Author: Massimo Imazio, Cardiology Department, Maria Vittoria Hospital and Department of Public Health and Pediatrics, University of Torino
30-year-old woman (66 kg) with recurrent pericarditis on corticosteroids (prednisone 25mg/day plus colchicine 0.5mg BID).First episode of acute pericarditis 4 years ago (chest pain, mild pericardial effusion and elevation of CRP); aetiological diagnostic work-up was negative (idiopathic).First Tx: ibuprofen 600mg BID.First recurrence within 6 months treated by prednisone 50mg with good initial response and planned tapering within 4 weeks.Recurrences at each attempt to reduce prednisone under 15-25mg/day.Now referred as second opinion to manage the therapy.Current tx: prednisone 25mg/day plus colchicine 0.5 mg BID.
Question 1: How would you confirm the diagnosis of recurrence?
1. Recurrent pain is sufficient to make the diagnosis in a patient with previous pericarditis, especially if the patient is able to recognize the same “chest pain”.2. Recurrent pain is not sufficient and recurrent pericardial effusion is mandatory.3. Recurrent pain is not sufficient and objective evidence of pericarditis is needed (e.g. elevation of C-reactive protein).4. There are no specific criteria and clinical judgement is essential.
Answer 3 is the most suitable, even though there is not a completely right reply.We should introduce specific criteria according to 2015 ESC guidelines to be more accurate.
CMR = cardiac magnetic resonance; CT = computed tomography; ECG = electrocardiogram.aUsually within 18-24 months but a precise upper limit of time has not been established.
Circulation 2007;115:2739–2744. - N Engl J Med 2013;369:1522–1528.Lancet 2014;S0140–6736: 62709–9. - JAMA 2014;312:1016–1023 J Am Soc Echocardiogr 2013;26:965–1012.e15 - Eur Heart J Cardiovasc Imaging 2014;16:12–31
Overweight (BMI 26kg/m2) with abdominal “strie rubre” related to prolonged corticosteroid therapy.Pericarditic chest pain (7/10) similar to previous “pericarditic chest pain”.ECG: non-specific ST/T changes.Echocardiogram: mild pericardial effusion.Elevation of WBC count and CRP.
1. Increase the dose of prednisone to 1mg/kg/day.2. Add a NSAID and fast tapering of prednisone is warratend as soon as the symptoms are controlled .3. Add a NSAID and try to manage the recurrence without increasing the dose of prednisone, then slow tapering of prednisone is warranted.4. Try a new therapy resorting to alternative immunosuppressive therapy.
New ESC guidelines favors the option 3.
CRP = C-reactive protein; ECG = electrocardiogram; NSAIDs = non-steroid anti-inflammatory drugs.
Tx = treatment. aTapering should be considered for aspirin and NSAIDs.bLonger tapering times for more difficult, resistant cases may be considered.
a. Avoid higher doses except for special cases, and only for a few days, with rapid tapering to 25 mg/day. Prednisone 25 mg is equivalent to methylprednisolone 20 mg.b. Every decrease in prednisone dose should be done only if the patientis asymptomatic and C-reactiveprotein is normal, particularly for doses <25 mg/day.
Corticosteroid is mantained at 25 mg/day.Colchicine is maintained as 0.5mg BID since tolerated but 0.5mg may be enough (see 2015 ESC guidelines).Ibuprofen is prescribed as 600mg TID as attack dose for 10 days then tapered. A gastroprotection is prescribed with a proton pump inhibitor.A subsequent tapering is suggested reducing prednisone to 2.5mg every 2 weeks after remission of the recurrence attack.
Ibuprofen is not tolerated and withdrawn with worsening symptoms.An attempt with aspirin also fails because of gastrointestinal intolerance.Indomethacin is not tolerated because of severe headache, dizziness and epigastric pain.
1. Increase the dose of prednisone to 1mg/kg/day.2. Consider azathioprine.3. Prescribe intravenous immunoglobulins.4. Prescribe anakinra 100mg day sc.5. Consultation for pericardiectomy.
