial clinical remission

and CRP normalization. , However, dose tapering should respect drug pharmacokinetics and offer antiinflammatory protection throughout the day.11 Details about are the treatment schedule in acute pericarditis are depicted in Table 2.11

Colchicine should be administered in every case of acute pericarditis (unless contraindicated) since it is the only medication which has dramatically reduced (halved) the rate of recurrences. To overcome potential problems with patients' compliance and/or drug withdrawal, dose adjustment should be performed according

to age, body weight and renal function (Table 2).

Corticosteroids is a second-line treatment option in patients with acute pericarditis. It seems that a dose between 0.2 and 0.5 mg/kg/die of prednisone (or equivalent dose of an alternative agent) outmatches the dose of 1-1.5mg/kg/die which

is recommended in guidelines, regarding both safety and efficacy. , The main problem associated with steroids administration in pericarditis concerns the higher rate of recurrences, probably caused by the enhanced viral replication due to immunosuppression. Despite this indisputable fact, steroid use should not be 'demonized' since it is a valuable treatment option in several conditions. Rephrasing Abraham Lincoln's saying 'the problem with steroids relates not to the use of a bad thing but to the abuse of a good thing'. Actually, steroids should be used when aspirin/NSAIDs are ineffective after at least 1 week of treatment, provided that the highest tolerable dose has been prescribed, in cases of true allergy of intolerance to the latter medications, in secondary (specific) cases where steroids constitute the recommended treatment (e.g. systemic inflammatory diseases), in advanced kidney

disease, in pregnant women beyond the 20th week of gestation, and probably in cases with intense inflammation and/or concomitant pleuro-pericardial involvement (e.g. post-pericardiotomy syndrome).1,4,5,11 A gradual tapering of corticosteroids is essential, with each reduction made only in absence of symptoms and after CRP normalization, particularly for dosages of prednisone lower than 10-15 mg daily.4

Last but not least, gastroprotection should be provided to all patients under aspirin-NSAIDs treatment and vitamin D, calcium and diphosphonates should be administered when >5-7.5mg of prednisone are prescribed to premenopausal women and men age >50 years for >3 months.4,5,11,14

Prognosis of acute pericarditis is excellent in the idiopathic forms with serious complications being uncommon (tamponade 1.2% and permanent constriction~0.5% in a 60-month follow-up period).15 The rate of recurrence is 15-30% depending to the colchicine use and the great majority of recurrences are expected within 18-20 weeks.1,12,16 Myocardial involvement (myopericarditis) do not seem to affect long-term prognosis, whereas cases of perimyocarditis (prevalent myocardial involvement, with affected contractility and regional wall motion abnormalities) should be probably regarded and treated in the same way with pure myocarditis treatment.4 The most severe complication of acute pericarditis is cardiac tamponade. Timely recognition and treatment of tamponade is of paramount importance since hemodynamic collapse can lead rapidly to death. Recently, the European Society of cardiology proposed a

scoring system which aims to affect the decision of timing of pericardial drainage. The above-mentioned score-system takes into account several parameters including etiology, clinical presentation and imaging and offers information about the indication of immediate or urgent need for drainage (either percutaneous or surgical), or about

the possibility to schedule the procedure safely in an elective basis and transfer patients to a specialized institution.

2. Recurrent pericarditis

Recurrent pericarditis is the most problematic complication of acute pericarditis due to its detrimental impact on patients' quality of life. In the era of colchicine the rate of recurrences has been dramatically reduced to approximately 17%, at least in idiopathic forms.12,16 Patients with a first recurrence have an even higher percentage of a second one (up to50%) and about a half of cases exhibit 1-2 recurrences (although individual cases with many recurrences have been reported).1,2,16,18

Mechanisms involved on pericarditis recurrences classically include infections (exacerbations of the initial one or reinfections), inadequate initial full dose regimen or too rapid drug tapering, or autoimmunity which is believed to account for 2/3 o cases.16,19-21 A novel piece of research however, has been recently added another possible mechanism involved in relapses appearance, namely autoinflammation.19,21 Autoinflammatory diseases include those genetic disorders characterized by primary dysfunction of the innate immune system. They appear with recurrent episodes of serosal inflammation, leukocytosis, and familial occurrence. Examples are Familial Mediterranean Fever and the tumor-necrosis factor receptor-1-associated periodic

syndrome (TRAPS) which in a relevant investigation accounted for 6% of recurrent

idiopathic pericarditis cases. Autoinflammatory disorders should be considered in cases of early onset of the disease, positive family history for pericarditis, late

relapses (>18-20monts), and most importantly failure of colchicine therapy and need

for immunosuppression to control the disease.

