Surviving the Storm: Cardiac Tamponade and Effusive Constrictive Pericarditis Complicated by Pericardial Decompression Syndrome Induced by COVID-19 Infection in the Setting of Newly Diagnosed Acute Myeloid Leukemia (AML)

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Abstract

Coronavirus disease 2019 (COVID-19)-induced pericarditis and pericardial myocarditis are common entities; however, the development of pericardial effusion post-COVID-19 infection has only been reported in about 5% of cases. Rapid and acute progression to pericardial tamponade is uncommon, and progression to effusive constrictive pericarditis (ECP) and pericardial decompression syndrome (PDS) is an even rarer phenomenon. We describe these phenomena in this report to raise awareness and aid clinicians in the early diagnosis and management of these conditions. We report a case of a 45-year-old female with a past medical history of recent COVID-19 infection, uncontrolled diabetes mellitus, and hypertension who presented with severe chest pain, which was determined to be acute pericarditis post-COVID-19 infection. The patient developed a large pericardial effusion leading to cardiac tamponade within one day of initial presentation. Urgent pericardiocentesis was performed but was complicated by rapid decompensation of the patient, which has been assumed to be ECP following pericardiocentesis and PDS.

Close monitoring of acute pericarditis with pericardial effusion is required in these patients for the early detection of cardiac tamponade, which requires urgent pericardiocentesis. Judicious post-pericardiocentesis follow-up is also required for the early diagnosis of conditions such as ECP and PDS. These cases are generally managed symptomatically, but in cases of severe ECP syndrome, pericardial stripping may be required.

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2015 ESC Guidelines for the diagnosis and management of pericardial diseases

Yehuda Adler, Philippe Charron, Massimo Imazio … (2016)

