Pericarditis and Perocardial Diseases in Children: Clinical Guidelines

List of Abbreviations

BP – blood pressure

ASA** – acetylsalicylic acid**

ASLO – antistreptolysin O

HIV – human immunodeficiency virus

CHD – congenital heart disease

SCD – sudden cardiac death

GC – glucocorticoids

CTD – connective tissue diseases

IL-1 — interleukin-1

IRP – idiopathic recurrent pericarditis

CT – computed tomography

CTR – cardiothoracic ratio

CK – creatine kinase

LV – left ventricle

IVS – interventricular septum

ICF – International Classification of Functioning, Disability and Health

MDT – multidisciplinary rehabilitation team

MRI – magnetic resonance imaging

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

renal failure – renal failure

PCPS – post-pericardiotomy syndrome

PCR – polymerase chain reaction

RP – recurrent pericarditis

SBP – systolic blood pressure

SLE – systemic lupus erythematosus

HF – heart failure

ESR – erythrocyte sedimentation rate

HPS – heart injury syndromes

CRP – C-reactive protein

TSH – thyroid-stimulating hormone

EF – ejection fraction

FC – functional class

PE – physical exertion

CHF – chronic heart failure

CVP – central venous pressure

PCI – percutaneous coronary interventions

ECG – electrocardiogram (electrocardiogram recording)

EchoCG – echocardiography

** – the drug is included in the list of vital and essential drugs

# – off-label use of the drug is possible

Terms and Definitions

Acute pericarditis— a clinical syndrome characterized by pericardial inflammation with or without concomitant pericardial effusion.

Incessant pericarditis is pericarditis with a continuous course following an acute episode without achieving remission.

Chronic pericarditis is the presence of pericardial effusion lasting for more than 3 months.

Recurrent pericarditis is a condition in which, following a documented first episode of acute pericarditis, there is an asymptomatic period of 4–6 weeks or longer followed by the reappearance of signs of pericarditis.

Pericardial cavity is a closed slit-like space surrounding the heart and containing about 10–50 ml of serous fluid.

Constrictive pericarditis is a condition characterized by thickening and fusion of the pericardial layers (with calcification in 50% of cases), leading to compression of the heart chambers and restriction of their diastolic filling.

Pericardial effusion is inflammation of the pericardium accompanied by the accumulation of effusion in the pericardial space.

Cardiac tamponade is a life-threatening condition characterized by rapidly progressive or gradual compression of the heart due to the accumulation of fluid, blood, pus, thrombotic masses, or gas around it as a result of inflammation, trauma, cardiac rupture, or aortic dissection.

Hydropericardium— excessive accumulation of transudate in the pericardial cavity.

Chylopericardium is excessive accumulation of chylous effusion in the pericardial cavity.

Pericardiocentesis— a therapeutic and diagnostic procedure involving puncture of the chest wall and pericardium to remove fluid, blood, pus, lymph, or transudate, in some cases followed by drainage of the pericardial cavity.

Pericardiectomy is a surgical operation for the resection of the pericardial layers.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pericarditis is the most common form of pericardial disease, characterized by inflammation of the pericardial layers of various etiologies with or without effusion into its cavity [1].

Pericarditis can be an independent pathological process (isolated form) or a cardiac manifestation of a systemic disease (e.g., autoimmune or autoinflammatory disease) [2,3].

The clinical presentation of pericarditis is variable in terms of onset time, symptoms, and prognosis.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology of pericarditis

Pericarditis can be either an independent disease or secondary to other conditions. All etiological factors that may be involved in the development of pericarditis can be conventionally divided into three groups: infectious, non-infectious, and idiopathic [4].

1. Infectious causes:

   - viral: enteroviruses (such as Coxsackie A and B, ECHO); viruses of the Coronaviridae family; members of the Herpesviridae family (such as human herpesvirus 6 [HHV6], Epstein-Barr virus, and cytomegalovirus); parvovirus B19; influenza virus, adenoviruses, chickenpox, mumps, rubella, hepatitis B and C viruses, HIV;

   - bacterial: Mycobacterium tuberculosis (frequent, other bacteria rare), Coxiella burnetii, Borrelia burgdorferi, rarely: Pneumococcus spp., Meningococcus spp., Gonococcus spp., Streptococcus spp., Staphylococcus spp., Haemophilus spp., Chlamydia spp., Mycoplasma, Legionella, Leptospira, Listeria, Providencia stuartii.

   In children, Staphylococcus aureus is the most common cause of bacterial pericarditis, accounting for 40–80% of cases. During the first 3 months after cardiac surgery, S. aureus is the most frequent cause of purulent pericarditis.

   - fungal (very rare): Aspergillus spp., Blastomyces spp., Candida spp. (most common in immunocompromised children), Histoplasma spp. (most common in immunocompetent individuals);

   - parasitic (very rare): Toxoplasma spp., Echinococcus spp., Trypanosoma cruzi.

2. Non-infectious causes:

   • Autoimmune (frequent):

     - systemic inflammatory diseases: systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, vasculitis, dermatomyositis, mixed connective tissue disease;

     - autoinflammatory diseases: familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), IgG4-related diseases;

     - post-cardiac injury syndromes: immune-mediated conditions after cardiac trauma in predisposed individuals;

     - other: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), polyarteritis nodosa, sarcoidosis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), Whipple's disease, giant cell arteritis, Behcet's disease, rheumatic fever;

     - chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation;

   • Neoplastic:

     - Primary tumors (rare): malignant – pericardial mesothelioma, fibrosarcoma, and angiosarcoma; benign – lipomas, fibromas;

     - Secondary metastatic tumors: frequently in lung and breast cancer, lymphoma, melanoma, etc.;

   • Metabolic:

     - Uremia, hypothyroidism, hypothyroidism, anorexia nervosa;

   • Traumatic:

     - Early onset (rare): direct injury: penetrating wound, esophageal perforation. Indirect injury: non-penetrating chest wound, blunt chest trauma;

     - Delayed onset: post-cardiac injury syndromes (e.g., post-pericardiotomy syndrome, post-myocardial infarction);

   • Iatrogenic causes: following percutaneous coronary intervention, pacemaker lead placement, radiofrequency ablation, etc.;

   • Drug-induced causes: lupus-like syndromes caused by drugs such as procainamide**, isoniazid**, methyldopa**; hypersensitivity reaction with eosinophilia (beta-lactam antibacterial drugs, penicillins, tryptophan); conventional antineoplastic drugs, often combined with cardiomyopathy – doxorubicin**, daunorubicin**, cyclophosphamide**, anthracyclines, and related compounds; targeted antineoplastic drugs, tumor immunotherapy, monoclonal antibodies, amiodarone**, thiazide diuretics (thiazides), streptomycin**, oral anticoagulants ( antithrombotic agents), certain vaccines, serum sickness reactions, etc.;

   • Radiation-induced: early onset and late onset (15–20 years later);

   • Pericarditis caused by diseases of the heart and adjacent organs: myocarditis, myocardial infarction, chronic heart failure, pulmonary arterial hypertension, pneumonia, pleural empyema;

   • Other: amyloidosis, chylopericardium, polycystic kidney disease, pericardial cysts, hereditary partial and complete absence of the pericardium.

3. Idiopathic pericarditis.

In a number of cases, patients have no identifiable cause. Idiopathic pericarditis accounts for 37% to 68% of all cases of pericarditis.

In such cases, a viral (direct or indirect viral injury) or autoimmune etiology is most commonly suspected [3,4].

Pathogenesis of Pericarditis

The pathogenesis of pericarditis is due to a complex interaction between trigger factors and the body's immune system. Interleukin-1 alpha and interleukin-1 beta play a special role in pathogenesis, maintaining a progressive autoinflammatory cycle through the activation of a signaling pathway involving the synthesis of inflammatory molecules – cyclooxygenase, prostaglandins, and interleukin-6. Interleukin-6 can increase C-reactive protein levels, which in turn serves as a marker of the efficacy of anti-inflammatory therapy [5,6,7].