Diagnostic work-up in recurrent cases is reasonable to be more extensive and include second option tests and diagnostic pathways, in an effort to unveil secondary and potentially treatable secondary conditions. It is emphasized that idiopathic recurrent pericarditis is not necessarily a life-time diagnosis and patients should be periodically reassessed for clinical and laboratory markers of secondary forms. In a relevant investigation with long-term follow up a secondary form emerged in ~10% of

cases, mainly a connective tissue disease.

As already described for acute pericarditis the treatment options in recurrent forms include aspirin-NSAIDs, colchicine and corticosteroids and the overall management should be tailored in an individualized fashion.1,3,4,24 Although the dose regimens are largely the same in acute and recurrent pericarditis, the treatment length should be more extended (perhaps doubled) in the latter, at least according to some

experts. , CRP serum levels should be monitored in order to access treatment efficacy and schedule dose tapering and treatment length.4 (Table 2).

Colchicine is the mainstay treatment in recurrent pericarditis. Its safety and

effectiveness in this setting has been tested in several clinical trials including CORE,

CORP and CORP-2. Colchicine was proved effective (and safe) in the whole

spectrum of recurrent pericarditis, such as first recurrence (CORE-CORP)26,27 and

multiple recurrences (CORP-2)28. Thus, colchicine use has a class I indication in recurrent pericarditis, where the administration of 0.5mg bid (or adjusted regimen where required), halves the percentage of first or subsequent recurrences. Steroids administered at the lower effective dosages constitute a valid treatment option in all clinical scenarios already described for acute pericarditis. Dose tapering should be very slow at the critical threshold for the individual patient for recurrences. In case of symptoms recurrence during steroid tapering, administration of aspirin or NSAIDs is

recommended in an effort to avoid an increase of steroids dose which leads to vicious circles.4

In recent years the term refractory idiopathic recurrent pericarditis (or colchicine-resistant steroid-dependent pericarditis) has been introduced in clinical practice to describe hard-to-control cases with multiple recurrences that require high doses of corticosteroids (namely prednisone >15mg daily or equivalent) for long periods to be controlled.4 True refractory pericarditis accounts for approximately 5% of recurrent cases.5 Referral of these difficult-to-treat patients to specialized centers for evaluation and treatment is strongly encouraged. According to the best available evidence, treatment options in true refractory recurrent pericarditis include the following options. The first one consists of combined triple therapy including corticosteroids, colchicine and aspirin or NSAIDs. Aspirin-NSAIDs should be preferably added when recurrence appears, or earlier when the dose threshold of steroids for relapses is being reached.4 In patients receiving steroids/NSAIDs to control symptoms, whether steroids or NSAIDs should be withdrawn first, should be considered in an individual basis taking into account patients' tolerance and overall profile. Nevertheless, any drug dose tapering or discontinuation should be preceded by CRP normalization.

Alternative to the above mentioned treatments include classic immunosuppressant (mainly azathioprine), anakinra, and intravenous immunoglobulins. Since all the above options are off-label and adverse effects are a serious matter of concern, all potential candidates should be informed in detail and an inform-consent is mandatory. Azathioprine is the most widely used agent over time in this context. Data on his efficacy are available from a retrospective study including 40

cases. The dose administered was 1.5-2.5mg/kg/day (mean 2.12mg) and the mean

time period on treatment was ~14 months (Table 2). The medication turned out both safe and effective in reducing the number of recurrences. Most importantly, in a considerable proportion of patients (~60%), it caused sustained remission of the disease after discontinuation of steroids. It should be stressed that azathioprine has a delayed onset of action (>1.5 month) and thus they are not suitable for the treatment of the acute attack.

