Diagnosis of acute pericarditis

escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-15/Diagnosis-of-acute-pericarditis

Background
The pericardium, derived from the Greek words περί, “around”, and κάρδιον, “heart”, is a
thin fibroelastic sac, which contains the heart and the roots of the great vessels. It
consists of two layers, a serous visceral (inner portion) and a fibrous parietal layer (outer
portion). In physiologic conditions, the pericardial cavity contains 10-50 mL of plasma
ultrafiltrate (i.e., pericardial fluid) [1]. Inflammation of the pericardial sac is called
pericarditis.

The main pericardial syndromes encompass pericarditis (acute, subacute, chronic,

recurrent), pericardial effusion, cardiac tamponade and pericardial masses. Pericarditis
is the most common form of pericardial disease worldwide and is typically encountered
in young and middle-aged people [2]. It represents 0.2% of all hospital admissions of
cardiovascular aetiology and approximately 5% of patients with non-ischaemic aetiology
chest pain, presenting in the emergency departments of North America and Western
Europe [2]. Acute pericarditis is the most common pericardial syndrome in clinical
practice [3].

This article reviews the causes, clinical picture, inflammatory parameters,

electrocardiogram (ECG) and multimodality imaging findings and briefly discusses the
differential diagnosis of acute pericarditis.

Aetiology
Pericarditis may be an isolated disease or the first manifestation of an underlying
systemic disease. Causes of acute pericarditis can be broadly classified into infectious
and non-infectious [3,4] (Table 1). The aetiology is multifactorial and depends on the
epidemiological background, patient population and clinical setting [3]. In particular, the
most common cause of pericarditis in developed countries is viruses, whereas
tuberculosis is the most frequent cause in developing countries. With regard to endemic
regions, tuberculosis often coexists with human immunodeficiency virus (HIV). Notably,
the most common non-infectious causes are secondary to autoimmune diseases,
metastatic tumours and post-cardiac injury syndromes [5].

Table 1. Main causes of acute pericarditis [1-3,6,19].

Categories Causes Frequency

A. IDIOPATHIC Unknown Most frequent

cause

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 Categories Causes Frequency

B. INFECTIOUS
CAUSES

Viral Epstein-Barr, influenza, hepatitis, human Most frequent

immunodeficiency virus, mumps, echovirus, cause in
adenovirus, cytomegalovirus, varicella, rubella, human developed
herpesvirus, parvovirus, coxsackie countries

Bacterial Mycobacterium tuberculosis, Coxiella burnetii, Rare (with the

streptococcus, staphylococcus, pneumococcus, exception of
legionella, salmonella, haemophilus mycobacterium
tuberculosis)

Fungal Candida, aspergillosis, histoplasmosis, blastomycosis Very rare

Parasitic Toxoplasma, echinococcus Very rare

C. NON-
INFECTIOUS
CAUSES

Neoplastic Primary: pericardial mesothelioma Frequent as

secondary
Secondary tumours: leukemia, breast cancer, lung metastasis
cancer,

lymphoma, melanoma

Metabolic Hypothyroidism, renal failure, hypercholesterolaemia, Frequent

gout, anorexia nervosa

Cardiovascular Acute myocardial infarction, Dressler syndrome, aortic Frequent

dissection

Autoimmune Rheumatoid arthritis, systemic lupus erythematosus, Frequent

Sjogren syndrome, dermatomyositis, sarcoidosis,
systemic vasculitides, Behcet syndrome, familial
mediterranean fever

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 Categories Causes Frequency

Traumatic and Catheterisation, surgery, chest trauma, radiation Frequent

iatrogenic

Drug-related Phenytoin, minoxidil, isoniazid, procainamide, Rare

hydralazine, methyldopa, doxorubicin, amiodarone,
clozapine, streptomycin

Other Congenital absence of pericardium Rare

Diagnostic evaluation
The main diagnostic evaluation consists of medical history (recent viral infection) and
physical examination (to detect pericardial rubs at auscultation and additional possible
signs of a systemic disease that may be responsible for pericarditis); blood tests (WBCs,
ESR, CRP, troponin, complete blood count [CBC], urea, creatinine); ECG; transthoracic
echocardiography (TTE); and chest X-ray.