Pharmacotherapy, such as colchicine, anti-inflammatory therapy with NSAIDs and glucocorticoids, and immunotherapy, can target various areas of the complex pathophysiology of pericarditis [8].

1.3 Epidemiology of the Disease or Condition

Epidemiological data on acute pericarditis are limited to single-center reports and are rather sparse. According to these data, the incidence of acute pericarditis in the general population is 30–150 cases per 100,000 per year, accounting for 0.2% to 5% of all emergency department visits for chest pain [9,10,11,12].

Recurrent pericarditis develops in 35% of pediatric patients; a risk factor for this form of the disease is the discontinuation of colchicine during the initial acute episode or a rapid dose reduction and early withdrawal of glucocorticoids [13,14,15].

1.4 Features of Coding the Disease or Condition

I30 – Acute Pericarditis

I30.0 – Acute nonspecific idiopathic pericarditis

I30.1 – Infectious pericarditis

I30.8 – Other forms of acute pericarditis

I30.9 – Acute pericarditis, unspecified

I31 – Other Diseases of Pericardium

I31.0 – Chronic adhesive pericarditis

I31.1 – Chronic constrictive pericarditis

I31.2 – Hemopericardium, not elsewhere classified

I31.3 – Noninflammatory pericardial effusion (chylopericardium)

I31.8 – Other specified diseases of pericardium

I31.9 – Disease of pericardium, unspecified (cardiac tamponade)

I32* – Pericarditis in Diseases Classified Elsewhere

I32.0 – Pericarditis in bacterial diseases classified elsewhere

I32.1 – Pericarditis in other infectious and parasitic diseases classified elsewhere

I32.8 – Pericarditis in other diseases classified elsewhere

1.5 Classification of the disease or condition

Based on the duration of the course, the following are distinguished:

- acute pericarditis (up to 4–6 weeks);

- subacute/incessant pericarditis (more than 4–6 weeks, but less than 3 months without remission);

- chronic pericarditis (more than 3 months);

- recurrent pericarditis (occurs after the first episode of acute pericarditis with an asymptomatic period of at least 4–6 weeks): it can be intermittent (with asymptomatic periods without therapy for more than 6 weeks) and incessantly recurrent (cessation or reduction of anti-inflammatory therapy triggers a recurrence in less than 6 weeks).

Based on the presence or absence of effusion, the following are distinguished:

- dry (fibrinous);

- exudative/exudative-constrictive:

by the nature of the effusion:

– transudate (hydropericardium),

– exudate: serous, hemorrhagic, purulent (pyopericardium), chylous (chylopericardium).

Based on the volume of effusion measured by echocardiography at end-diastole for school-age children and adolescents:

- small effusion (50–100 ml or <10 mm);

- moderate effusion (100–500 ml or 10–20 mm);

- large effusion (>500 ml or >20 mm).

Based on the presence of hemodynamic disturbances:

- without hemodynamic disturbances;

- cardiac tamponade;

- pericardial constriction.

1.6 Clinical presentation of the disease or condition

The following forms of pericarditis are encountered in clinical practice:

Acute pericarditis is an inflammatory lesion of the pericardium with or without effusion in its cavity. The disease has an acute onset, presenting with chest pain at onset, usually sharp, but may also be described as dull, pressing, or throbbing. It typically worsens in the supine position and eases or resolves when the patient sits up or leans forward. Inspiration and cough may intensify the pain, necessitating differential diagnosis with pleurisy. The pain may radiate to the back and shoulders [1,4,11,13].

In younger children, abdominal pain, dyspeptic symptoms, vomiting, and abdominal tenderness are common, requiring the exclusion of surgical abdominal pathology and gastrointestinal diseases. Pain may increase with rapid backward head tilting (Gerke's sign). Equivalents of the pain syndrome in infants may be sudden, unexplained episodes of severe agitation, pallor, sometimes vomiting, and increased dyspnea and tachycardia [1,4,11,13].

Malaise, fever, myalgia, and cardiac arrhythmias may occur. Dyspnea develops less frequently; its appearance or worsening indicates an increasing volume of exudate. With rapid accumulation of effusion, abdominal pain caused by stretching of the liver capsule may occur. Physical examination reveals a pericardial friction rub, which is best heard along the left sternal border when the patient leans forward; however, with a large volume of effusion, the pericardial friction rub may be absent [1,4,13,15].

Recurrent pericarditis – idiopathic recurrent pericarditis is characterized by alternating episodes of remission and sterile inflammation of the pericardium combined with fever and elevated acute-phase reactants; some patients present with polyserositis, arthralgia, myalgia, and liver involvement [16].

Chronic pericarditis – the clinical presentation has no fundamental differences from recurrent pericarditis, although symptoms may be less pronounced [16].

Constrictive pericarditis – caused by inflammation, fibrosis, and calcification of the pericardium followed by the development of diastolic right- and/or left-ventricular heart failure [17]. The initial stage of the disease is characterized by hemodynamic disturbances occurring only during physical exertion. The classic clinical presentation during the manifest period is characterized by symptoms predominantly of right-ventricular heart failure in the absence of ventricular dysfunction. Patients complain of fatigue, peripheral edema, shortness of breath, and abdominal distension. Compression of the superior and inferior venae cavae at their entry into the right atrium is also observed, resulting in jugular venous distension that increases during inspiration and facial puffiness. Due to venous congestion, hepatomegaly, pleural effusion, and ascites develop. There is wide variability in the duration of the period between initial pericardial inflammation and the onset of constriction; both direct evolution of subacute/chronic pericarditis into constrictive pericarditis and prolonged symptom development over several years are possible [4,18].

Cardiac tamponade – a life-threatening condition that occurs after the sudden and/or excessive accumulation of fluid, pus, blood, or gas in the pericardial space, which restricts adequate filling of the heart chambers, disrupts normal hemodynamics, and ultimately causes hypotension and cardiac arrest.

Clinical signs of cardiac tamponade include severe weakness, dizziness, and possible syncope. The typical posture of the patient is sitting leaning forward. Physical examination reveals skin pallor, cold sweat, cyanosis, tachycardia, dyspnea, hypotension, muffled heart sounds, the appearance or worsening of hepatomegaly, ascites, and edema. A specific symptom is pulsus paradoxus, defined as a drop in systolic blood pressure during inspiration by more than 10 mmHg during quiet breathing. The combination of arterial hypotension, muffled heart sounds, and jugular venous distension is known as Beck's triad. The severity of hemodynamic disturbances depends on the rate of tamponade development, the volume of effusion, pericardial compliance, filling pressures, and the mobility of the heart chambers [1,4,18]. Cardiac tamponade more frequently complicates the first episode of pericarditis than recurrences.

2. Diagnostics, medical indications and contraindications for diagnostic methods

According to the European Society of Cardiology guidelines (2015), the diagnosis of acute pericarditis requires at least 2 of the 4 criteria: 1) chest pain; 2) pericardial friction rub; 3) electrocardiographic changes; and 4) presence of pericardial effusion [1].

To assess disease activity, inflammatory markers are determined (e.g., serum C-reactive protein level, erythrocyte sedimentation rate, and differential leukocyte count) along with signs of inflammatory pericardial involvement using various imaging modalities (contrast-enhanced computed tomography or magnetic resonance imaging of the heart) [1].

Given the limited number of studies on pericarditis in pediatric patients, there are currently no evidence-based guidelines for multimodal imaging in pediatric pericarditis, unlike in adults. The need for additional diagnostic tests depends on the etiology of the pericarditis, whether it is isolated or part of a systemic disease, and the duration of the condition [1,4,19,20].

2.1 Complaints and Anamnesis

LoE C, GoR 5

Medical history taking should include the following points

• timing of symptom onset and their dynamic changes

• preceding episodes of viral or bacterial infections

• presence of comorbid conditions (connective tissue diseases, systemic vasculitis, autoinflammatory syndromes, hypothyroidism, renal failure, amyloidosis, tumors), records of dispensary registration with a pediatric cardiologist or other specialists, surgical interventions (correction of congenital heart defects, etc.)