Abbreviations and acronyms ADA adenosine deaminase AMI acute myocardial infarction ANA anti-nuclear antibody bFGF basic fibroblast growth factor CK creatine kinase CMR cardiac magnetic resonance CMV cytomegalovirus CP Child–Pugh CRP C-reactive protein CT computed tomography EBV Epstein–Barr virus ECG electrocardiogram ESR erythrocyte sedimentation rate ESRD end-stage renal disease FDG fluorodeoxyglucose FMF familial Mediterranean fever GM-CSF granulocyte-macrophage colony-stimulating factor HHV human herpesvirus HIV human immunodeficiency virus HR hazard ratio IL interleukin IVIG intravenous immunoglobulins LCE late contrast-enhanced NSAIDs non-steroidal anti-inflammatory drugs OR odds ratio PAH pulmonary arterial hypertension PCIS post-cardiac injury syndromes PCR polymerase chain reaction PET positron emission tomography PPS post-pericardiotomy syndrome RCT randomized controlled trial spp. species SSFP steady-state free-precession STIR short-tau inversion-recovery TB tuberculosis TNF tumour necrosis factor TRAPS tumour necrosis factor receptor-associated periodic syndrome TSH thyroid stimulating hormone Tx treatment uIFN-γ unstimulated interferon-gamma VEGF vascular endothelial growth factor Preamble Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . The experts of the writing and reviewing panels provided declarations of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC Guidelines covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement all guidelines, condensed pocket guidelines versions, summary slides, booklets with essential messages, summary cards for non-specialists, and an electronic version for digital applications (smartphones, etc.) are produced. These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available on the ESC website. The National Societies of the ESC are encouraged to endorse, translate and implement the ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. Table 1 Classes of recommendations Table 2 Levels of evidence 1. Introduction The pericardium (from the Greek περί, ‘around’ and κάρδιον, ‘heart’) is a double-walled sac containing the heart and the roots of the great vessels. The pericardial sac has two layers, a serous visceral layer (also known as epicardium when it comes into contact with the myocardium) and a fibrous parietal layer. It encloses the pericardial cavity, which contains pericardial fluid. The pericardium fixes the heart to the mediastinum, gives protection against infection and provides lubrication for the heart. Pericardial diseases may be either isolated disease or part of a systemic disease. 1–5 The main pericardial syndromes that are encountered in clinical practice include pericarditis (acute, subacute, chronic and recurrent), pericardial effusion, cardiac tamponade, constrictive pericarditis and pericardial masses. 1,4,5 All medical therapies for pericardial diseases are off-label, since no drug has been registered until now for a specific pericardial indication. 1.1 What is new in pericardial diseases? Pericardial diseases are relatively common in clinical practice and new data have been published since the publication of the 2004 ESC Guidelines on pericardial diseases. 1 New diagnostic strategies have been proposed for the triage of patients with pericarditis and pericardial effusion and allow the selection of high-risk patients to be admitted as well as when and how additional diagnostic investigations are to be performed. 4–9 Moreover, specific diagnostic criteria have been proposed for acute and recurrent pericarditis in clinical practice. 2,4–15 Multimodality imaging for pericardial diseases has become an essential approach for a modern and comprehensive diagnostic evaluation. Both the American Society of Echocardiography and the European Association of Cardiovascular Imaging have provided recommendation documents in recent years. 2,3 The aetiology and pathophysiology of pericardial diseases remain to be better characterized, but new data supporting the immune-mediated pathogenesis of recurrences and new forms related to autoinflammatory diseases have been documented, especially in paediatric patients. 4,6 The first epidemiological data have become available. 7,16 Age and gender issues are now more evident and clear, including specific recommendations for patients during pregnancy. 17–27 Major advances have occurred in therapy with the first multicentre randomized clinical trials. 10,11,13–15 Colchicine has been demonstrated as a first-line drug to be added to conventional anti-inflammatory therapies in patients with a first episode of pericarditis or recurrences in order to improve the response to therapy, increase remission rates and reduce recurrences. 10,11,13–15 Specific therapeutic dosing without a loading dose and weight-adjusted doses have been proposed to improve patient compliance. 11,15 New therapeutic choices have become available for refractory recurrent pericarditis, including alternative immunosuppressive therapies (e.g. azathioprine), intravenous immunoglobulins (IVIGs) and interleukin-1 (IL-1) antagonists (e.g. anakinra). 20–23,28–32 Pericardiectomy has been demonstrated as a possible valuable alternative to additional medical therapies in patients with refractory recurrent pericarditis. 33 The first large prospective and retrospective studies (>100 patients) have investigated the prognosis and complication risk in patients with acute and recurrent pericarditis. 7,9,34–38 Imaging techniques for the detection of pericardial inflammation [e.g. cardiac magnetic resonance (CMR)] may identify forms of initial reversible constrictive pericarditis, allowing a trial of medical anti-inflammatory therapy that may reduce the need for surgery. 2,39–41 In conclusion, significant new data have become available since 2004, and a new version of guidelines has become mandatory for clinical practice. Nevertheless, in the field of pericardial diseases there are a limited number of randomized controlled trials (RCTs). Therefore the number of class I level A indications are limited. 2. Epidemiology, aetiology and classification of pericardial diseases 2.1 Epidemiology Despite the relative high frequency of pericardial diseases, there are few epidemiological data, especially from primary care. Pericarditis is the most common disease of the pericardium encountered in clinical practice. The incidence of acute pericarditis has been reported as 27.7 cases per 100,000 population per year in an Italian urban area. 7 Pericarditis is responsible for 0.1% of all hospital admissions and 5% of emergency room admissions for chest pain. 4,5,42 Data collected from a Finnish national registry (2000–9) showed a standardized incidence rate of hospitalizations for acute pericarditis of 3.32 per 100,000 person-years. 16 These data were limited to hospitalized patients and therefore may account for only a minority of cases, as many patients with pericarditis are commonly not admitted to hospital. 8,9,42,43 Men ages 16–65 years were at higher risk for pericarditis (relative risk 2.02) than women in the general admitted population, with the highest risk difference among young adults compared with the overall population. Acute pericarditis caused 0.20% of all cardiovascular admissions. The proportion of caused admissions declined by an estimated 51% per 10-year increase in age. The in-hospital mortality rate for acute pericarditis was 1.1% and was increased with age and severe co-infections (pneumonia or septicaemia). 16 However, this is a study based on hospital admissions only. Recurrences affect about 30% of patients within 18 months after a first episode of acute pericarditis. 10,11 2.2 Aetiology A simple aetiological classification for pericardial diseases is to consider infectious and non-infectious causes (Table 3 ). 4,6,12,44 The aetiology is varied and depends on the epidemiological background, patient population and clinical setting. In developed countries, viruses are usually the most common aetiological agents of pericarditis, 6 whereas tuberculosis (TB) is the most frequent cause of pericardial diseases in the world and developing countries, where TB is endemic. In this setting, TB is often associated with human immunodeficiency virus (HIV) infection, especially in sub-Saharan Africa. 44 Table 3 Aetiology of pericardial diseases. The pericardium may be affected by all categories of diseases, including infectious, autoimmune, neoplastic, iatrogenic, traumatic, and metabolic CMV = cytomegalovirus; EBV = Epstein-Barr virus; GM-CSF = granulocyte-macrophage colonystimulating factor; HHV = human herpesvirus; spp = species; TNF = tumor necrosis factor. 3. Pericardial syndromes Pericardial syndromes include different clinical presentations of pericardial diseases with distinctive signs and symptoms that can be grouped in specific ‘syndromes’. The classical pericardial syndromes include pericarditis, pericardial effusion, cardiac tamponade and constrictive pericarditis. Pericardial effusion and cardiac tamponade may occur without pericarditis and will be considered in separate chapters. Specific considerations apply to cases with pericarditis and concomitant myocardial inflammatory involvement, usually referred to in the literature as ‘myopericarditis’. 3.1 Acute pericarditis Acute pericarditis is an inflammatory pericardial syndrome with or without pericardial effusion. 1–11,42 The clinical diagnosis can be made with two of the following criteria (Table 4 ): 2,4–15 (i) chest pain (>85–90% of cases)—typically sharp and pleuritic, improved by sitting up and leaning forward; (ii) pericardial friction rub (≤33% of cases)—a superficial scratchy or squeaking sound best heard with the diaphragm of the stethoscope over the left sternal border; (iii) electrocardiogram (ECG) changes (up to 60% of cases)—with new widespread ST elevation or PR depression in the acute phase ( Web Figure 1 ); and (iv) pericardial effusion (up to 60% of cases, generally mild) ( Web Figure 2 ). Additional signs and symptoms may be present according to the underlying aetiology or systemic disease (i.e. signs and symptoms of systemic infection such as fever and leucocytosis, or systemic inflammatory disease or cancer). 45 Table 4 Definitions and diagnostic criteria for pericarditis (see text for explanation) 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. Widespread ST-segment elevation has been reported as a typical hallmark sign of acute pericarditis ( Web Figure 1 ). However, changes in the ECG imply inflammation of the epicardium, since the parietal pericardium itself is electrically inert. 5–7,34 Typical ECG changes have been reported in up to 60% of cases. 10,11 The temporal evolution of ECG changes with acute pericarditis is highly variable from one patient to another and is affected by therapy. Major differential diagnoses include acute coronary syndromes with ST-segment elevation and early repolarization. 6,12,46 Elevation of markers of inflammation [i.e. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as elevation of the white blood cell count] is a common and supportive finding in patients with acute pericarditis and may be helpful for monitoring the activity of the disease and efficacy of therapy. 