Option 1 is not correct according to ESC guidelines. 2,3 and 4 are possible options according to local practice and expertise (we used anakinra). They should be discussed as therapeutic option for refractory recurrent pericarditis.
In this case we treated the patient with anakinra 100mg sc for 6 months with good control of symptoms and subsequent fast tapering of corticosteroids within 1 month.Colchicine was mantained for 6 months.No recurrences occurred after anakinra withdrawal.
Refractory recurrent pericarditis is a troublesome condition, usually immune-mediated but without a well-established classical “rheumatological diagnosis”.Inadequate tx of acute and recurrent pericarditis is a main cause of incessant or recurrent course in clinical practice.Aspirin or NSAID plus colchicine comes first.Avoid corticosteroids and use low to moderate doses if needed; slow tapering is critical.Consider triple tx for more difficult cases (ASA/NSAID plus colchicine plus low-moderate dose of corticosteroids).If true resistance to triple tx consider new therapeutic options: azathioprine, IVIG, anakinra and pericardiectomy as last option.
The patient was admitted to our hospital to obtain diagnostic endomyocardial biopsy (EMB). As inpatient he agreed to undergo CMRI, which showed findings compatible with previous myocarditis, preserved biventricular function, intramural LGE (mid septal), epicardial LGE (mid septal inferior); oedema sequences (T2) were not diagnostic. TnI was constantly abnormal (4-5 microg/L, normal 0.00-0.045), complement fractions (C3,C4) and reactive C protein (RCP) were normal.Coronary flow reserve on the anterior descending coronary artery by 2 D echo-adenosine was normal. While in hospital on telemetric monitoring he developed haemodinamically stable sustained VT (figure 1), which responded to amiodarone I.V. bolus and was switched from atenolol to sotalol 80m mg tid.
Right catheterization showed normal pulmonary pressures (PA mean 11 mmHg, mean wedge 7 mmHg), normal cardiac index (3.65 ml/min/m2); EMB was performed from the right ventricle (4 samples) without complications. EMB diagnosis was of infection-negative (autoimmune) lymphocytic myocarditis (Figure 2).
ICD was not implanted in keeping with the ESC 2015 guidelines (11) and with the 2013 Myocarditis Position statement (8) and sotalol 80 mg tid was kept as anti-arrhythmic treatment. However, a Loop recorder was implanted to monitor the patient arrhythmogenic burden and its response during immunosuppression therapy. Immunosuppression therapy included prednisone 1 mg/kg/d with subsequent taper and Azathioprine 2 mg/Kg/d. After 2 months of immunosuppression TnI high sensitivity was markedly reduced to 0,47 microg/L (normal 0,00-0,045). 24 hour ECG Holter monitoring showed reduced arrhythmia: sinus rhythm, mean HR 66 (44-107), 1618 VEBs, 34 couplets, no NSVT. On 2D-Echo: LVEF was 60%. After 15 months of immunosuppression during tapering, ECG Holter monitoring showed a reactivation of arrhythmias: SR, mean HR 65 (44-105), 52 77 VEBs, 71 couplets, 6 NSVT longest 6 beats, 193 bpm. On 2D- Echo: LVEF was 64%. TnI was negative. Therefore tapering was stopped (the patient was at this time off steroids and treated only with azathioprine). After 36 months on immunosuppression TnI was negative, loop recorder revealed no arrhythmia; 2D-Echo showed LVEF of 64%. Azathioprine was tapered and stopped in the following 2 months. At last follow-up in December 2015, after 14 months off azathioprine, TnI is negative, there are no arrhythmias by loop recorder and 2D- Echo is normal, with LVEF of 64%. He is still on sotalol 80 mg tid.
We can’t make the final diagnosis. The clinical findings are in keeping with clinically suspected myocarditis according to Task Force criteria (8). ECG and 2D-echo were not in keeping with arrhythmogenic cardiomyopathy (ARVC). Additional information could have been provided by cardiac MRI, e.g. presence or absence of oedema and/or LGE, distribution of LGE, but this was initially refused by the patient. In addition, CMRI performed prior to EMB as inpatient failed to show active myocardial inflammation. Anyhow, the final differential diagnosis of infectious (viral or bacterial–positive) or immune-mediated (infection-negative) acute or chronic myocarditis or of other causes, e.g. a hot phase of ARVC, could only be based upon EMB (1-8). Both the troponin increase and the ventricular arrhythmia would be consistent with active myocarditis, either lymphocytic, eosinophilic or giant-cell (8-10).