• data on vaccinations and tuberculin skin tests

• epidemiological history

• information on current medications the patient is taking at the time of examination (drugs and toxins associated with pericardial diseases: procainamide**, methyldopa**, isoniazid** (drug-induced lupus syndrome); benzylpenicillin**, tryptophan, cromoglicic acid** (hypersensitivity reaction); minoxidil, cyclosporine**, bromocriptine**, amiodarone**, sulfonamides (idiosyncrasy); tyrosine kinase inhibitors (chemotherapy cytotoxicity).

The primary complaint of patients with acute pericarditis, present in the vast majority of patients, is chest pain.

Comments: the characteristics of the pain syndrome vary widely from moderate to "infarction-like"; it is related to respiration, coughing, and changes in body position, with radiation to the trapezius muscle, and typically decreases in intensity in the sitting position leaning forward.

Shortness of breath most frequently occurs in acute pericarditis and is caused by the development of diastolic dysfunction.

In the context of systemic disease, extracardiac manifestations of the underlying condition (fever, night sweats, arthritis, weight loss, and rash) may predominate. Abdominal pain and dyspeptic symptoms are rarely observed, predominantly in younger age groups. The equivalent of pain syndrome in infants may be sudden, unexplained episodes of acute distress, pallor, shortness of breath, tachycardia, and sometimes vomiting [1,4,11,21].

In a study by Ratnapalan S. et al., the most common symptoms of acute pericarditis among children and adolescents presenting to the emergency department were chest pain (96%), fever (55%), and vomiting (32%), while cough, dyspnea, and fatigue were less frequently observed [11].

2.2 Physical Examination

CBR C, LOR 5.

When examining the child, attention should be paid to:

• forced posture: sitting with the torso leaned forward, sometimes resting on the forehead

• less frequently observed are bulging in the precordial and xiphoid areas, absence of active respiratory muscle movements in the epigastric region, and smoothing of the left intercostal spaces

• in constrictive pericarditis, facial and neck edema, acrocyanosis, dyspnea, Kussmauss sign (jugular venous distension during inspiration), pulsus paradoxus, and signs of right- and left-ventricular heart failure are revealed.

On palpation, the cardiac apex beat is markedly weakened and displaced upward and inward, and intensifies in the supine position.

On percussion, the boundaries of relative cardiac dullness are markedly expanded to the left (outward from the apex beat), right, and upward, and change depending on the patient's body position. With significant effusion, dullness of the percussion note, a bronchial tint to breath sounds, and egophony are determined below the angle of the left scapula (Ewart's sign), due to compression of the lower lobe of the left lung. When the patient leans forward, the pericardial fluid shifts and the lung expands, which is accompanied by the disappearance of dullness and the appearance of crackles (Pins' sign).

On cardiac auscultation:

• heart sounds will be muffled depending on the volume and nature of the effusion.

• tachycardia may be present without other signs of heart failure.

• a pericardial friction rub is a specific sign of acute pericarditis, can be heard along the lower left sternal border and intensifies when leaning forward, has no relation to heart sounds and cardiac cycle phases, but depends on the respiratory phase.

• in constrictive pericarditis, a triple heart rhythm appears (the "third heart sound" or pericardial knock is identified – an additional sound at the beginning of diastole characterized by rapid diastolic filling).

Comments: the pericardial friction rub can be strictly localized (heard at a single point) or widespread, but is always limited to the zone of absolute cardiac dullness; it varies greatly in timbre from soft and short to coarse "scraping" or "creaking" (with increased fibrinous deposits on the pericardial leaflets), and is heard either only during expiration or only during inspiration, whereas a pleural friction rub can only be heard during inspiration, which is used for differential diagnosis.

When examining a child with acute cardiac tamponade, Beck's triad will manifest: hypotension, jugular venous distension, and muffled heart sounds. An important diagnostic criterion is the presence of pulsus paradoxus—an inspiratory drop in systolic blood pressure of 10 mmHg or more during normal breathing. In gradually developing tamponade, the clinical picture resembles worsening heart failure (predominantly right-sided): anxiety, pallor, cold sweat, acrocyanosis, orthopnea, increasing dyspnea and tachycardia, hepatomegaly, jugular venous distension, and pulsus paradoxus. Cardiac tamponade is most frequently recorded in patients with acute pericarditis of specific etiology (malignant neoplasms, tuberculosis, etc.).

2.3 Laboratory Diagnostics

An important point is the interpretation of laboratory test results in conjunction with the clinical picture and instrumental diagnostic data, since pathognomonic laboratory markers for pericarditis are absent.

LoE C, GoR 5

Comments: changes in the complete blood count are determined by the etiology of the process (viral, bacterial, autoimmune, allergic), its acuity and activity, but are neither sensitive nor specific for acute pericarditis. However, inflammatory markers play an important role in determining process activity and the optimal duration of therapy.

LoE C, GoR 5

Comments: dysproteinemia is noted (hypoalbuminemia, elevated α2- and γ-globulins); creatinine and serum potassium levels are elevated in uremia. LDH, ALT, and AST activity reflects the activity of the overall infectious and inflammatory process.

GoR C, LoE 4

Comments: cardiac isoenzymes (troponin, creatine kinase MB [CK-MB]) are elevated in acute pericarditis in 30% of cases, typically with prominent ST-segment elevation on the ECG, more frequently with concomitant myocarditis. Unlike acute coronary syndrome, an elevation in troponin I or T is not a negative prognostic marker in myopericarditis.

Other laboratory tests are performed to clarify the suspected etiology of pericarditis [21]:

1. intradermal tuberculin test (recombinant tuberculosis allergen in standard dilution** and bacterial allergens**);

2. microbiological (culture) blood test for sterility;

3. virological blood tests by PCR methods (qualitative determination of Cytomegalovirus DNA in blood by PCR; qualitative determination of Epstein-Barr virus DNA in blood by PCR; qualitative determination of human herpesvirus type 6 [HHV6] DNA in blood by PCR; qualitative determination of herpes simplex virus types 1 and 2 DNA in blood by PCR; quantitative determination of parvovirus B19 DNA in peripheral blood by PCR; qualitative determination of Varicella-Zoster virus DNA in blood by PCR; determination of Adenovirus DNA);

4. qualitative determination of human immunodeficiency virus DNA by PCR;

5. quantitative determination of hepatitis C virus RNA in blood by PCR; quantitative determination of hepatitis B virus DNA in blood by PCR;

6. determination of Mycoplasma pneumoniae DNA in blood by PCR; molecular biological blood test for Chlamydophila pneumoniae by PCR;

7. blood procalcitonin level test;

8. coagulogram (exploratory hemostasis screening);

9. determination of antinuclear antibodies (ANA) on HEp-2 cell line, rheumatoid factor in blood, and anticardiolipin antibodies in blood (in systemic lupus erythematosus, rheumatoid arthritis, etc.); antistreptolysin-O in blood serum (in acute rheumatic fever);

10. determination of antistreptolysin-O titer in serum (in rheumatism);

11. blood total triiodothyronine (T3) test, blood free triiodothyronine (FT3) test, blood serum free thyroxine (FT4) test, blood thyroid-stimulating hormone (TSH) test.

LoE C, GoR 5

2.4 Instrumental Diagnostics

LoE C, GoR 5

Comments: acute pericarditis is characterized by widespread ST-segment elevation or PR-segment depression, with typical staging of changes (Figures 1 and 2):

• Phase 1: widespread ST-segment elevation, PR-segment depression;

• Phase 2: resolution of ST elevation, decreased T-wave amplitude;

• Phase 3: T-wave inversion;

• Phase 4: normalization of ECG parameters;

It should be remembered that ECG changes are associated with involvement of the myocardium adjacent to the epicardium. PR-segment depression combined with ST-segment elevation are quite specific for pericarditis, but up to 40% of patients have atypical changes or a complete absence thereof.