Anakinra is another treatment option recently introduced in the medical armamentarium for recurrent pericarditis. It is an interleukin-1 antagonist administered at a daily dose of 100mg in adults which is delivered through a

subcutaneous injection for at least 6-12 months. - In a recent systematic review of all published cases anakinra turned-out as a safe and highly effective steroid sparing

agent. The drug allowed an immediate clinical remission with CRP normalization within few days. During the full-dose regimen no cases of symptoms recurrence have been reported. However, after drug discontinuation recurrences appear early (within few weeks), at a rate of ~75%. Gradual tapering according to preliminary

observations seems to lower the rate of recurrences.

Finally, according to a recent systematic review, intravenous immunoglobulins administered at a daily dose of dose 400-500 mg/kg for 5 consecutive days constitute a well-tolerated, rapidly acting, and effective steroid-sparing option in refractory recurrent pericarditis.34

We wish to stress that the above mentioned off-label alternatives to conventional treatment are not based on solid evidence and treatment choices should depend on local expertise and availability. Pericardiectomy nowadays is rarely required and should be regarded as the last resort in refractory pericarditis cases presenting with recurrent tamponade, and in patients unable to tolerate the

aforementioned conventional treatment. In centers of excellence the perioperative

mortality and major morbidity and are very low (0 and 3% respectively).

The prognosis of recurrent pericarditis is excellent in idiopathic forms, while in secondary ones the underlying condition mainly affects the long-term outcome.4,36 In a systematic review of all publications including 230 patients with a follow-up of ~60 months, the rate of tamponade was 3.5% (occurring mostly during the initial attack), whereas cases of constrictive pericarditis and left ventricular dysfunction

were never reported.

Beyond efficacious treatment, the primary goal for health physicians dealing with pericardial diseases should be the prevention of recurrences rather than their treatment. In this context, the inappropriate use of medical therapies may account at least in a subset of cases for disease recurrence. For instance the early (and unjustified) use of steroids may facilitate viral replication and disease recurrence. Moreover, fast tapering or discontinuation of anti-inflammatory therapy, before complete symptoms remission and CRP normalization, as well as colchicine non-use are associated with recurrent disease.4 Additional research is urgently required so as to identify those patients prone to recurrences and to clarify the mechanisms leading

to disease recurrence.

3. Constrictive pericarditis

Constrictive pericarditis along with pericardial tamponade and recurrent pericarditis constitute the most common complications of pericarditis.15 The appearance of pericardial constriction is rather rare in acute idiopathic pericarditis and exceptional as already mentioned in recurrent pericarditis. However, in tuberculosis endemic areas constrictive pericarditis is a major health care problem with high

morbidity and mortality.4,15 Thus, awareness of the local epidemiology is very important in suspecting, investigating and diagnosing the disease.

Concerning the diagnostic work-up in constrictive pericarditis nowadays echocardiography with the application of novel echocardiographic techniques (including tissue Doppler imaging and speckle tracking), computed tomography and cardiac MRI (cMR) with gadolinium have improved diagnostic accuracy and allowed the diagnosis of the disease at earlier stages, before myocardial involvement which negatively affects patients outcome. In particular, cMR with cine imaging highlights in an excellent way the interventricular interdependence observed in constriction pericarditis through the pathological motion (bounce) of the interventricular septum. Most importantly, with the use of modern imaging modalities, the use of cardiac catheterization which is classically considered the gold-standard for the diagnosis of pericardial constriction may be sometimes omitted. In the recently published echocardiographic criteria for the diagnosis of constrictive pericarditis by the Mayo Clinic group, cardiac catheterization was not considered a prerequisite for the final

diagnosis and it has been performed only in 48% of patients before operation. It should be emphasized that increased pericardial thickness that has been traditionally considered an essential finding to diagnose constrictive pericarditis, it is not observed in 18% of surgically proven cases.40

Constrictive pericarditis has been traditionally considered a condition requiring surgical management and total pericardiectomy is the recommended treatment option.4,41 Patients candidates for surgical treatment are those needing chronic diuretic therapy, increasing jugular venous pressure, evidence of hepatic

impairment and reduced exercise tolerance. , On the contrary, surgical treatment is not indicated in early asymptomatic constriction, and in advanced stages with

myocardial fibrosis and severe functional impairment (NYHA class IV). The operative mortality in the latter cases is quite prohibitive (30-40% as compared with 6-19% in a lower NYHA class).2,42

In recent years the term transient constriction has been introduced in clinical practice by Sagrista-Sauleda et al. to describe a transitory constriction physiology observed in 9% of patients with acute effusive pericarditis during the resolution phase of the effusion.43 In the authors experience constriction in such cases regressed within a mean time of 2.7 months.