2,47 Patients with concomitant myocarditis may present with an elevation of markers of myocardial injury [i.e. creatine kinase (CK), troponin]. 7,34 A chest X-ray is generally normal in patients with acute pericarditis since an increased cardiothoracic ratio only occurs with pericardial effusions exceeding 300 ml. 48 In the case of pleuropulmonary diseases, signs of pleuropericardial involvement may be found in patients with pericarditis. 2,3 Recommendations for diagnosis of acute pericarditis CK = creatine kinase; CRP = C-reactive protein; ECG = electrocardiogram. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. 3.1.1 Clinical management and therapy It is not mandatory to search for the aetiology in all patients, especially in countries with a low prevalence of TB, because of the relatively benign course associated with the common causes of pericarditis and the relatively low yield of diagnostic investigations. 6,8,12,49 Specific final identifiable causes (non-viral–non-idiopathic) as well as high-risk features in the context of acute pericarditis have been identified as being associated with an increased risk of complications during follow-up (tamponade, recurrences and constriction). 9,12,43,50 The major risk factors associated with poor prognosis after multivariate analysis include high fever [>38°C (>100.4°F)], subacute course (symptoms over several days without a clear-cut acute onset), evidence of large pericardial effusion (i.e. diastolic echo-free space >20 mm), cardiac tamponade and failure to respond within 7 days to non-steroidal anti-inflammatory drugs (NSAIDs). 9,43,50 Other risk factors should also be considered (i.e. ‘minor risk factors’); these are based on expert opinion and literature review, including pericarditis associated with myocarditis (myopericarditis), immunodepression, trauma and oral anticoagulant therapy. On this basis a triage for acute pericarditis is proposed (Figure 1 , Web Table 6 ). 5,6,43 Any clinical presentation that may suggest an underlying aetiology (e.g. a systemic inflammatory disease) or with at least one predictor of poor prognosis (major or minor risk factors) warrants hospital admission and an aetiology search. 9,43,49–51 On the other hand, patients without these features can be managed as outpatients with empiric anti-inflammatories and short-term follow-up after 1 week to assess the response to treatment. 9 Recommendations for the management of acute pericarditis aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. dSee Figure 1 (both major and minor predictors of poor prognosis). In patients identified with a cause other than viral infection, specific therapy appropriate to the underlying disorder is indicated 49,51 and the epidemiological background (high vs. low prevalence of TB) should be considered. 8,12,52 The first non-pharmacological recommendation is to restrict physical activity beyond ordinary sedentary life until resolution of symptoms and normalization of CRP for patients not involved in competitive sports. 53 Athletes are recommended to return to competitive sports only after symptoms have resolved and diagnostic tests (i.e. CRP, ECG and echocardiogram) have been normalized. 53,54 A minimal restriction of 3 months (after the initial onset of the attack) has been arbitrarily defined according to expert consensus. 54 We suggest applying this restriction only to athletes, while a shorter period (until remission) may be suitable for non-athletes. Aspirin or NSAIDs are mainstays of therapy for acute pericarditis. 5,6,55,56 Different anti-inflammatory drugs have been proposed (Table 5 ). Table 5 Commonly prescribed anti-inflammatory therapy for acute pericarditis b.i.d. = twice daily; CRP = C-reactive protein; NSAIDs = non-steroidal anti-inflammatory drugs; Tx = treatment. aTapering should be considered for aspirin and NSAIDs. bTx duration is symptoms and CRP guided but generally 1–2 weeks for uncomplicated cases. Gastroprotection should be provided. Colchicine is added on top of aspirin or ibuprofen. The choice of drug should be based on the history of the patient (contraindications, previous efficacy or side effects), the presence of concomitant diseases (favouring aspirin over other NSAIDs when aspirin is already needed as antiplatelet treatment) and physician expertise. 56 Figure 1 Proposed triage of pericarditis. Colchicine is recommended at low, weight-adjusted doses to improve the response to medical therapy and prevent recurrences. 10,11,57–59 Tapering of colchicine is not mandatory but may be considered to prevent persistence of symptoms and recurrence. 5,6,56 Corticosteroids should be considered as a second option in patients with contraindications and failure of aspirin or NSAIDs because of the risk of favouring the chronic evolution of the disease and promoting drug dependence; in this case they are used with colchicine. If used, low to moderate doses (i.e. prednisone 0.2–0.5 mg/kg/day or equivalent) should be recommended instead of high doses (i.e. prednisone 1.0 mg/kg/day or equivalent). 35 The initial dose should be maintained until resolution of symptoms and normalization of CRP, then tapering should be considered. 5,6,35,47,56 Recommendations for the treatment of acute pericarditis CRP = C-reactive protein; ECG = electrocardiogram; NSAIDs = non-steroidal anti-inflammatory drugs. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. dAdded to colchicine. 3.1.2 Prognosis Most patients with acute pericarditis (generally those with presumed viral or idiopathic pericarditis) have a good long-term prognosis. 36 Cardiac tamponade rarely occurs in patients with acute idiopathic pericarditis, and is more common in patients with a specific underlying aetiology such as malignancy, TB or purulent pericarditis. Constrictive pericarditis may occur in 3 months. 48 The Task Force suggests that the term ‘acute’ should be adopted for new-onset pericarditis, ‘incessant’ for pericarditis with symptoms persisting for >4–6 weeks (that is generally the approximate length of conventional anti-inflammatory therapy and its tapering), 11,60 and ‘chronic’ for pericarditis lasting >3 months. 3.3 Recurrent pericarditis Recurrent pericarditis is diagnosed with a documented first episode of acute pericarditis, a symptom-free interval of 4–6 weeks or longer and evidence of subsequent recurrence of pericarditis (Table 4 ). 11,13–15 Diagnosis of recurrence is established according to the same criteria as those used for acute pericarditis. CRP, 2,47 computed tomography (CT) and/or CMR may provide confirmatory findings to support the diagnosis in atypical or doubtful cases showing pericardial inflammation through evidence of oedema and contrast enhancement of the pericardium. 2,39 The recurrence rate after an initial episode of pericarditis ranges from 15 to 30%, 10,11 and may increase to 50% after a first recurrence in patients not treated with colchicine, 13–15 particularly if treated with corticosteroids. In developed countries, the aetiology is often not identified in most immunocompetent patients, and it is generally presumed to be immune-mediated. 60–62 A common cause of recurrence is inadequate treatment of the first episode of pericarditis. In up to 20% of cases, when additional virological studies have been conducted on pericardial fluid and tissue, a viral aetiology is detected. 63 3.3.1 Therapy Recurrent pericarditis therapy should be targeted at the underlying aetiology in patients with an identified cause. Aspirin or NSAIDs remain the mainstay of therapy (Table 6 , Web Box, Web Table 1A). Colchicine is recommended on top of standard anti-inflammatory therapy, without a loading dose and using weight-adjusted doses (i.e. 0.5 mg once daily if body weight is 3 months), distribution (circumferential or loculated), haemodynamic impact (none, cardiac tamponade, effusive-constrictive), composition (exudate, transudate, blood, rarely air, or gas from bacterial infections) and, in particular, by its size (Table 8 ) based on a simple semiquantitative echocardiographic assessment as mild ( 20 mm) ( Web Figure 2 ). 48 This semiquantitative assessment has also proven to be useful in estimating the risk of specific aetiology and complications during follow-up in the setting of pericarditis. 9,48,51 In the last 20 years, five major surveys have been published on the characteristics of moderate to large pericardial effusions ( Web Table 3 ). 74–78 Table 7 Tapering of corticosteroids 35 (dosage information is provided for prednisone) aAvoid higher doses except for special cases, and only for a few days, with rapid tapering to 25 mg/day. Prednisone 25 mg are equivalent to methylprednisolone 20 mg. bEvery decrease in prednisone dose should be done only if the patient is asymptomatic and C-reactive protein is normal, particularly for doses 60%), where TB is endemic. 52,79 In the setting of pericarditis with pericardial effusion, the prevalence of malignant or infectious aetiologies ranges from 15 to 50% depending on the published series. 6,9 3.5.1 Clinical presentation and diagnosis The clinical presentation of pericardial effusion varies according to the speed of pericardial fluid accumulation. If pericardial fluid is rapidly accumulating, such as after wounds or iatrogenic perforations, the evolution is dramatic and even small amounts of blood may cause an increase in intrapericardial pressure within minutes and overt cardiac tamponade. On the other hand, a slow accumulation of pericardial fluid allows the collection of a large effusion in days to weeks before a significant increase in pericardial pressure causes symptoms and signs ( Web Figure 3 ). 48,80,81 Classic symptoms include dyspnoea on exertion progressing to orthopnoea, chest pain and/or fullness. Additional occasional symptoms due to local compression may include nausea (diaphragm), dysphagia (oesophagus), hoarseness (recurrent laryngeal nerve) and hiccups (phrenic nerve). Non-specific symptoms include cough, weakness, fatigue, anorexia and palpitations, and reflect the compressive effect of the pericardial fluid on contiguous anatomic structures or reduced blood pressure and secondary sinus tachycardia. 82–84 Fever is a non-specific sign that may be associated with pericarditis, either infectious or immune mediated (i.e. systemic inflammatory diseases). 45 Physical examination may be absolutely normal in patients without haemodynamic compromise. When tamponade develops, classic signs include neck vein distension with elevated jugular venous pressure at bedside examination, pulsus paradoxus and diminished heart sounds on cardiac auscultation in cases of moderate to large effusions. 82–84 Pericardial friction rubs are rarely heard; they can usually be detected in patients with concomitant pericarditis. 