LCR C, LoE 3

Comments: echocardiography is the first-line diagnostic test and can assist not only in verifying the diagnosis, but also in identifying patients at high risk for complications.

EchoCG allows assessment of the amount of pericardial effusion by measuring it between the pericardial layers in diastole in centimeters.

In accordance with this measurement, the following are distinguished:

• Trivial effusion (visible only in systole)

• Small effusion – separation of pericardial layers in diastole <10 mm

• Moderate effusion – separation of 10–20 mm

• Large effusion – separation of 21–25 mm

• Very large effusion – separation >25 mm – "swinging heart".

Also, EchoCG may reveal specific features of pericardial effusion such as the presence of fibrin strands and clots.

According to EchoCG, cardiac tamponade reveals the following changes: "swinging" heart, early diastolic collapse of the right ventricle, late diastolic collapse of the right atrium, dilation of the inferior vena cava with virtually no inspiratory collapse, abnormal interventricular septal motion, increased respiratory variability (>25%) of mitral inflow velocity, inspiratory decrease and expiratory increase of forward diastolic flow in the pulmonary veins, respiratory variability of ventricular volumes, aortic flow velocity (echocardiographic manifestation of pulsus paradoxus), and engorgement of the inferior vena cava [30] (Figure 3).

GoR C, LoE 4

Comments: targeted chest X-ray findings in patients with acute pericarditis rarely reveal abnormalities, as cardiothoracic ratio enlargement occurs only with pericardial effusions exceeding 300 mL. Early signs of exudative pericarditis include altered cardiac silhouette configuration ("globular", "triangular", "trapezoidal"). If the pleura is involved in the pathological process, patients with pericarditis may show signs of pleuropericardial disease.

LoE C, GoR 5

Comments: Contrast-enhanced cardiac MRI is performed in cases where effusion is not detected on echocardiography, when a specific localization of effusion is suspected, or when the myocardium is involved in the pathological process [1,4,29-32].

Contrast-enhanced cardiac MRI has high sensitivity in identifying the stage of inflammation and determining the phase of the disease. Late gadolinium enhancement (ATC V08CA Paramagnetic contrast media) on contrast-enhanced cardiac MRI has a 94% sensitivity in determining the severity of inflammatory pericardial involvement (Figure 4) [33].

Figure 4. Late gadolinium enhancement (ATC V08CA Paramagnetic contrast media) on contrast-enhanced cardiac MRI. Mild thickening of the parietal and visceral layers of the pericardium (yellow arrows) and pericardial effusion between them (blue arrow) [33].

LoE C, GoR 5

2.5 Other Procedures

Analysis of pericardial fluid obtained by pericardiocentesis. Pericardiocentesis is used for both diagnostic and therapeutic purposes.

Indications for pericardiocentesis include [1,4,20,32-35]:

1. Signs of cardiac tamponade.

2. Moderate/severe effusion accompanied by clinical symptoms and unresponsive to medical therapy.

3. In the presence of a large pericardial effusion, diagnostic pericardiocentesis is indicated when a bacterial or neoplastic etiology is suspected, and the diagnosis can only be established by identifying the etiological agent in the pericardial fluid.

Comments: the density and pH of the pericardial fluid, cell count, protein content, and glucose and triglyceride concentrations are determined. However, these parameters are nonspecific and do not allow establishing the etiology. When oncological diseases are suspected, cytological examination and tumor marker analysis are performed. When tuberculosis is suspected, molecular biological testing of the pericardial fluid is performed to differentiate species of the Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG). To identify the etiology, culture for flora and microbiological (cultural) examination of the pericardial fluid for aerobic and facultatively anaerobic microorganisms are performed; to confirm viral etiology, the PCR method is used to detect the infectious agent.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

There is a limited number of studies on the treatment of pericarditis in children [8]. Randomized clinical trials in the pediatric group have not been conducted. These guidelines are based on the 2015 European Society of Cardiology Guidelines for the diagnosis and management of pericardial diseases [1], which are based on expert opinion or derived from studies conducted in adults [8,36].

Treatment of pericarditis includes non-pharmacological treatment (activity regimen, diet therapy), drug therapy (etiotropic, symptomatic, treatment of the underlying disease), treatment of complications, and surgical treatment.

3.1. Conservative management

3.1.1. Treatment of acute pericarditis

Non-pharmacological treatment.

LoE C, GoR 5

Comments: once a compensated state is achieved, the child is transferred to a semi-bed rest regimen, which continues throughout the period of pain and fever, until normalization of biochemical markers of the inflammatory process [1,37,38].

ESC IIaC (LoE 5 GoR C)

Comments: resumption of training 3 months after acute pericarditis is possible only after the persistent disappearance of clinical symptoms, normalization of inflammatory marker levels (CRP, ESR), ECG, and echocardiographic findings [1,39-43].

Pharmacotherapy.

The mainstay of pharmacotherapy is the administration of anti-inflammatory drugs. #Ibuprofen**, #Nimesulide, and #colchicine are the basic drugs for the treatment of acute nonspecific pericarditis. Glucocorticoids may be prescribed according to indications. The choice of drug should be based on medical history, including the analysis of the efficacy of previously used drugs and individual tolerance, taking into account existing contraindications due to concomitant diseases [1,8,14,15,25,26,36].

Table 2 presents the strategy for selecting medications in children according to the 2015 ESC Guidelines for the diagnosis and management of pericardial diseases [1].

Table 2. Strategy for selecting medications for the treatment of pericarditis, classes of recommendations according to the European Society of Cardiology (ESC) guidelines [1].

IL-1, interleukin 1; NSAIDs, non-steroidal anti-inflammatory and antirheumatic drugs

ESC IC (Level of Evidence 5, Grade of Recommendation C)

Comments: high doses of NSAIDs are used to achieve rapid control of pericarditis symptoms. Pharmacotherapy appears to have the most significant impact on the recurrence rate in patients with idiopathic pericarditis, as the incidence of recurrent pericarditis can reach more than 50% in inadequately treated patients [1,14,15,25,36]. Clinical experience shows that NSAID therapy allows stabilization of 90-95% of all pericarditis cases.

The drug of first choice in children from 3 months of age is #Ibuprofen** (ATC code: M01AE01) at a dose of 30-50 mg/kg/day (maximum 600 mg per dose or 1.8 g/day) divided into 3 doses every 8 hours. Dose reduction is carried out gradually: by 2 mg/kg/dose every 8 hours once every 1-2 weeks after normalization of C-reactive protein (CRP) levels; once a dose of 4 mg/kg/dose every 8 hours is reached, the drug can be discontinued [36]. #Ibuprofen** has a favorable effect on coronary blood flow. The choice of #ibuprofen** as a first-line drug in children is due to the minimal number of side effects.

#Indometacin (ATC code: M01AB01) is prescribed to children from 2 years of age at 0.25-1 mg/kg/dose every 6-12 hours (maximum dose 50 mg/dose or 150 mg/day). Dose reduction is carried out gradually: by 0.25 mg/kg/dose every 6-12 hours once every 1-2 weeks; once a dose of 0.25 mg/kg/dose every 12 hours is reached, the drug can be completely discontinued [1,36,44].

#Naproxen (ATC code: M01AE02) is prescribed to children over 2 years of age at a dose of 5-7.5 mg/kg/dose every 12 hours orally (maximum dose 500 mg/dose or 1 g/day). Dose reduction is carried out gradually: by 0.25 mg/kg/dose every 6-12 hours once every 1-2 weeks; once a dose of 0.25 mg/kg/dose every 12 hours is reached, the drug can be completely discontinued [1,36,44].

#Ketorolac** (ATC code: M01AB15) is prescribed in exceptional cases when the patient cannot take oral medications, only in a hospital setting. Dose for children aged 2-16 years or weighing <50 kg: 0.5 mg/kg/dose IV every 6 hours (maximum dose 15 mg/injection or 60 mg/day) for 1-4 days intravenously. At age >17 years or weight >50 kg: 30 mg intravenously every 6 hours (maximum dose 120 mg/day) for 1-4 days intravenously [36].