In a subsequent review published by the Mayo Clinic group, the rate of transient constriction in 212 patients first presenting with echocardiographic findings of constrictive pericarditis was 17%.44 The average time elapsed between initial diagnosis and resolution of the disorder in this database was 8.3 weeks. Interestingly, no transitory forms were observed in patients with constrictive pericarditis following radiation therapy. Patients with reversible constriction were treated with various medication regimens (mainly NSAIDS and steroids), whereas spontaneous haemodynamics normalization was observed in 14% of cases.

To summarize the new important concept which arose from the above observations is that in hemodynamically stable patients who present for the first time with features suggesting constrictive pericarditis, a trial of anti-inflammatory treatment (probably of 2-3 months duration), may be offered before referral for total pericardiectomy.4

The role of imaging in predicting transient vs. permanent forms of constriction is very important. Baseline late gadolinium enhancement (LGE) pericardial thickness >3mm (sensitivity 86% and specificity 80%) and qualitative LGE intensity (moderate or severe in 93% of transient forms and 33% in permanent, p=0.002) emerged as the

most powerful parameters for the prediction of transient forms.45 In addition, higher baseline CRP values were able to differentiate transient from permanent forms (59±52 versus 12±14 mg/L, p= 0.04).45

4. Chronic idiopathic pericardial effusion

This section deals with the incidental finding of pericardial effusion in either symptomatic or asymptomatic patients in the absence of clinical and laboratory findings (mainly CRP elevation) suggesting acute pericarditis.

It is implied than even in the absence of evidence of a specific cause, a detailed medical history, clinical examination as well as a group of blood tests possibly including screening for common causes of pericardial effusion (such as thyroid and kidney function tests and screening for connective tissue diseases), should be undertaken in an effort to establish a secondary condition, especially for moderate and large effusions.4

Pericardial effusion is defined chronic if persists more than 3-month time

period. , In the presence of chronic pericardial effusion it is reasonable for the treating physician to express concerns with respect to evolution of the disorder towards cardiac tamponade and hemodynamic collapse. In this context, the amount of pericardial effusion may have a predictive role. Indeed, small pericardial effusions have been traditionally regarded as a benign condition, and as such, not requiring specific treatment and close follow-up.4 Concerns about the latter approach were raised by a recent publication where even small sized pericardial effusions (<1cm in diastole) were found to be independently associated with mortality, even after adjustment for several possible confounders.46 Although the above-mentioned (and unexpected results) need confirmation in future trials, the latter study had a substantial

contribution in the assessment of the progression (or regression) of small-sized pericardial effusion. During a mean follow up of 2.3±1.9 years, 60% of effusions resolved, 28% remained unchanged and 5% increased, although no case of tamponade was recorded.46

In case of moderate pericardial effusion (sized>1cm and <2cm in diastole) the index of suspicion of an underlying condition should be high since approximately 60% of cases with moderate to large effusions are associated with secondary conditions.4 Pericardiocentesis, if technically feasible, should be deserved to symptomatic patients or when a neoplastic or bacterial etiology (including

tuberculosis) are suspected.

In the presence of large pericardial effusion with hemodynamic impairment pericardicentesis is a mandatory procedure to prevent circulatory collapse.4 Notably, when cardiac tamponade occur in the absence of inflammatory markers the possibility of neoplastic disease is very likely.4 In the absence of cardiac tamponade, the indications of pericardiocentesis are the same with those above reported for moderate effusions. According to some authorities any large chronic idiopathic pericardial effusion, in particular if right chambers collapse is present, should be treated with pericardiocentesis since approximately 1/3 of cases may progress to cardiac tamponade in the long term either unexpectedly, or in the context of acute pericarditis,

chest trauma etc.