8 The diagnosis of pericardial effusion is generally performed by echocardiography, which also enables semiquantitative assessment of the pericardial effusion size and its haemodynamic effects. Although echocardiography remains the primary diagnostic tool for the study of pericardial diseases because of its widespread availability, portability and limited costs, CT and CMR provide a larger field of view, allowing the detection of loculated pericardial effusion and pericardial thickening and masses, as well as associated chest abnormalities. 2,3,84 Recommendations for the diagnosis of pericardial effusion CMR = cardiac magnetic resonance; CRP = C-reactive protein; CT = computed tomography. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. 3.5.2 Triage and management When a pericardial effusion is detected, the first step is to assess its size, haemodynamic importance (especially the presence of cardiac tamponade) and possible associated diseases (either cardiovascular or systemic diseases). Pericardial effusion is often associated with known or unknown (e.g. hypothyroidism) medical conditions (up to 60% of cases). 48,75,82 If inflammatory signs are present, the clinical management should be that of pericarditis. Cardiac tamponade without inflammatory signs is associated with a higher risk of a neoplastic aetiology (likelihood ratio 2.9), whereas a severe effusion without cardiac tamponade and inflammatory signs is usually associated with a chronic idiopathic aetiology (likelihood ratio 20). 75 A practical routine evaluation for triage of pericardial effusion is presented in Figure 3 . 48,82 Recommendations for the initial management of pericardial effusion aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. dSimilar risk criteria as for pericarditis (see Figure 1 ). In chronic effusion with no definite aetiology, there are no data on non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids. If markers of inflammation are elevated, a trial of NSAIDs and/or colchicine and/or low-dose corticosteroids may be tried. 3.5.3 Therapy Therapy of pericardial effusion should be targeted at the aetiology as much as possible. In about 60% of cases, the effusion is associated with a known disease and the essential treatment is that of the underlying disease. 48,75,82 When pericardial effusion is associated with pericarditis, management should follow that of pericarditis. When a pericardial effusion becomes symptomatic without evidence of inflammation or when empiric anti-inflammatory drugs are not successful, drainage of the effusion should be considered. Pericardiocentesis with prolonged pericardial drainage of up to 30 ml/24 h may be considered in order to promote adherence of pericardial layers and prevent further accumulation of fluid; however, evidence to support this indication is based on case reports, retrospective studies and expert opinion. 48,82,84 Figure 3 A simplified algorithm for pericardial effusion triage and management. Unfortunately, there are no proven effective medical therapies to reduce an isolated effusion. In the absence of inflammation, NSAIDs, colchicine and corticosteroids are generally not effective. 82,85 Pericardiocentesis alone may be necessary for the resolution of large effusions, but recurrences are also common, and pericardiectomy or less invasive options (i.e. pericardial window) should be considered whenever fluid reaccumulates, becomes loculated or biopsy material is required. 48 Recommendations for the therapy of pericardial effusion NSAIDs = non-steroidal anti-inflammatory drugs. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. 3.5.4 Prognosis and follow-up The prognosis of pericardial effusion is essentially related to the aetiology. 48,82,86 The size of the effusion is correlated with the prognosis, as moderate to large effusions are more common for specific aetiologies such as bacterial and neoplastic conditions. 9,48 Idiopathic pericardial effusion and pericarditis have an overall good prognosis with a very low risk of complications, especially if the effusion is mild to moderate. In contrast with these observations, a recently published prospective study has shown that even with mild pericardial effusion the overall prognosis may be worse than in age- and sex-matched controls. 87 Large idiopathic chronic effusions (>3 months) have a 30–35% risk of progression to cardiac tamponade. 88 Also, subacute (4–6 weeks) large effusions not responsive to conventional therapy and with echocardiographic signs of collapse of the right chambers may have an increased risk of progression according to some authors, who recommend preventive drainage in such cases. 89 Documented idiopathic pericarditis has a very low risk of constrictive pericarditis despite several recurrences: here the risk is related to the aetiology and not the number of recurrences. 36 The follow-up of pericardial effusion is mainly based on the evaluation of symptoms and the echocardiographic size of the effusion, as well as additional features such as inflammatory markers (i.e. CRP). 48 A mild idiopathic effusion ( 10 mm) may worsen, and especially severe effusions may evolve towards cardiac tamponade in up to one-third of cases. For idiopathic moderate effusions, an appropriate timing for echocardiographic follow-up may be an echocardiogram every 6 months. For a severe effusion, an echocardiographic follow-up may be every 3–6 months. A tailored follow-up is also warranted considering the relative stability or evolution of the size. 48 Specific considerations on pericardial effusion in the postoperative setting are discussed in the section on post-cardiac injury syndromes (section 5.5). 3.6 Cardiac tamponade Cardiac tamponade is a life-threatening, slow or rapid compression of the heart due to the pericardial accumulation of fluid, pus, blood, clots or gas as a result of inflammation, trauma, rupture of the heart or aortic dissection. 81,84 Clinical signs in a patient with cardiac tamponade include tachycardia, hypotension, pulsus paradoxus, raised jugular venous pressure, muffled heart sounds, decreased electrocardiographic voltage with electrical alternans and an enlarged cardiac silhouette on chest X-ray with slow-accumulating effusions. 81–84 A key diagnostic finding is pulsus paradoxus (conventionally defined as an inspiratory decrease in systolic arterial pressure of >10 mmHg during normal breathing). Pulsus paradoxus is due to exaggerated ventricular interdependence occurring in cardiac tamponade, when the overall volume of cardiac chambers becomes fixed and any change in the volume of one side of the heart causes the opposite changes in the other side (i.e. inspiratory increase of venous return and right chambers with decreased volume of left chambers and reduced systemic blood pressure). The magnitude of clinical and haemodynamic abnormalities depends on the rate of accumulation and amount of pericardial contents, the distensibility of the pericardium and the filling pressures and compliance of the cardiac chambers ( Web Figure 3 ). Various causes for cardiac tamponade are listed in Table 9 . Table 9 Causes of cardiac tamponade The stiffness of the pericardium determines fluid increments precipitating tamponade, as illustrated by characteristic pericardial pressure–volume (strain–stress) curves: there is an initial slow ascent, followed by an almost vertical rise ( Web Figure 3 ). This steep rise makes tamponade a ‘last-drop’ phenomenon: the final increment produces critical cardiac compression and the first decrement during drainage produces the largest relative decompression. 80–84 In a patient with clinical suspicion of cardiac tamponade, several diagnostic tools are required. An ECG may show signs of pericarditis, with especially low QRS voltages and electrical alternans. Both ECG signs are generally considered to be an expression of the damping effect of pericardial fluid and swinging heart. Echocardiography is the single most useful diagnostic tool to identify pericardial effusion and estimate its size, location and degree of haemodynamic impact. Also, echocardiography is used to guide pericardiocentesis with excellent safety and efficacy. Signs of tamponade can be identified by echocardiography: swinging of the heart, early diastolic collapse of the right ventricle, late diastolic collapse of the right atrium, abnormal ventricular septal motion, exaggerated respiratory variability (>25%) in mitral inflow velocity, inspiratory decrease and expiratory increase in pulmonary vein diastolic forward flow, respiratory variation in ventricular chamber size, aortic outflow velocity (echocardiographic pulsus paradoxus) and inferior vena cava plethora. 2,3,82,84 CT and CMR are often less readily available and are generally unnecessary unless Doppler echocardiography is not feasible. Cardiac catheterization is rarely used to diagnose cardiac tamponade. It will show equilibration of average diastolic pressure and characteristic respiratory reciprocation of cardiac pressures, i.e. an inspiratory increase on the right and a concomitant decrease on the left—the proximate cause of pulsus paradoxus. Except in low-pressure tamponade, diastolic pressures throughout the heart are usually in the range of 15–30 mmHg. The treatment of cardiac tamponade involves drainage of the pericardial fluid, preferably by needle pericardiocentesis, with the use of echocardiographic or fluoroscopic guidance, and should be performed without delay in unstable patients. Alternatively, drainage is performed by a surgical approach, especially in some situations such as purulent pericarditis or in urgent situations with bleeding into the pericardium. A triage system ( Web Figure 4 ) has been proposed by the ESC Working Group on Myocardial and Pericardial Diseases in order to guide the timing of the intervention and the possibility of transferring the patient to a referral centre. 84 This triage system is essentially based on expert consensus and requires additional validation in order to be recommended in clinical practice. Recommendations for the diagnosis and treatment of cardiac tamponade aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. 3.7 Constrictive pericarditis Constrictive pericarditis can occur after virtually any pericardial disease process, but only rarely follows recurrent pericarditis. 37 The risk of progression is especially related to the aetiology: low ( 8 cm/s or hepatic vein expiratory diastolic reversal ratio >0.78 (sensitivity 87%, specificity 91%; specificity may increase to 97% if all criteria are present with a correspondent decrease of sensitivity to 64%. 95 3.7.3 Therapy Although the mainstay of treatment of chronic permanent cases is surgery, medical therapy may have a role in at least three conditions. First, medical therapy of specific aetiologies (i.e. tuberculous pericarditis) may be useful to prevent the progression to constriction. Antituberculosis antibiotics may significantly reduce the risk of constriction from >80% to 20 mm) ( Web Figure 2 ). 48 In order to allow follow-up studies, it is recommended that the images be documented digitally and the effusion size described in a detailed way in the echocardiographic report, including not only the extent, but also the location of each measurement. However, the haemodynamic tolerance is more related to the rapidity of appearance of the effusion than to its total volume. 