ESC III (LE 5, GR C)

Due to the lack of randomized controlled trials in children comparing the efficacy of various NSAIDs, clinicians should choose a drug based on their clinical experience and the availability of dosage forms [1,44].

As soon as patients with acute pericarditis experience resolution of symptoms and normalization of inflammatory markers, including CRP, a gradual tapering of the NSAID dose can be initiated over 3-4 weeks. However, some patients with recurrent pericarditis may require more prolonged treatment and a longer tapering period ranging from several weeks to several months [1].

Table 3 summarizes data on the NSAIDs most frequently used in children, their dosages, tapering regimens, and the side effects of the most studied NSAIDs.

Table 3. Dosing, monitoring, and clinical recommendations for the use of NSAIDs in idiopathic pericarditis in children [1,36].

ESC IIa C (LE 5, GR C)

Comments: given the high frequency of recurrent acute pericarditis in children, #colchicine may be added to NSAIDs to prevent recurrence and improve response to pharmacotherapy).

The lower level of recommendation is due to the fact that at the time of writing the ESC clinical guidelines in 2015, data regarding the use of #colchicine were scarce and contradictory. However, more data have been published since then, supporting the use of #colchicine in the treatment of pericarditis in children [8,14,15,36].

A number of studies have demonstrated that #colchicine administration was associated with a lower rate of recurrence compared to treatment without #colchicine [8,14,15,36].

Currently, #colchicine is not approved for the treatment of pericarditis in adults and children and is used off-label [36].

The 2015 ESC guidelines recommend #colchicine at a dose of 0.5 mg/day in 2 divided doses in patients under 5 years of age and 1.0 to 1.5 mg/day 2–3 times a day in patients older than 5 years [1].

For acute pericarditis, the duration of administration is 3 months; for recurrent pericarditis, 6–12 months [1,8,14,15,36].

The duration of treatment can be extended (if the drug is well tolerated and there are no side effects) until clinical symptoms completely resolve [1,14,45–47]. It is not strictly necessary to taper #colchicine gradually, but such a tapering regimen helps to further reduce the risk of recurrence [20,26,27,36].

ESC IIIC (LEL 5 GRC)

ESC IA (LE 5, GR C)

The administration of systemic glucocorticoids is indicated for pericarditis occurring against the background of autoimmune diseases, uremic pericarditis, or recurrent pericarditis with severe symptoms [1,25,46,47].

It is worth noting that glucocorticoid therapy carries a risk of the disease becoming chronic [36].

Although systemic corticosteroids are effective in the initial stage of pericarditis treatment, rapid tapering of the drug due to concerns about systemic side effects may contribute to the development of incessant pericarditis and/or recurrence of pericarditis symptoms [20,36,46].

Attempts should be made to use systemic glucocorticoids in low therapeutic doses: #prednisolone** 0.25–0.5 mg/kg per day or equivalent doses of other glucocorticoids.

ESC III (LE 3, GR C)

Comments: The initial dose should be continued until symptoms resolve and all laboratory abnormalities (including CRP) and instrumental findings normalize, followed by gradual tapering [18,20,29,36,46,47].

The tapering period for systemic corticosteroids may take several months. Tables 4 and 5 present #prednisolone** tapering regimens in children.

Table 4. Recommendations for #prednisolone** dose reduction based on daily dose calculation in mg/kg [48].

Table 5. Recommendations for #prednisolone** dose reduction based on daily dose calculation in mg [1].

If symptoms recur during glucocorticoid dose reduction, it is necessary to return to the last effective dose for 2–3 months, followed by another attempt at slow tapering [1,48].

ESC IA (LE 5, GR C)

ESC IA (LE 5, GR C)

Comments: proton pump inhibitors and antacids are preferred in children [36,45].

ESC IB (LOD 5, LOE C)

3.1.2. Treatment of recurrent pericarditis

Non-pharmacological treatment.

ESC IIaC (LoE 5 GoR C)

ESC IIaC (LoE 5 GoR C)

Pharmacotherapy.

ESC IA (LE 5, GR C)

ESC IIA (LOD 5, LOE C)

Comments: in patients with recurrent pericarditis, #colchicine is used either as monotherapy or in combination with NSAIDs [1,26,49].

The efficacy of #colchicine in the treatment of recurrent pericarditis has been proven in randomized clinical trials [26].

ESC IIaC (LoE 5 GoR C)

ESC IIB (LOD 5, LOE C)

Glucocorticoids (GCs) belong to second-line therapy for recurrent pericarditis and are prescribed only when NSAIDs are ineffective. The dose depends on the etiology of pericarditis, clinical course, and severity of the disease. It is impractical to exceed a dose of 0.5 mg/kg of body weight per day. The goal of treatment is to reduce the synthesis of pro-inflammatory cytokines.

The advantages of GCs include high efficacy, rapid relief of pericarditis symptoms, and the absence of undesirable drug interactions. At the same time, this therapy may lead to steroid resistance and adverse side effects [50].

Recurrent pericarditis requires slow discontinuation of GCs in accordance with the existing algorithm [50].

ESC IIвС (LOD 2, LOE B)

Comments: interleukins IL-1β and IL-1α are considered the primary cytokines in the development of pericarditis recurrence, triggering an inflammatory response [7,48,51]. Therefore, the use of interleukin inhibitors is pathogenetically justified in patients with recurrent pericarditis when first- and second-line treatments are ineffective.

The dose of #anakinra** used in children is 1–2 mg/kg per day subcutaneously (but not exceeding 100 mg per day) [8,48,51,54,55].

ESC IIaC (LoE 5 GoR C)

ESC IIbC (LOD 5, LOE C)

3.1.3. Treatment of incessant and chronic pericarditis

Cases of chronic exudative pericarditis are frequently observed in children. The causes of this phenomenon are insufficiently studied. Factors contributing to the transition to a chronic process include the etiology (e.g., tuberculous pericarditis is prone to chronicity), an undiagnosed acute or subacute onset, and consequently the lack of timely treatment, which leads to pronounced thickening of the pericardial layers, making them poorly permeable (and thus poorly accessible) for drug penetration into the pericardial sac, further complicating therapy [8,21,60,62].

Chronic pericarditis may present with a continuous, slow increase in the amount of pericardial fluid (in which case differential diagnosis with pericardial effusion due to malignancy and anomalous lymphatic duct drainage must be performed) or with a practically constant amount of fluid that changes only slightly over time, decreasing or increasing. In the case of such a clinical course, studies aimed at identifying systemic connective tissue diseases should also be conducted [1,60,61].

For successful treatment of chronic pericarditis, it is important to determine the etiology of the disease and make efforts to target the causative agent or the underlying condition that caused the pericarditis.

Chronic pericarditis is often an indication for surgical treatment due to the ineffectiveness of other known treatment methods. The indication for surgery is a combination of unresponsive non-surgical treatments and a potential threat of cardiac tamponade.

3.1.4. Treatment of pericardial effusion and tamponade

Despite the fact that the efficacy of pericardial effusion treatment is directly dependent on identifying the underlying etiology, the cause of the effusion can only be determined in 50% of cases [1,62–64].

If the effusion is not inflammatory in origin (i.e., pericardial effusion is present, but without signs of pericarditis) and its volume increases to the point of risking cardiac tamponade, pericardiocentesis should be considered. Pericardiocentesis with prolonged drainage up to 30 mL/24 h should be considered to prevent further fluid reaccumulation.

ESC IC (LoE C, GoR 5)

Comments: the subsequent clinical course is similar to uncomplicated pericarditis [1,29].

ESC IC (LoE C, GoR 5)

ESC IIIC (LoE C, GoR 5)

ESC IIIC (LEL 5 GRC)

3.1.5. Treatment of bacterial pericarditis

The most common types of bacterial pericarditis are purulent pericarditis and tuberculous pericarditis [65,66].