Finally, in the absence of ongoing inflammation (i.e. elevated CRP) conservative treatment of chronic idiopathic effusions of any size with medical therapy (including aspirin-NSAIDs, colchicine and/or steroids) is not effective.4 In Figure 1 the recommended approach of patients with chronic pericardial effusion is

provided with respect to the presence or absence of inflammation and to the effusion site.

Conclusions

In recent years several trials have changed our traditional clinical practice in the field of pericardial diseases, concerning diagnostic work-up and medical therapy. It is important for physicians to become familiar with the current trends so as to treat their patients successfully according to the best available evidence. Although several pieces of the puzzle of pericardial disorders are still missing, ongoing clinical and basic research are expected to provide the rest of information needed to untie the Gordian knot of pericardial diseases.

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Figure legend

Figure 1. Recommended triage of patients with pericardial effusion. The intersecting part of the 3 cycles corresponds to cases with CRP elevation which should be treated according to the recommendations provided for acute pericarditis. In the free parts of the cycles are included cases pericardial effusion cases without CRP elevation. In the latter cases the management depends on the degree (small, moderate and large) of pericardial effusion.

Table 1. Most common causes of acute pericarditis

Infectious (2/3 of cases) Non-infectious (1/3 of cases)

Viral (most viral forms are labeled as idiopathic since it is often difficult and technically demanding to unveil un underlying viral infection) Autoimmune (including systemic autoimmune, autoinflammatory diseases and pericardial injury syndromes

Bacterial (tuberculous in 4%-5% of cases) Neoplastic

Fungal or parasitic (extremely rare) Metabolic

Traumatic

Drug related (rare)

Table 2. Empiric treatment schedule in acute and recurrent pericarditis

Drug Recommended attack dose Treatment length with attack dose Tapering

Aspirin 750-1000mg tid (range 1.5- 4 g/daily) Till symptoms and CRP normalization Each week when CRP is normalized (i.e. 1000mg tid for 1 week, 750mg tid for 1 week then 500mg tid for 1 week)

Ibuprofen 600mg tid (range 1.2-3.2g/daily) Till symptoms and CRP normalization Each week when CRP is normalized (i.e. 600-400-600mg/day for 1 week, 400-400-600mg/day for 1 week, then 400mg tid for 1 week)

Indomethacin 25-50mg tid Till symptoms and CRP normalization Each week when CRP is normalized (i.e. 50-25-50mg/day for 1 week, 25-25-50mg/day for 1 week, then 25mg tid for 1 week)

Colchicine Attack dose not necessary. 0.5mg bid (0.5 mg/day if <70 kg or intolerance, age >70years. Dose adjustment in reduced creatinine clearance) First attack: 3 months, recurrence: at least 6 months May be required in recurrent forms according to some authorities

Prednisone 0.2-0.5 mg/kg/day (or equivalent dose of another corticosteroid) Till symptoms and CRP normalization Tapering when CRP is normalized. Slow tapering at the threshold for the individual patient for recurrences

Anakinra 1-2 mg/kg, up to100mg sc daily To be established. Long-term administration (6-12 months) is usually required. Recommended by most authorities

Azathiorpine 1.5-2.5mg/kg/day Depends on the individual patient. Usually >1year Not recommended

Intravenous immunoglobulins 400-500 mg/kg/day 5 consecutive days Repeated cycles may be required according to the clinical response

CRP=C-reactive protein, bid=twice a day, tid= three times a day, sc=subcutaneously

SMALL EFFUSIONS (<lcm) Periodical follow-up

CRP ELEVATION: Treat as acute pericarditis

MODERATE EFFUSIONS

(>lcm aud <2cm) Search for specific diaguoses (uoii idiopathic causes account for -60% of cases)

LARGE EFFUSIONS Ç 2cm) Pericardiceatesis in cases of:

i. Tamponade, i. Suspicion of bacterial or

neoplastic etiology, iii. Chronic large effusion without tamponade with right chambers collapse