48,80 Loculated pericardial effusions or pericardial effusions that contain clots (e.g. after cardiac surgery) may be difficult to diagnose using a transthoracic approach and may require transoesophageal echocardiography. 3,4 Specific findings in pericardial syndromes are discussed in the pertinent paragraphs. 4.1.3 Computed tomography CT should be regarded as a valuable complementary imaging modality to echocardiography. 3,4,41,108,109 CT is the most accurate technique to image calcified tissue. 2,3 Current multidetector CT scanners combine acquisition speed, high contrast and spatial resolution with volumetric scanning to provide excellent anatomical detail of the heart and pericardium. The anatomical region of interest covered by CT can be limited to the heart and pericardium (‘cardiac CT’), although in patients with neoplastic, inflammatory or aortic disease it may encompass the chest entirely and possibly also include the abdomen and pelvis. 108,109 Low-radiation cardiac CT is feasible using prospective electrocardiographic triggering. 108,109 Although the functional consequences of pericardial disease on the heart can be evaluated by CT—at the expense of significantly higher radiation doses—echocardiography and CMR are more appropriate for assessing this feature. Intravenous administration of iodinated contrast material is recommended to increase the density of blood and to depict pericardial inflammation. The normal pericardium is visible as a thin curvilinear structure surrounded by the hypodense mediastinal and epicardial fat, and has a thickness ranging from 0.7 to 2.0 mm. The pericardial sinuses and their respective recesses are visible, in particular when they contain small amounts of pericardial fluid. The main CT findings in pericardial effusion and pericarditis are summarized in Table 12 . 41,108,109 Table 12 Diagnostic contribution of the different imaging modalities in various pericardial diseases CMR = cardiac magnetic resonance; CT = computed tomography; HU = Hounsfield units; IVC = inferior vena cava; LGE= late gadolinium enhancement; LV = left ventricle; RV = right ventricle. In patients with neoplastic disease, pericardial involvement may occur by direct tumour invasion or metastatic spread. CT is important in treatment planning and patient follow-up. The diagnosis of (congenital) pericardial cysts—presenting as well-defined, fluid-dense structures along the left or right heart border—as well as the differential diagnosis with other cystic structures, such as bronchogenic or duplication cysts, is usually straightforward. Finally, CT can be helpful to establish the diagnosis in congenital absence of the pericardium by showing displacement of cardiac structures through the pericardial defect. CT is also essential in the preoperative workup of some patients with constrictive pericarditis, especially to depict the extension of calcifications and for those with a history of prior cardiothoracic surgery. 109 4.1.4 Cardiac magnetic resonance Over the years, CMR has shifted from a morphologic imaging modality towards a comprehensive one, allowing visualization and tissue characterization of the pericardium (and heart) in patients with pericardial disease and appraisal of the consequences of pericardial abnormalities on cardiac function and filling patterns. 110,111 As such, it is probably the preferred imaging modality to optimally assess pericardial disease. 112,113 Cardiac and pericardial morphology are evaluated by dark-blood T1-weighted fast spin-echo and bright-blood cine steady-state free-precession (SSFP) imaging. Cine SSFP imaging has become the reference sequence to assess and quantify cardiac volumes, myocardial mass and ventricular function. When acquired in real-time, this sequence can be used to assess ventricular coupling by assessing the changes in ventricular septal shape and motion over the respiratory cycle. 109,110 Tissue characterization of the heart and pericardium is achieved by dark-blood T1-weighted and dark-blood T2-weighted, short-tau inversion-recovery (STIR) spin-echo imaging, cine SSFP imaging and T1-weighted contrast-enhanced and/or late contrast-enhanced (LCE) imaging following intravenous administration of paramagnetic gadolinium chelates. 3,4,114 The LCE sequence uses an inversion-recovery pre-pulse to increase image contrast and is well suited to visualize pericardial inflammation. 114,115 Ventricular inflow and venous flow patterns can be evaluated using phase contrast imaging. 111 Similar to CT, the normal pericardium appears on T1-weighted imaging as a thin hypointense (‘dark’) curvilinear structure surrounded by hyperintense (‘bright’) mediastinal and epicardial fat. Normal pericardial thickness ranges from 1.2 to 1.7 mm. The imaging characteristics of pericardial effusion and pericarditis at CMR are shown in Table 12 . It should be emphasized that CMR can accurately distinguish between mixed myopericardial diseases such as mixed inflammatory forms (e.g. myopericarditis or perimyocarditis) and post-myocardial infarction pericardial injury. 116,117 In patients with constrictive pericarditis, CMR is particularly important in the diagnosis of atypical presentations, such as those with minimally thickened pericardium or effusive-constrictive pericarditis, and those with potentially reversible or transient forms of constrictive pericarditis, showing enhancement of the pericardial layers at LCE imaging. 115,118,119 Compared with CT, CMR has the advantage of providing information with regard to the haemodynamic consequences of the non-compliant pericardium on cardiac filling, 109–111 and has the potential of showing fibrotic fusion of pericardial layers. 120 In patients with congenital pericardial pathology and pericardial malignancy, CMR shares the advantages of CT, but allows better tissue characterization and the possibility of evaluating the functional consequences. 121 Moreover, novel techniques, such as diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging, open perspectives for improved tissue characterization in patients with pericardial tumours. 122 4.1.5 Nuclear medicine In selected cases, positron emission tomography (PET) alone, or preferably in combination with CT (PET/CT), can be indicated to depict the metabolic activity of pericardial disease. Pericardial uptake of 18F-fluorodeoxyglucose (FDG) tracer in patients with solid cancers and lymphoma is indicative of (malignant) pericardial involvement, thus providing essential information on the diagnosis, staging and assessment of the therapeutic response. 123 The uptake is usually intense and often associated with a focal soft tissue mass. 124 PET/CT is also of value in identifying the nature of inflammatory pericarditis. In particular, tuberculous pericarditis yields higher FDG uptakes than idiopathic forms. 125 However, differentiation between benign and malignant pericardial disease, as well as differentiation between physiological and pathological cardiac FDG uptake by PET/CT, remains challenging. 123 4.1.6 Cardiac catheterization Cardiac catheterization is not routinely used for the diagnosis of pericardial disease, as current non-invasive techniques are usually able to solve the differential diagnosis of a patient with the suspicion of heart disease involving the pericardium. However, right heart catheterization may be useful in certain circumstances. Early recognition of abnormal haemodynamics related to cardiac tamponade during invasive procedures (i.e. epicardial ablation, percutaneous aortic valve implantation, complex angioplasty or complex procedures involving trans-septal punctures, among others) may help avoid serious consequences for the patient. In addition, the differentiation between constrictive pericarditis and restrictive cardiomyopathy is sometimes difficult and may require an invasive test. In cardiac tamponade, the right atrial pressure waveform has an attenuated or an absent Y-descent. Absent Y-descent is secondary to diastolic equalization of pressures in the right atrium and right ventricle and lack of effective flow across the tricuspid valve in early ventricular diastole. Also, equalization of mean right atrial, right ventricular and pulmonary artery diastolic pressures and mean pulmonary capillary wedge pressures can be present. Other haemodynamic abnormalities include elevation of filling pressures in all four cardiac chambers, right ventricle and left ventricle peak systolic pressures out of phase, peak aortic pressure varying more than 10–12 mmHg and a decrease in cardiac output. 126,127 The differentiation of constrictive pericarditis from restrictive cardiomyopathy remains difficult. Visualization of the pericardium by CT or CMR may help in detecting an abnormal pericardium. But these tests provide anatomical information and do not necessarily reflect the pathophysiological abnormality present. Also, patients with surgically proven constrictive pericarditis may have a normal-appearing pericardium on imaging studies. Alternatively patients may have abnormal pericardial thickness in the absence of constriction, especially after radiation therapy or prior cardiac surgery. Classically, direct measurements of pressures show M- or W-shaped atrial pressure waveforms and ‘square root’ or ‘dip-and-plateau’ right ventricular pressure waveforms, reflecting impaired ventricular filling. End-diastolic pressure equalization (typically within 5 mmHg) occurs between these cardiac chambers in constrictive pericarditis because of the fixed and limited space within the thickened and stiff pericardium. Pulmonary artery systolic pressures are usually normal in pericardial constriction; higher pulmonary pressures suggest a restrictive cardiomyopathy. 126 Recently a novel haemodynamic parameter has been tested to differentiate both entities. 96 Specifically, the ratio of the right ventricular to left ventricular systolic pressure–time area during inspiration versus expiration (systolic area index) was used as a measurement of enhanced ventricular interaction. In patients with surgically documented constrictive pericarditis, during inspiration there is an increase in the area of the right ventricular pressure curve compared with expiration. The area of the left ventricular pressure curve decreases during inspiration as compared with expiration. In contrast, patients with restrictive myocardial disease documented by endomyocardial biopsy usually present a decrease in the area of the right ventricular pressure curve during inspiration as compared with expiration. The area of the left ventricular pressure curve is unchanged during inspiration as compared with expiration. This systolic area index presented a 97% sensitivity and 100% predictive accuracy for identifying patients with surgically proven constrictive pericarditis. 96 4.1.7 Multimodality imaging Echocardiography, cardiac CT and CMR are often used as complementary imaging modalities (Table 13 ). The choice of one or multiple imaging modalities is driven by the clinical context or condition of the patient. A modern approach for the management of pericardial diseases should include the integration of different imaging modalities in order to improve the diagnostic accuracy and clinical management of patients. 