Treatment of tuberculous pericarditis should be carried out in conjunction with a phthisiatrician, who determines the scope and nature of specific antituberculous therapy [47,67,68].

Purulent pericarditis most often develops acutely during the course of an underlying bacterial disease due to the dissemination of the pathogen into the pericardial sac. Less common causes of purulent pericarditis include infected wounds or trauma (including suboptimal implanted devices and structures). Purulent pericardial effusion is a life-threatening condition requiring immediate treatment and active management. With timely and adequately initiated treatment, purulent pericarditis has a good prognosis in 85% of cases [68].

Parenteral (intramuscular or, preferably, intravenous) administration of antibacterial therapy, selected according to the pathogen or empirically if the pathogen has not yet been identified, is the preferred route of administration. Purulent effusion typically becomes loculated and tends to accumulate rapidly; therefore, timely drainage is important to prevent cardiac tamponade. Subxiphoid pericardiostomy and irrigation of the pericardial cavity are used as surgical treatments [68].

Not addressed by ESC (LoE C, GoR 4)

3.1.6. Treatment of constrictive pericarditis

In the absence of clinical symptoms, a watchful waiting strategy may be adopted until symptoms appear [69,70].

Previously, diuretics were actively used in the early stages of the disease to reduce pulmonary and systemic congestion. However, they should be used with caution, as any reduction in intravascular volume can cause a corresponding decrease in cardiac output.

The development of symptoms of constrictive pericarditis in a patient (distended jugular veins, lower extremity and foot edema, hepatomegaly, ascites, as well as palpitations, oliguria, and low cardiac output) requires prompt surgical treatment [26]. At the same time, it should be borne in mind that the long-term presence of a rigid pericardium against the background of a growing child's body can lead to the rapid development of severe manifestations of heart failure. Surgical treatment in the delayed period may be associated with much greater difficulties, especially if calcification of constrictive pericarditis begins to occur (particularly of tuberculous etiology).

Conservative therapy for constrictive pericarditis is also used when the causative agent of the disease has been identified, which helps slow down the further progression of constriction, as well as for anti-inflammatory, immunomodulatory, and symptomatic treatment [1,71-73].

3.2. Surgical treatment of pericarditis

In most cases, pericardial involvement is secondary, and diagnosing the underlying cause is often difficult. The main indications for interventional and surgical interventions in pericardial diseases are the presence of a very large pericardial effusion (compromising the function of other organs and systems), cardiac tamponade, and constrictive pericarditis. Surgical treatment is also indicated in bacterial pericarditis for diagnostic purposes in cases of moderate-to-large effusion of unknown etiology [1,74].

The aim of surgical treatment is to achieve cardiac decompression, drainage of the pericardial cavity, removal of blood clots and fibrin, and administration of therapeutic agents into the pericardial cavity. The leading methods of surgical treatment are pericardiocentesis, open drainage of the pericardial cavity via a subxiphoid approach, and the creation of a pericardial window in cases of persistent moderate-to-large effusion accumulation. A pericardial window can also be created thoracoscopically by performing pericardial fenestration.

The surgical method of treatment in the event of constrictive pericarditis is partial (over the ventricular region in cases where separation of the pericardium from the myocardium is difficult and there is a risk of myocardial injury, e.g., in pronounced calcification in tuberculous pericarditis) or total pericardiectomy [26,74,75].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

LE 4 GSR C

ESC IC (Level of Evidence 5, Grade of Recommendation C)

LNC 4 LeC C

Comments: pericardiocentesis should be performed by an experienced physician, as it can be accompanied by complications in 4–10% of cases. The most frequent and severe complication of pericardiocentesis is myocardial injury and perforation. Life-threatening arrhythmias, internal thoracic artery injury, pneumothorax and hemothorax, abdominal organ injury, vasovagal reactions, and infectious complications are also possible [1,76].

Performing pericardiocentesis without percutaneous drainage of the pericardial cavity is impractical.

The indication for drain removal is a decrease in the daily fluid output to a negligible amount.

Pericardiocentesis is associated with an increased risk in cases of loculated effusion along the lateral or posterior surface of the heart, or if the echo-free space on ultrasound is less than 10 mm. In these cases, open surgical drainage of the myocardial cavity may be safer.

Pericardiocentesis and percutaneous drainage of the myocardial cavity are frequently associated with a high recurrence rate [1,76,78].

LE 4 GSR C

LE 4 GSR C

In constrictive and adhesive pericarditis, cardiolysis and pericardiectomy are indicated [80,81]. Indications for surgery are determined by clinical data and the results of instrumental diagnostic methods. It is important to note that surgery should not be delayed for long when the first signs of decompensation appear during conservative therapy, since subsequent secondary organ changes will be irreversible.

Cardiolysis is a surgical procedure to dissect adhesions between the pericardial layers and between the heart and surrounding tissues. Cardiolysis cannot be considered a radical and curative surgical procedure; furthermore, there is a high probability of cardiac injury and the formation of new adhesions.

LNC 5 LeC C

Comments: ultrasound-guided pericardiocentesis and drainage, along with biopsy acquisition, are usually part of surgical interventions such as creating a pericardial window or pericardiectomy [1].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

LE 4 GSR C

Comments: visualization of the pericardial cavity allows for the removal of thick purulent exudate accumulations in the pericardial sinuses and ensures adequate drainage [78-80].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation measures for pericarditis are determined by the phase of the disease, are based on the principles of rehabilitation for children with heart failure, and provide for a phased and continuous approach. Rehabilitation includes medical, psychological, and socio-economic aspects [82,83].

Rehabilitation of children with pericarditis involves assessing the child's rehabilitation potential, developing an individual rehabilitation plan, defining a system of measures, structures, and methods, as well as predicting expected positive outcomes based on the rehabilitation diagnosis [84-85].

Physical rehabilitation methods have not been developed for patients with pericarditis.

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments: There are no restrictions on ordinary physical activity. Clearance for physical education classes in physical education group 2 is possible after 6 months in the complete absence of disease symptoms, including inflammatory markers and pericardial effusion, as well as the absence of signs of constrictive pericarditis development, followed by transfer to physical education group 1 [42,43].

Athletes with pericarditis, regardless of etiology, must be banned from all sports activities during the acute stage of the disease for at least 3 months. Athletes may resume sports outside the acute stage of the disease, including the absence of effusion on echocardiography, provided that inflammatory markers have normalized.

Reliability of Evidence Grade C, Consensus Level of Evidence 5

5. Prevention and Dispensary Observation

Primary prevention of pericarditis includes adequate prevention of intrauterine infections, routine screening of pregnant women, prevention of enteroviral infections, nosocomial infections and infections in organized groups, immunoprophylaxis of controlled infections, expansion of the National Immunization Schedule, non-specific and specific seasonal prevention of influenza and acute respiratory viral infections, hardening, immunorehabilitation of "frequently ill" children and children at risk for severe viral infections, regular preventive examinations, and sanation of focal infections [21].

LeveL of Evidence C, Grade of Recommendation 5

Comments: if the patient is receiving interleukin-1-blocking drugs (interleukin inhibitors) (#Anakinra**, #Canakinumab**), the administration of live vaccines should be avoided during vaccination [36].

Secondary prevention of recurrent and constrictive pericarditis consists of adequate follow-up (dispensary observation) and rehabilitation of convalescents of pericarditis, especially those with risk factors for chronization, and children with latent and subclinical forms of focal infection [1,21].

LeveL of Evidence C, Grade of Recommendation 5

LeveL of Evidence C, Grade of Recommendation 5

Comments: during the first year of follow-up after hospital discharge, children are examined monthly for the first 3 months, then once a quarter, or more frequently if necessary.

At each visit, well-being and general condition are monitored, a physical examination is performed, along with a complete blood count, and an ECG for all patients with pericarditis every 3–6 months. Echocardiography is indicated twice a year, with the first test performed within the first 12 weeks after hospital discharge. During the first 12 weeks, serum C-reactive protein levels must also be measured. A high CRP level should be regarded as a harbinger of acute pericarditis recurrence and is also an important indicator requiring the search for a potentially underlying disease that may not have been previously identified. An initial appointment (examination, consultation) with an otorhinolaryngologist and an initial appointment (examination, consultation) with a dentist should be performed once a year.