Clinical presentation
Acute pericarditis is defined as an “inflammatory pericardial syndrome with or without
pericardial effusion” [3]. The diagnosis is clinical and can be made based on two of the
following criteria: a) pericardial chest pain in the patient’s medical history, b) pericardial
rubs upon auscultation, c) new widespread ST-elevation or PR depression on ECG, and d)
pericardial effusion (new or worsening). Supporting findings are elevation of
inflammatory markers and evidence of pericardial inflammation by computed
tomography (CT) or cardiac magnetic resonance (CMR) [3]. Specific features at
presentation such as temperature >38°C, subacute onset, large pericardial effusion (>20
mm) or tamponade and non-response to aspirin or nonsteroidal anti-inflammatory drugs
(NSAIDs) are major factors of poor prognosis. Minor factors include concomitant
myocarditis, immunodepression, trauma and oral anticoagulant therapy [3].

Patients with acute pericarditis typically present with chest pain (>85-90% of cases), that
usually radiates to the trapezius ridge, left shoulder, or arm and resembles ischaemic
pain. However, retrosternal pain in acute pericarditis is mainly sharp and pleuritic, which
augments in the supine position, with cough and deep inspiration. Conversely, it usually
subsides in the upright position and by leaning forward, due to decrease of the pressure
on the parietal pericardium [6]. Common associated signs and symptoms include low-
grade intermittent fever, dyspnoea, cough, malaise, myalgia and occasionally hiccoughs.
The medical history often reveals symptoms suggestive of viral infection.

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Auscultation exposes a pericardial friction rub (pathognomonic sign for pericarditis), due
to increased friction of inflamed pericardial layers, in about one third of patients with
acute pericarditis. It is a superficial scratchy or squeaking sound, best heard with the
diaphragm of the stethoscope over the left sternal border with the patient leaning
forward. It typically consists of three phases, corresponding to movement of the heart
during atrial systole (absent in atrial fibrillation), ventricular systole and the rapid filling
phase of early ventricular diastole [2,6]. Sometimes, pericardial rub has only two
components or even one component. Notably, pericardial friction rub can disappear not
only at healing of pericarditis, but also when there is development of more pericardial
fluid in the pericardial sac, reflecting either improvement or exacerbation of the disease.
In addition, friction rub in acute pericarditis can vary in intensity from moment to
moment, which rarely happens with the other forms of pericarditis. The auscultation of
pericardial friction rub is highly specific for acute pericarditis (specificity approximately
100%).

ECG findings
Typical ECG findings in acute pericarditis are present in no more than 60% of cases and
evolve in four stages (Figure 1). In particular, ECG initially (within hours to days) depicts
diffuse concave ST-segment elevation (in all leads, except aVR and often V1) with
concomitant PR depression (first stage), followed by (within the first week) return to
baseline of the latter deviations and T-wave flattening (second stage), diffuse T-wave
inversion after the ST-segment has become isoelectric (third stage) and, finally, ECG
normalisation or persistence of T-wave inversions (fourth stage) [6-8]. Sustained atrial or
ventricular arrhythmias are not frequent in acute pericarditis and their presence denotes
concomitant myocarditis or another not relevant cardiac disease [9].

Figure 1. ECG of a 32-year-old man with acute pericarditis, presenting with chest
pain. Note the characteristic concave ST elevation in leads I, II, aVL and V5-V6.

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The ECG of acute pericarditis often resembles that of ST-elevation myocardial infarction
(STEMI). ECG findings suggestive of acute pericarditis are: a) the occurrence of ST-
elevation less than 5 mm, b) ST-segment concavity, c) more extensive lead involvement,
d) less prominent reciprocal ST-segment depression, e) PR-segment elevation in aVR,
with reciprocal PR-segment depression in other leads, f) the absence of abnormal Q-
waves, g) variability in the time of T-wave inversion occurrence, following ST-segment
elevation, h) the lack of QRS widening and QT interval shortening in leads with ST
elevation [10].

Sometimes, acute pericarditis ECG should be differentiated from that of early

repolarisation. Notably, in acute pericarditis, the ratio of ST elevation to T-wave
amplitude in lead V6 usually exceeds 0.24 (positive and negative predictive values are
both 100%). This ECG sign is typical for the differential diagnosis with early repolarisation
[11].

An interesting study proposed the use of leads I and V4-V6 in order to differentiate acute
pericarditis from early repolarisation and left ventricular hypertrophy [12]. In particular,
the authors concluded that a ratio of the ST amplitude segment to the amplitude of the
T-wave ≥0.25, in leads I, V4, V5 and V6, was predictive of acute pericarditis. Notably, the
best predictive value of the ST/T ratio appeared when ST elevation presented in lead I.