2,3 Table 13 Comparison of non-invasive imaging modalities to study the pericardium CMR = cardiac magnetic resonance magnetic resonance; CT = computed tomography; ECG = electrocardiogram; TTE = transthoracic echocardiography. (-) not possible or poor; (+) moderate; (++) good; (+++) excellent. aIonizing radiation, potential nephrotoxicity of contrast medium, allergic reactions to contrast. bPatients with metallic implants, claustrophobia, potential nephrotoxicity of contrast medium, allergic reactions to contrast, restricted only to haemodynamically stable patients. cUse of ECG synchronized data acquisition. 4.2 Proposal for a general diagnostic work-up In the management of pericardial syndromes, a major controversy is the role of an extensive aetiological search and admission for all patients with pericarditis or pericardial effusion. 1,4,6,51 The epidemiological background is essential to develop a rational cost-effective management programme and the clinician should especially identify causes that require targeted therapies. 4,5,51,128–130 The approach may be different for research, when we attempt to reduce the number of ‘idiopathic’ cases. The diagnosis of idiopathic cases is essentially an exclusion diagnosis, supported by a typical clinical course. On this basis, auscultation, ECG, echocardiography, chest X-ray, routine blood tests, including markers of inflammation (i.e., CRP and/or ESR) and myocardial lesions (CK, troponins), are recommended in all cases of suspected pericarditis. Additional testing should be related to the suspected origin and clinical presentation. 5,6,128–130 The major specific causes to be ruled out are bacterial pericarditis (especially TB), neoplastic pericarditis and pericarditis associated with a systemic disease (generally an autoimmune disease) ( Web Table 5 ). 9,77,129–131 Each of these specific causes has a frequency of ∼5% of all unselected cases of pericarditis from developed countries ( Web Table 5 ), 9,77,129–131 while frequencies increase in moderate to large pericardial effusions ( Web Table 3 ). 8,74–78 Emerging additional causes include iatrogenic ones (percutaneous coronary interventions, pacemaker insertion, catheter ablation). 132 The aetiological spectrum is different in developing countries with a high prevalence of TB (e.g. 70–80% of pericarditis in sub-Saharan Africa, and often associated with HIV infection). 52,79 Certain clinical features at presentation may be associated with an increased risk of specific aetiologies (non-viral or non-idiopathic) and complications during follow-up (recurrences, tamponade, constriction) and are suggested as ‘high-risk features’ useful for the triage of pericarditis to establish the need for a full aetiological search and admission in a single patient (Figure 1 , Web Table 6 ). 8,9 Factors indicated as ‘major’ have been validated by multivariate analysis, while factors indicated as ‘minor’ are based on expert opinion and literature review: 9 they are essentially theoretical risk factors for complications and suggest the indication for admission and close monitoring of the evolution. Major risk factors include fever >38°C [hazard ratio (HR) 3.56], subacute course (symptoms developing over several days or weeks; HR 3.97), large pericardial effusion (diastolic echo-free space >20 mm in width) or cardiac tamponade (HR 2.15) and failure of aspirin or NSAIDs (HR 2.50). 9 Large effusion and tamponade (HR 2.51) and aspirin or NSAIDs failure (HR 5.50) also identify an increased risk of complications during follow-up (recurrences, tamponade, constriction). 9 Minor risk factors are pericarditis associated with myocarditis, immunodepression, trauma and oral anticoagulant therapy. For patients with predictors of poor prognosis, major or minor (Figure 1 ), hospitalization and a full aetiological search are warranted. 5,6,8,9,128 In contrast, when these negative predictors are absent, patients are at low risk of specific causes and complications, and outpatient management may be considered. 8 This approach is safe without an excess of complications and new unexpected diagnoses requiring a specific therapy. 8,9,128 The same approach is also useful for patients with recurrences who may generally be treated as outpatients, unless predictors of poor prognosis are present or a specific cause can be ruled out. With a clear diagnosis of idiopathic origin and a recurrence course with complete symptom-free periods between the episodes, it is also unnecessary to repeat a new aetiological search at each recurrence unless new clinical features become evident. First- and second-line general investigations are reported in the recommendations and Tables 14–16 . Recommendations for the general diagnostic work-up of pericardial diseases CK = creatine kinase; CMR = cardiac magnetic resonance; CRP = C-reactive protein; CT = computed tomography; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; NSAIDs = non-steroidal anti-inflammatory drugs. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. Table 14 First and second level investigations for pericarditis CK = creatine kinase; CMR = cardiac magnetic resonance; CRP = C-reactive protein; CT = computed tomography; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate. Table 15 Main analyses to be performed on pericardial fluid LDH = lactate dehydrogenase; TB = tuberculosis. aHigh values of protein and LDH are commonly interpreted as an exudate, as in pleural fluid, but have not been validated for pericardial fluid. Table 16 Suggested diagnostic flowchart in some common conditions in high risk patients ACE = angiotensin-converting enzyme; ANA = anti-nuclear antibodies; ANCA = anti-neutrophil cytoplasm antibodies; BNP = brain natriuretic peptide; CEA = carcinoembryonic antigen; CMV = cytomegalovirus; CT = computed tomography; EBV = Epstein-Barr virus; ENA = anti-extractable nuclear antigens; FMF = familial Mediterranean fever; HCV = hepatitis C virus; HHV = human herpesvirus; HIV = human immunodeficiency virus; IGRA = interferon-gamma release assay; MR = magnetic resonance; PCR = polymerase chain reaction; PET = positron emission tomography; spp = species; TB = tuberculosis; TRAPS = tumour necrosis factor receptor-associated periodic syndrome; TSH = thyroid stimulating hormone. aConsider storage of a sterile sample for further analyses. bSee viral pericarditis section—at present, these investigations have no therapeutic or prognostic implications. IGRAs are whole-blood tests that can aid in diagnosing Mycobacterium tuberculosis infection. They do not help to differentiate latent TB infection from TB disease. 5. Specific aetiologies of pericardial syndromes 5.1 Viral pericarditis 5.1.2 Definition and clinical spectrum Most cases of acute pericarditis in developed countries are based on viral infections or are autoreactive. 5,6,133–135 Acute viral pericarditis often presents as a self-limited disease, with most patients recovering without complications. 5,6,9,36 However, as a consequence of acute viral pericarditis, cardiac tamponade, recurrent pericarditis and, more rarely, constrictive pericarditis may also develop. 36 5.1.3 Pathogenesis Cardiotropic viruses can cause pericardial and myocardial inflammation via direct cytolytic or cytotoxic effects (e.g. enteroviruses) and/or via T and/or B cell–driven immune-mediated mechanisms (e.g. herpesviruses). Persistence of viral nucleic acid without virus replication in the peri(myo)cardium is known to sustain ongoing inflammation and effusions via (auto)immune processes directed against specific cardiac proteins by molecular mimicry. 133 5.1.4 Diagnosis The definite diagnosis of viral pericarditis requires a comprehensive workup of histological, cytological, immunohistological and molecular investigations in pericardial fluid and peri-/epicardial biopsies obtained in conjunction with pericardioscopy, permitting the evaluation of possible algorithms for a causative therapy. 133 In contrast, serological tests were found to be futile in the diagnosis of viral pericarditis. Whereas no up-regulation of pro-inflammatory cytokine expression is noted in the serum, TNF-α, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), IL-6, IL-8 and interferon-gamma (IFN-γ) are increased in the pericardial effusions of patients with pericarditis, indicating the presence of local inflammatory reactions. 134,135 Accordingly, there is no correlation of antiviral antibodies in the serum or virus isolation from throat or rectal swabs with positive molecular polymerase chain reaction (PCR)/in situ hybridization analyses for the detection of cardiotropic viruses in pericardial tissue and fluid. 136 5.1.5 Identification of viral nucleic acids Mainly by quantitative PCR techniques, nucleic acids of different cardiotropic RNA and DNA viruses have been detected in epicardial and pericardial biopsies and the pericardial fluid of children and adults with acute pericarditis, but also in patients with recurring and constrictive pericarditis. 133,137 Regarding RNA viruses, various subtypes of enteroviruses including echoviruses and coxsackieviruses of groups A (A4, A16) and B (CVB2, CVB3, CVB4) were identified in patients with acute and constrictive pericarditis. 137,138 Among the RNA viruses, influenza A viruses (e.g. H1N1, H5N1, H3N2) and occasionally chikungunya virus, human coronavirus NL-63, respiratory syncytial virus and dengue virus infections were suspected as aetiopathogenic agents in pericarditis. Compared with RNA viruses, nucleic acids of DNA viruses, including parvovirus B19 and herpesviruses [Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6)], are present in pericardial biopsies and pericardial fluid at greater frequencies and higher viral DNA copy numbers. 133 Whereas parvovirus B19, with up to 7 × 10 6 GE/lg DNA was predominantly detected in epicardial tissue, EBV was most frequently found in pericardial fluid. 133 DNA of varicella zoster virus, herpes simplex virus and adenoviruses is only rarely detected in pericarditis patients. Cytomegalovirus (CMV)-associated pericarditis is mainly found in immunocompromised and HIV patients. 1 In developing countries with a delayed roll-out of antiretroviral therapy, HIV-associated inflammatory reactions (often related to TB) of the pericardium and myocardium are common complications. 139 However, at present these investigations are usually not performed because of their complexity, cost, invasive nature and low availability. 5.1.6 Therapy Acute viral pericarditis often presents as a self-limiting disease that responds well to a short course of treatment with NSAIDs, with the adjunct of colchicine, especially for prevention of recurrences. 4–6,50,58,59 The identification of specific viral signatures aids in understanding the pathogenetic mechanisms in pericarditis, and might enable an individualized aetiologically driven specific treatment approach to be established by distinguishing a viral aetiology from autoreactive inflammation. 