This can be considered a case of unexplained ventricular arrhythmias and there is a Class IIb indication for performing an EMB according to the joint American Heart Association, American College of Cardiology and ESC 2007 Scientific Statement on the role of EMB (7). Conversely, according to the 2013 Position Statement of the Working Group on Myocardial and Pericardial Disease on Myocarditis (8) and the 2015 ESC guidelines on sudden cardiac death and ventricular arrhythmia (11), EMB is indicated, since the patient has a clinically suspected myocarditis with a combined presentation of pseudo-myocardial infarction with normal coronary arteries and of ventricular arrhythmias. The two most likely causes of this presentation are: isolated lymphocytic myocarditis or isolated giant cell myocarditis, since other features, in particular associated extra-cardiac immune-mediated diseases were ruled out (8-10). Our patient underwent right ventricular EMB, with classical histology, immunohistochemistry, molecular detection of common cardiotropic viruses by polymerase chain reaction (PCR) in myocardial tissue and on blood, and serum testing for anti-heart autoantibodies (AHA) (3,4,6). EMB showed (Figure 2) focal lymphomonocytic infiltrate with myocyte necrosis. The findings were indicative of lymphocytic myocarditis. PCR was negative for enteroviruses, influenza A and B viruses, cytomegalovirus, Epstein-Barr virus, Herpes simplexviruses, human herpes virus 6, addenoviruses, parvovirus B19. AHA test was strongly positive for organ-specific anti-heart autoantibodies (6). The final diagnosis was an infection-negative, isolated autoimmune lymphocytic myocarditis.
According to the 2013 Position Statement of the Working Group on Myocardial and Pericardial Disease on Myocarditis (8), ICD implantation should be post-poned if possible if there is active myocarditis, particularly in the context of primary prevention. Active myocardial inflammation is an arrhythmogenic substrate, but it may heal and the inflammation-associated arrhythmias may be reduced or disappear. In keeping with the 2013 Position Statement of the Working Group on Myocardial and Pericardial Disease on Myocarditis (8), the 2015 ESC guidelines (11) on sudden cardiac death and ventricular arrhythmia state that:
1) Anti-arrhythmic therapy should be considered in patients with symptomatic non-sustained or sustained VT during the acute phase of myocarditis (recommendation IIA, level C) 2) The implant of an ICD or pacemaker in patients with inflammatory heart diseases should be considered after resolution of the acute episode (recommendation IIA, level C). 3) In patients with haemodynamically compromising sustained VT occurring after the resolution of acute episodes, an ICD implantation should beconsidered if the patient is expected to survive more than 1 year with good functional status (recommendation IIA, level C).4) A wearable defibrillator should be considered for bridging until full recovery or ICD implantation in patients after inflammatory heartdiseases with residual severe LV dysfunction and/or ventricular electrical instability (recommendation IIA, level C).5) ICD implantation may be considered earlier in patients with giant cell myocarditis or sarcoidosis who had haemodynamically compromisingsustained VA or aborted cardiac arrest, due to adverse prognosis of these conditions, if survival more than 1 year with good functional status can be expected (recommendation IIB, level C). In our patient ICD was not implanted, in keeping with the 2013 Myocarditis Position statement and the ESC 2015 guidelines (11). However, a Loop recorder was implanted to monitor the patient arrhythmogenic burden and its response during immunosuppression therapy.
According to the 2013 Position Statement of the Working Group on Myocardial and Pericardial Disease on Myocarditis (8), NSAIDs and colchicine are not indicated in myocarditis. Conversely, immunosuppression may be considered in biopsy-proven virus-negative lymphocytic myocarditis refractory to standard therapy of heart failure and/or arrhythmia (8).
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