During the second year of dispensary follow-up, an initial appointment (examination, consultation) with a pediatrician and an initial appointment (examination, consultation) with a pediatric cardiologist are conducted once every 6 months. A complete blood count, ECG, and echocardiography are performed once a year, or more frequently if necessary. An initial appointment (examination, consultation) with an otorhinolaryngologist and an initial appointment (examination, consultation) with a dentist are performed once a year.

During the third year of dispensary follow-up, an initial appointment (examination, consultation) with a pediatrician and an initial appointment (examination, consultation) with a pediatric cardiologist are conducted once a year. A complete blood count, ECG, and echocardiography are performed once a year. An initial appointment (examination, consultation) with an otorhinolaryngologist and an initial appointment (examination, consultation) with a dentist are performed once a year [18,21].

LeveL of Evidence C, Grade of Recommendation 5

Comments: all parameters of which must be within the normal range (complete blood and urine counts, resting ECG, echocardiography assessing the pericardium, morphometric parameters, and myocardial pump and contractile function)

Comments: additional examinations such as electrocardiographic monitoring, immunobiochemical markers of myocardial damage, antimyocardial antibody titers, etc., are performed taking into account the etiology of pericarditis and as clinically indicated [42,43].

Following an episode of acute pericarditis, children are assigned to health group 4 for the first year, and are subsequently transferred to health group 3. Transfer to health group 2 is decided based on examination data. In chronic pericarditis, the decision is made individually depending on clinical, functional, and laboratory parameters (health group 3 or 4) [21].

The prognosis for patients with pericarditis is favorable; according to several prospective studies, the risk of developing heart failure and death in this patient category is not increased [86,87].

The prognosis depends on the etiology, time to diagnosis, timing and scope of therapy, response to therapy, and concomitant pathology.

Lack of response to NSAID therapy in acute pericarditis within 7 days is associated with a relatively poor disease course and is an independent risk factor for recurrence [10,88].

Vaccination is contraindicated during the first year after acute or idiopathic pericarditis, except for urgent epidemiological indications; in chronic pericarditis, the issue is considered on an individual basis. Vaccination should preferably be carried out using a modified schedule, provided the condition has stabilized and shows positive dynamics, no earlier than 1 year after disease onset. In autoimmune pericarditis associated with systemic connective tissue diseases, vaccination is not performed [21].

6. Organization of Medical Care

Indications for elective hospitalization:

Patients with high-risk factors for complications require inpatient treatment.

Such factors include:

- subacute onset, high fever, and leukocytosis,

- suspected development of cardiac tamponade or purulent pericarditis,

- large pericardial effusion according to echocardiography,

- resistance to NSAID therapy for 7 days,

- immunocompromised patients,

- history of oral anticoagulant therapy,

- acute trauma.

Average hospital stay: 14-21 days, depending on the severity of the condition.

Indications for discharging a patient with acute pericarditis from the hospital

Upon persistent clinical improvement, absence of pain syndrome, resolution of fever, normalization of inflammatory markers (CRP, ESR), return of the ST segment to the baseline, and normalization of the echocardiographic picture (regression of pericardial effusion), the patient is discharged from the hospital for further outpatient follow-up and treatment.

Children with uncomplicated acute pericarditis and a small amount of pericardial effusion can be treated and monitored on an outpatient basis.

7. Additional Information

7.1 Post-cardiac injury syndromes

The term "post-cardiac injury syndromes" (PCIS) is used to denote pericardial syndromes occurring after any damage to the myocardial membranes, including post-myocardial infarction pericarditis, post-cardiotomy syndrome (PPCS), and post-traumatic pericarditis [1,18,88,89,90].

7.1.1 Post-cardiotomy (post-pericardiotomy) syndrome

Post-cardiotomy syndrome is an inflammatory condition following open-heart surgery. The pathogenesis is associated with autoimmune processes resulting from myocardial damage (necrosis) following surgical interventions or chest trauma [89,90,91].

PPCS is characterized by signs of systemic inflammation, fever, and polyserositis. The autoimmune etiology is supported by the presence of a latent period (several weeks pass between the heart condition and the development of pericarditis), the efficacy of anti-inflammatory therapy, and the possibility of symptom recurrence [88]. The contribution of intraoperative infection to the development of post-cardiotomy syndrome is not ruled out [92].

According to various authors, post-cardiotomy syndrome occurs in 8.9-40% of patients undergoing open-heart surgery [85,89,92-96]. PPCS manifests on average 3-4 weeks after open-heart surgery and lasts an average of 3 weeks (2-100 days) [93,94]. Recurrence of this syndrome occurs in 4-38% of patients who have previously had it. In some patients, recurrence may occur up to 30 months after the initial manifestation, which is often an indication for pericardiectomy [94,95].

Diagnostic criteria are:

1. Fever of unknown origin;

2. Pericardial or pleural pain syndrome (chest pain occurring at the peak of inspiration or with a change in body position);

3. Pericardial and/or pleural friction rub (auscultation of murmurs);

4. Pericardial effusion and/or pleural effusion with elevated CRP.

At least two of the above symptoms are required for diagnosis [48].

It is very often difficult to differentiate post-pericardiotomy syndrome (PPCS) from common postoperative consequences such as exudative pericarditis and pleurisy. To establish a diagnosis, there must be evidence of inflammatory activity (elevated CRP levels) [25].

The clinical presentation is characterized by low-grade or high-grade fever accompanied by fatigue and increased fatigability. Pain symptoms manifest as chest pain unrelated to physical exertion, which may change in intensity with body position changes and pressure on the precordial area. Chest pain of pleural origin is typically associated with the act of breathing. The presence of significant pericardial and/or pleural effusion can lead to heart and/or respiratory failure (complaints of shortness of breath upon exertion or at rest, lower extremity edema, palpitations). Shortness of breath is the main symptom of respiratory failure [1,87].

Significant effusions occur in 10% of cases and can lead to cardiac tamponade [96]. Although this complication can be observed within 1 month after surgery, it most commonly occurs in the first days following the intervention and is usually associated with hemorrhage into the pericardial cavity. The occurrence of cardiac tamponade due to postoperative hemopericardium requires emergency reoperation. It should be noted that any cardiac surgical procedure, even minimally invasive ones (PCI, pacemaker implantation, radiofrequency ablation, etc.), can be complicated by hemopericardium and cardiac tamponade due to perforation of a vessel or heart chambers [97].

Diagnosis is based on medical history, physical examination, and the results of laboratory and instrumental examinations.

When post-pericardiotomy syndrome is suspected, the nature and timing of the prior surgery should be determined, and instrumental study data (echocardiography, targeted chest X-ray, contrast-enhanced cardiac CT) before and immediately after surgery should be evaluated. It is also necessary to clarify what anti-inflammatory therapy the patient has been/is receiving [1,18,51].

The clinical presentation of post-pericardiotomy syndrome is due to the presence of pericarditis and/or pleurisy manifestations (exudative, constrictive pericarditis, less commonly cardiac tamponade) combined with a systemic inflammatory response [1,18,51].

Pathognomonic symptoms include pericardial and/or pleural friction rub, muffled heart sounds, decreased breath sounds upon auscultation, jugular venous pulse (in the presence of exudative pericarditis), and cardiac tamponade. Lower extremity edema and hepatomegaly occur as manifestations of heart failure. Decreased pulse amplitude and tachycardia are due to exudative pericarditis.

To detect an inflammatory process, it is advisable for all patients to undergo serum C-reactive protein (CRP) testing [1,18].

All patients should undergo an echocardiographic examination to detect fluid in the pericardial and/or pleural cavities, thickening of the pericardial and/or pleural leaves, and collapsing of heart chambers [1,18].