Laboratory tests - markers of inflammation

Elevation of inflammatory markers is common in patients presenting with acute
pericarditis. Among them, the most widely used are the white blood cells (WBCs),
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). CRP is used not only
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to confirm the suspicion of acute pericarditis, but also to monitor the duration of disease
activity and regulate the treatment based on the individual patient’s characteristics [13].

In the presence of concomitant myocarditis and pericarditis (myopericarditis), serum

biomarkers of myocardial injury, such as CK and troponin I or T, are increased. The
evaluation of troponins is mainly for the exclusion of myopericarditis, as they do not
seem to exhibit prognostic value on acute pericarditis [14]. Interestingly, pericarditis
patients with elevated biomarkers of myocardial injury almost always exhibit ECG
changes characteristic of ST-segment elevation.

The prognostic role of carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1),

which is an immune inhibitory protein, and MHC class I chain related protein A (MICA),
which exhibits an immune stimulating function, in patients with acute and recurrent
pericarditis is promising [15]. CEACAM1 and MICA are serum proteins that can be
released from damaged or inflamed tissues, in patients with pericarditis. Markel et al
[15] reported that patients with acute pericarditis show high serum CEACAM1 levels,
either due to unique splicing in the injured pericardial cells or due to other mechanisms
such as proteolytic cleavage. In the same study, serum MICA levels were elevated in
some of the pericarditis patients, but without reaching statistical significance. However,
in the subgroup of patients with recurrent pericarditis, a significant positive correlation
between serum MICA concentrations and recurrences was observed, independently of
other potentially confounding parameters linked to recurrences [15]. The authors
concluded that CEACAM1 could serve as a potentially novel biomarker for pericarditis
and MICA as an innovative prognostic marker in these patients.

A routine laboratory evaluation should include markers of renal function (urea,

creatinine), electrolytes, LDH and transaminases (SGOT, SGPT). If there is a clinical
indication, more specific tests may be ordered, such as blood cultures, thyroid function
hormones, antinuclear antibodies (ANA), anti-neutrophil cytoplasm antibodies (ANCA),
anti-extractable nuclear antigens (ENA), HIV testing and even pericardial biopsy [3].

Chest X-ray
In patients presenting with acute pericarditis, the chest X-ray is usually within normal
limits, since an increased cardiothoracic index is exhibited when pericardial effusion is
more than 300 mL. Signs of pleuropericardial involvement may be found in the chest X-
ray of patients with acute pericarditis, in the background of pleuropulmonary disease.
Chest X-ray may reveal diseases such as malignancies, sarcoidosis, or several infections,
which may be the cause of acute pericarditis. Occasionally, small pleural effusions are
present, presumably due to viral or possibly mycoplasmal infections. A patient
presenting with new and otherwise unexplained cardiomegaly, especially in the setting of
clear lung fields, should be evaluated for acute pericarditis [6].

Echocardiography
Echocardiography is low cost, widely available and can be performed on an urgent basis.
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It provides valuable information regarding the thickening and hyperechogenicity of
pericardial layers, the presence or absence of pericardial effusion, its volume and its
concomitant haemodynamic effects (tamponade, restriction) [6,16]. Pericardial effusion,
either new appearing or worsening, is typically mild and is evident in 60% of cases [6]
(Figure 2). With the use of the M-mode, pericardial effusion is demonstrated as an echo-
free space between the inner and outer layer of pericardium at cardiac systole and
diastole, whereas a simple systolic separation may be considered physiologic [1].
Pericardial effusion, based on the size at diastole, is characterised as mild (<10 mm),
moderate (10-20 mm) or large (>20 mm) [1]. Unfortunately, TTE may exhibit a number of
limitations such as poor acoustic window due to obesity or chronic obstructive
pulmonary disease (COPD), limited tissue characterisation and a relatively high
dependence on the operator [17]. That is why several other imaging techniques have
evolved during recent years, assisting in the diagnostic work-up of patients with
pericarditis.

Figure 2. The echocardiographic examination (parasternal short-axis view) of a 60-

year-old woman with acute pericarditis reveals echo-free space (>1 and <2 cm)
located posteriorly, suggestive of moderate pericardial effusion.