133 Some experts suggest antiviral treatment similar to that for myocarditis (IVIG therapy in acute systemic enteroviral, CMV, EBV and parvovirus B19 infection, oral valganciclovir in HHV-6 perimyocarditis, IFN-α for enteroviral pericarditis). 133 However, these treatments are still under evaluation and rarely used. Involvement of infectious disease specialists is recommended. So far, no therapy is available to solve the problem of virus persistence and consecutive inflammation, particularly when induced by herpesviruses and parvovirus B19 infections. 133 Importantly, corticosteroids are generally not indicated in viral pericarditis, as they are known to reactivate many virus infections and thus lead to ongoing inflammation. 133 Recommendations for the diagnosis and therapy of viral pericarditis HCV = hepatitis C virus; HIV = human immunodeficiency virus. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. dIn the absence of such an argument, the term ‘presumed viral pericarditis’ should be used. 5.2 Bacterial pericarditis Bacterial pericarditis is relatively uncommon in clinical practice in developed countries with a low prevalence of TB. Tuberculous pericarditis is the most common form all over the world and the most common cause of pericardial diseases in developing countries. We will discuss this form and also purulent pericarditis, which is less common. 5.2.1 Tuberculous pericarditis Tuberculous pericarditis accounts for ≤4% of pericardial disease in the developed world. 5,6,52 . In contrast, TB is the cause of clinically significant pericardial effusion in >90% of HIV-infected and 50–70% of non-HIV-infected individuals who live in developing countries where TB is endemic. 77 The disease can occur at any age, and men are affected more frequently than women. 140 Clinical evidence of chronic cardiac compression mimicking congestive heart failure is the most common presentation. 79,93 Clinical presentations are pericardial effusion, effusive-constrictive pericarditis and constrictive pericarditis. 79 Tuberculous pericarditis has a mortality rate of 17–40% at 6 months after diagnosis. 141 It should be emphasized that the majority of the information on tuberculous pericarditis comes from endemic areas in underdeveloped countries and immunodepressed patients. The applicability of this information to the Western world is questionable. 5.2.1.1 Diagnosis A ‘definite’ diagnosis of tuberculous pericarditis is based on the presence of tubercle bacilli in the pericardial fluid or on histological section of the pericardium, by culture or by PCR (Xpert MTB/RIF) testing; a ‘probable’ diagnosis is made when there is proof of TB elsewhere in a patient with unexplained pericarditis, a lymphocytic pericardial exudate with elevated unstimulated interferon-gamma (uIFN-γ), adenosine deaminase (ADA) or lysozyme levels and/or an appropriate response to antituberculosis chemotherapy in endemic areas. 79 uIFN-γ offers superior accuracy for the diagnosis of microbiologically confirmed tuberculous pericarditis compared with the ADA assay and the Xpert MTB/RIF test. 142 A protocol for the evaluation of suspected tuberculous pericardial effusion is proposed in Table 17 . Table 17 A step-wise protocol for the evaluation of suspected tuberculous pericarditis and pericardial effusion ADA = adenosine deaminase; CT = computed tomography; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; TB = tuberculosis. 5.2.1.2 Management A regimen consisting of rifampicin, isoniazid, pyrazinamide and ethambutol for at least 2 months followed by isoniazid and rifampicin (total of 6 months of therapy) is effective in treating extrapulmonary TB. Treatment for ≥9 months gives no better results and has the disadvantages of increased cost and increased risk of poor compliance. 143 The evolution towards constrictive pericarditis is a serious potential complication. Constriction generally develops within 6 months of presentation with effusive pericarditis (effusive-constrictive pericarditis). 79 Tuberculous pericardial constriction is almost always associated with pericardial thickening. Prior to the introduction of effective TB chemotherapy, up to 50% of patients with effusive tuberculous pericarditis progressed to constriction. Rifampicin-based antituberculosis treatment reduced the incidence of constriction to 17–40%. Appropriate antibiotic therapy is essential to prevent this progression. 79,144 In addition, two interventions may reduce the incidence of constriction: the first is intrapericardial urokinase 145 and second, the Investigation of the Management of Pericarditis (IMPI) trial has shown that high-dose adjunctive prednisolone reduces the incidence of constrictive pericarditis by 46% regardless of HIV status. 97 Adjunctive corticosteroid therapy with prednisolone for 6 weeks had a neutral effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or pericardial constriction; however, this therapy was associated with an increased risk of HIV-associated malignancies in the prednisolone-treated group. 97 Adjunctive steroid therapy was associated with a reduced incidence of pericardial constriction and hospitalization. The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients. On this basis, it may be reasonable to use adjunctive corticosteroids in patients with tuberculous pericarditis without HIV infection and to avoid them in HIV-infected individuals because of the increased risk of malignancy. 97 Recommendations for the diagnosis and treatment of tuberculous pericarditis and effusion HIV = human immunodeficiency virus; TB = tuberculosis. aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. Recommendations for the general management of constrictive tuberculous pericarditis aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations. 5.2.2 Purulent pericarditis 5.2.2.1 Epidemiology Purulent pericarditis is rare, accounting for 10 mm in thickness should be investigated for a possible subacute rupture. 180,181 The treatment is generally supportive, as most cases are self-limited. However, a minority of patients may have persistent symptoms that require more than supportive care. For these patients, aspirin plus colchicine may be considered. Late post-AMI pericarditis (Dressler syndrome) is rare ( 38°C), subacute course without a clear-cut acute onset, large pericardial effusion (i.e. diastolic echo-free space >20 mm), cardiac tamponade, failure to respond to NSAID therapy, myopericarditis, immunodepression, trauma or oral anticoagulant therapy. aClass of recommendation. bLevel of evidence. 10. Web addenda All Web figures and Web tables are available in the online addenda at: http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Pericardial-Diseases-Guidelines-on-the-Diagnosis-and-Management-of 11. Appendix ESC Committee for Practice Guidelines (CPG): Jose Luis Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain), Gonzalo Barón-Esquivias (Spain), Helmut Baumgartner (Germany), Jeroen J. Bax (The Netherlands), Héctor Bueno (Spain), Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey), Donna Fitzimons (UK), Oliver Gaemperli (Switzerland), Paulus Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellotti (Belgium), Gregory Y.H. Lip (UK), Petros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi (Switzerland), Adam Torbicki (Poland), Antonio Vaz Carneiro (Portugal), Stephan Windecker (Switzerland). ESC National Cardiac Societies actively involved in the review process of the 2015 ESC Guidelines on the diagnosis and management of pericardial diseases: Albania: Albanian Society of Cardiology, Naltin Shuka; Armenia: Armenian Cardiologists Association, Hamayak Sisakian; Austria: Austrian Society of Cardiology, Julia Mascherbauer; Azerbaijan: Azerbaijan Society of Cardiology, Elnur Isayev; Belarus: Belarusian Scientific Society of Cardiologists, Vadim Shumavets; Belgium: Belgian Society of Cardiology, Guy Van Camp; Bulgaria: Bulgarian Society of Cardiology, Plamen Gatzov; Croatia: Croatian Cardiac Society, Jadranka Separovic Hanzevacki; Cyprus: Cyprus Society of Cardiology, Hera Heracleous Moustra; Czech Republic: Czech Society of Cardiology, Ales Linhart; Denmark: Danish Society of Cardiology, Jacob Eifer Møller; Egypt: Egyptian Society of Cardiology, Mohamed Wafaie Aboleineen; Estonia: Estonian Society of Cardiology, Pentti Põder; Finland: Finnish Cardiac Society, Jukka Lehtonen; Former Yugoslav Republic of Macedonia: Macedonian Society of Cardiology, Slobodan Antov; France: French Society of Cardiology, Thibaud Damy; Germany: German Cardiac Society, Bernhard Schieffer; Greece: Hellenic Cardiological Society, Kyriakos Dimitriadis; Hungary: Hungarian Society of Cardiology, Robert Gabor Kiss; Iceland: Icelandic Society of Cardiology, Arnar Rafnsson; Israel: Israel Heart Society, Michael Arad; Italy: Italian Federation of Cardiology, Salvatore Novo; Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov; Latvia: Latvian Society of Cardiology, Pēteris Stradiņš; Lithuania: Lithuanian Society of Cardiology, Ausra Kavoliuniene; Luxembourg: Luxembourg Society of Cardiology, Andrei Codreanu; Malta: Maltese Cardiac Society, Philip Dingli ; Moldova: Moldavian Society of Cardiology, Eleonora Vataman; Morocco: Moroccan Society of Cardiology, Mustapaha El Hattaoui; Norway: Norwegian Society of Cardiology, Stein Olav Samstad; Poland: Polish Cardiac Society, Piotr Hoffman; Portugal: Portuguese Society of Cardiology, Luís Rocha Lopes; Romania: Romanian Society of Cardiology, Doina Ruxandra Dimulescu; Russia: Russian Society of Cardiology, Grigory P Arutyunov; Serbia: Cardiology Society of Serbia, Milan Pavlovic; Slovakia: Slovak Society of Cardiology, Juraj Dúbrava; Spain: Spanish Society of Cardiology, Jaume Sagristà Sauleda; Sweden: Swedish Society of Cardiology, Bert Andersson; Switzerland: Swiss Society of Cardiology, Hajo Müller; The Netherlands: Netherlands Society of Cardiology, Berto J. Bouma; Turkey: Turkish Society of Cardiology, Adnan Abaci ; UK: British Cardiovascular Society, Andrew Archbold; Ukraine: Ukrainian Association of Cardiology, Elena Nesukay. †Affiliation: Massimo Imazio, Coordinator, Cardiology Department, Maria Vittoria Hospital and Department of Public Health and Pediatrics, University of Torino, Torino, Italy. Email: massimo.imazio@unito.it The CME text ‘2015 ESC Guidelines on the diagnosis and management of pericardial diseases’ is accredited by the European Board for Accreditation in Cardiology (EBAC). EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of Medical Specialists (UEMS). In compliance with EBAC/EACCME Guidelines, all authors participating in this programme have disclosed any potential conflicts of interest that might cause a bias in the article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the programme are declared to the participants prior to the CME activities. CME questions for this article are available at: European Heart Journal http://www.oxforde-learning.com/eurheartj and European Society of Cardiology http://www.escardio.org/guidelines

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Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study

Brian Hanley, Kikkeri N. Naresh, Candice A. Roufosse … (2020)

Summary Background Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.

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Coronavirus Disease 2019 (COVID-19) CT Findings: A Systematic Review and Meta-analysis

Cuiping Bao, Xuehuan Liu, Han Zhang … (2020)

Purpose To date, considerable knowledge gaps remain regarding the chest CT imaging features of COVID-19. We performed a systematic review and meta-analysis of results from published studies to date to provide a summary of evidence on detection of COVID-19 by chest CT and the expected CT imaging manifestations. Methods Studies were identified by searching PubMed database for articles published between December 2019 and February 2020. Pooled CT positive rate of COVID-19 and pooled incidence of CT imaging findings were estimated using a random-effect model. Results A total of 13 studies met inclusion criteria. The pooled positive rate of the CT imaging was 89.76% and 90.35% when only including thin-section chest CT. Typical CT signs were ground glass opacities (83.31%), ground glass opacities with mixed consolidation (58.42%), adjacent pleura thickening (52.46%), interlobular septal thickening (48.46%), and air bronchograms (46.46%). Other CT signs included crazy paving pattern (14.81%), pleural effusion (5.88%), bronchiectasis (5.42%), pericardial effusion (4.55%), and lymphadenopathy (3.38%). The most anatomic distributions were bilateral lung infection (78.2%) and peripheral distribution (76.95%). The incidences were highest in the right lower lobe (87.21%), left lower lobe (81.41%), and bilateral lower lobes (65.22%). The right upper lobe (65.22%), right middle lobe (54.95%), and left upper lobe (69.43%) were also commonly involved. The incidence of bilateral upper lobes was 60.87%. A considerable proportion of patients had three or more lobes involved (70.81%). Conclusions The detection of COVID-19 chest CT imaging is very high among symptomatic individuals at high risk, especially using thin-section chest CT. The most common CT features in patients affected by COVID-19 included ground glass opacities and consolidation involving the bilateral lungs in a peripheral distribution.

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Journal ID (nlm-ta): Cureus

Journal ID (iso-abbrev): Cureus

Journal ID (issn): 2168-8184

Title: Cureus

Publisher: Cureus (Palo Alto (CA) )

ISSN (Electronic): 2168-8184

Publication date (Electronic, pub): 22 March 2024

Publication date (Electronic, collection): March 2024

Volume: 16

Issue: 3

Electronic Location Identifier: e56710

Affiliations

[1 ] Internal Medicine, Saint Michael's Medical Center, Newark, USA

[2 ] Pulmonology and Critical Care, Saint Michael's Medical Center, Newark, USA

[3 ] Cardiology, Saint Michael's Medical Center, Newark, USA

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Wassim Abouzeid w.said@ 123456hotmail.com

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DOI: 10.7759/cureus.56710

PMC ID: 11032651

PubMed ID: 38646402

SO-VID: 0aa2d1ff-1278-4830-a950-ea6eda1a85f5

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This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date accepted : 22 March 2024

Surviving the Storm: Cardiac Tamponade and Effusive Constrictive Pericarditis Complicated by Pericardial Decompression Syndrome Induced by COVID-19 Infection in the Setting of Newly Diagnosed Acute Myeloid Leukemia (AML)

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Novel Coronavirus Disease COVID-19

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2015 ESC Guidelines for the diagnosis and management of pericardial diseases

Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study

Coronavirus Disease 2019 (COVID-19) CT Findings: A Systematic Review and Meta-analysis

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