CT/CMR
Multimodality imaging is an integral part of acute pericarditis diagnostic work-up and,
apart from echocardiography which is considered the first-line test, includes CT and/or
CMR (second-line imaging tests). Cardiac CT manifests several advantages regarding
pericarditis investigation such as the assessment of pericardial calcifications and

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thickening and also the evaluation of concomitant diseases. Advanced techniques such
as ECG gating provide excellent images without motion artefacts [18]. However, major
limitations are the use of ionising radiation and iodinated contrast, the unmet need for
breath-hold and the inability to assess unstable patients or patients with arrhythmias [6].
On the other hand, CMR can provide the characterisation of cardiac tissue, the
assessment of thickening and constriction and the evaluation of myocardial involvement.
CMR does not require radiation or nephrotoxic contrast agents. Furthermore, baseline
late gadolinium enhancement (LGE) seen on CMR may correlate with inflammation
severity [18]. A CMR protocol for pericardial disease usually encompasses cine imaging,
black-blood imaging of the heart and pericardium, tagging, phase-contrast sequences
and delayed enhancement imaging in order to evaluate the LGE [18]. Unfortunately, this
technique also has several weaknesses as it is time-consuming, high cost, not widely
available and requires stable patients and rhythms. In addition, patients with severe
renal impairment and pacemakers may not be eligible candidates [6].

Differential diagnosis
A number of pathologies characterised by chest pain such as acute coronary syndromes,
aortic dissection, pulmonary embolism, pneumonia, pneumonitis, gastric ulcer,
gastroesophageal reflux disease, pneumothorax and herpes zoster are part of the
differential diagnosis with acute pericarditis [19,20] (Table 2).

Table 2. Differential diagnosis of acute pericarditis [19,20].

Angina

Acute coronary syndromes

Aortic dissection

Aortic stenosis

Oesophagitis

Oesophageal spasm

Oesophageal rupture

Gastric ulcer

Pancreatitis

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 Pulmonary embolism

Pulmonary hypertension

Pneumonia

Pneumonitis

Pleuritis

Tuberculosis

Pneumothorax

Musculoskeletal disorders

Trauma

Herpes zoster

Depression

Panic disorder

Acute pericarditis is usually distinguished from myocardial ischaemia or infarction (based

on the clinical findings, ECG, markers of myocardial necrosis and imaging modalities
such as echocardiography), but coronary angiography is sometimes required to resolve
the issue. Finally, not infrequently, acute pericarditis is a manifestation of a presenting,
silent MI.

Specific forms of pericarditis

According to the 2015 ESC guidelines on pericardial disease [3], the definite diagnosis of
viral pericarditis derives from the comprehensive work-up of histological, cytological,
immunohistological and molecular investigations in pericardial fluid and
pericardial/epicardial biopsies, otherwise the term “presumed viral pericarditis” should
be used. For the diagnosis of purulent pericarditis, urgent pericardiocentesis is
recommended and pericardial fluid should be sent for bacterial, fungal and tuberculous
studies, and blood should be drawn for cultures. Furthermore, urgent TTE or CT is

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recommended in patients with a history of chest trauma and systemic arterial
hypotension. Lastly, as far as malignancies are concerned, cytological analyses of
pericardial fluid are recommended.

Conclusions
Acute pericarditis is the most frequent among the pericardial syndromes. Its aetiology is
multifactorial. The cardinal symptom is chest pain that sometimes needs to be
differentiated from the ischaemic pain. Diagnosis is clinical and is made when two out of
the four following criteria are fulfilled: a) chest pain, b) pericardial rubs, c) ECG changes,
d) pericardial effusion. Supporting findings are the increase in inflammatory markers and
evidence of inflammation in imaging (CT/CMR). The emerging role of new inflammatory
markers (i.e., CEACAM1 and MICA) is hopeful. Multimodality imaging is vital during the
diagnostic work-up of patients with acute pericarditis.

Notes to editor

Authors:

Dr. Andrew Xanthopoulos1, MD, PhD; Professor John Skoularigis2, MD, PhD, FESC

1. Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic,

Cleveland, OH, USA;

2. University General Hospital of Larissa, Department of Cardiology, Larissa, Greece

Author for correspondence:

Dr. Andrew Xanthopoulos, Department of Cardiovascular Medicine, Heart and Vascular

Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

Email address: andrewvxanth@gmail.com

Conflict of interest statement

The authors have no conflicts of interest to declare.

The content of this article reflects the personal opinion of the author/s and is not
necessarily the official position of the European Society of Cardiology.

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