To detect fluid in the pericardial and/or pleural cavities, thickening of the pericardial and/or pleural leaves, and infiltrative lung changes, radiography of the heart, pericardium, and lungs is indicated for all patients [98,99]. It must be taken into account that the presence of less than 300 ml of fluid in the pericardial cavity does not lead to an increase in the cardiothoracic ratio (CTR) [1,18].

An ECG is required to diagnose pathological changes in electrical conductivity [99]. In the acute phase of post-pericardiotomy syndrome, ECG changes characteristic of acute pericarditis are noted (widespread PR segment depression or ST segment elevation in multiple leads, reflecting epicardial involvement). When tamponade occurs, ECG changes are characterized by low QRS voltage, flattened or inverted T waves [98,99].

To diagnose pathological changes in the heart and lungs in patients with suspected post-pericardiotomy syndrome, contrast-enhanced cardiac computed tomography and contrast-enhanced cardiac magnetic resonance imaging are justified [99,100]. CT and MRI have a larger field of view than echocardiography, making it possible to detect effusion in the pericardial and pleural cavities, assess effusion volume and localization, as well as thickening of the pericardium and pleural leaves.

Treatment of post-pericardiotomy syndrome

All patients with post-pericardiotomy syndrome need to follow a restrictive regimen, which implies a sedentary lifestyle from the moment of the first clinical manifestations for a period of three months until symptoms regress and laboratory and instrumental parameters normalize (decrease in blood CRP levels to normal, absence of ST-segment elevation and PR-segment depression, and absence of significant effusion in the pericardial and pleural cavities according to echocardiography) [1,18].

Conservative treatment of post-pericardiotomy syndrome

Medical treatment is based on anti-inflammatory therapy, which promotes the disappearance of symptoms and achievement of remission, and reduces the recurrence rate [1,96]. All patients are prescribed NSAIDs in combination with gastroprotectors (proton pump inhibitors) [1]. To assess the efficacy and duration of drug therapy, blood serum C-reactive protein levels are monitored [1].

Glucocorticoids are not first-line drugs in children with post-pericardiotomy syndrome [101].

The prescription of glucocorticoids to patients with post-pericardiotomy syndrome is possible only if NSAIDs are ineffective and in the absence of contraindications, since their use can cause chronization of the process and withdrawal syndrome. Glucocorticoids should be prescribed at the following dosage: #prednisolone** 0.2-0.5 mg/kg/day or equivalent. The dosage should be maintained until symptoms disappear and CRP normalizes.

A 2019 meta-analysis found that perioperative #colchicine intake was associated with a significant reduction in the risk of PPCS [102].

7.1.2 Traumatic pericardial effusion.

In approximately 20-30% of cases after major chest trauma, especially of its left half, signs of pericarditis appear. When traumatic pericardial effusion is suspected after major chest trauma, all patients must undergo ECG, targeted chest X-ray, and echocardiography [1,18]. Performing this diagnostic complex makes it possible to clarify the diagnosis, assess effusion size and its hemodynamic significance.

After confirmation of the diagnosis, anti-inflammatory therapy is indicated for all patients [1,18,101,102].

In the event of a life-threatening situation, emergency thoracoscopy must be performed, which has an advantage over preliminary pericardiocentesis [1,18]. In the absence of hemodynamic disorders, treatment of this condition includes NSAID therapy.

7.2 Hydropericardium in endocrine diseases

Hypothyroidism is the most frequent cause of hydropericardium in endocrine diseases. Hypothyroidism causes pericardial effusion due to increased permeability of epicardial vessels and reduced albumin lymphatic drainage, leading to fluid accumulation in the pericardial space. Pericardial diseases caused by hypothyroidism are underdiagnosed. Early treatment initiation and complication prevention depend on early diagnosis via systematic screening for hypothyroidism [103-105].

The severity of hydropericardium depends on the degree of thyroid deficiency and disease duration. Clinical manifestations include symptoms of both pericardial effusion and hypothyroidism. Effusion-related symptoms include shortness of breath, chest pain, fatigue, and edema. Symptoms of hypothyroidism include drowsiness, dry skin, hair loss, slowed speech, constipation, memory loss, feeling cold, hoarseness, and depressed mood. Diastolic arterial hypertension frequently develops. External manifestations such as general and periorbital edema, a pale-yellowish puffy face, and sluggish facial expressions are characteristic. Underestimating the symptoms of hypothyroidism in patients with hydropericardium complicates the identification of the cause and leads to a delayed start of effective treatment [103-105].

Laboratory and instrumental examinations reveal marked dyslipidemia characteristic of hypothyroidism, low QRS voltage, and prolonged QT interval on the ECG. Echocardiography should be used to diagnose pericardial effusion and estimate its volume, while contrast-enhanced cardiac computed tomography and cardiac magnetic resonance imaging provide more complete information.

When detecting a pericardial effusion of unknown etiology, thyroid function should be assessed first, even in the absence of signs and symptoms of hypothyroidism [103]. To rule out hypothyroidism, it is necessary to test the blood level of thyroid-stimulating hormone (TSH) [104].

If the TSH level is elevated, serum free thyroxine ($FT_4$) and blood anti-thyroperoxidase antibody levels should be measured. In overt hypothyroidism, an elevated TSH level and a low free thyroxine ($FT_4$) level in the blood are detected; in subclinical hypothyroidism, an elevated TSH level is present. Cardiac tamponade in hypothyroidism is rare due to the slow accumulation of fluid in the pericardial cavity [105, 106].

Treatment.

Currently, there is insufficient data on the management of patients with hydropericardium caused by thyroid disorders. Early initiation of treatment and prevention of complications (development of cardiac tamponade) depend on the early diagnosis of hypothyroidism.

First of all, all patients with hypothyroidism and hydropericardium are indicated for replacement therapy to achieve and maintain normal blood levels of TSH and thyroid hormones. The drug of choice for replacement therapy is levothyroxine sodium** (small doses (25 mcg daily), followed by titration under TSH level monitoring) due to its efficacy, long-standing clinical experience, high bioavailability, and favorable profile, with subsequent titration under TSH level monitoring [105]. Recommendations for the treatment of hydropericardium in hypothyroid patients are based on clinical observation data; randomized clinical trials in this area have not been conducted. There are data on the efficacy of #ASA** and NSAIDs, #colchicine, and glucocorticoids [107]. Some NSAIDs may affect thyroid hormone levels, complicating the assessment of replacement therapy efficacy. However, according to clinical observations, such an effect has not been identified with the use of #indometacin and #ibuprofen** [108]. When using #colchicine, it must be taken into account that the presence of hypothyroidism requires a more cautious approach to dose selection. #Colchicine is excreted via the P-glycoprotein system, the expression of which may decrease when thyroid functional activity is reduced. In patients with hypothyroidism, the excretion of #colchicine may decrease and its plasma concentration may increase, which can lead to adverse effects (nausea, diarrhea, myopathy, liver dysfunction). Hypothyroidism can cause myopathy in 25–60% of cases, increasing the likelihood of adverse effects in patients receiving #colchicine [108]. Therefore, in patients with hypothyroidism, #colchicine should be prescribed in lower doses, and careful monitoring of clinical symptoms of myopathy and creatine phosphokinase (CPK) levels is required. It is advisable to consider treatment with #colchicine until the TSH level reaches the normal range [108, 109].

Glucocorticoids may be used in patients with hypothyroidism-induced hydropericardium in case of intolerance or contraindications to NSAID and #colchicine therapy, as well as in patients with recurrent pericarditis [105, 108, 109]. In this case, blood 1,25-OH vitamin D levels must be determined, since both hypothyroidism and glucocorticoids increase the risk of osteoporosis.

In hyperthyroidism, pericardial effusion is rarely detected. Cases of hydropericardium have been described in patients with severe thyrotoxicosis, symptoms of congestive heart failure, and atrial fibrillation [105, 106]. Cardiac tamponade is extremely rare. As with hypothyroidism, patients with hyperthyroidism and hydropericardium primarily require treatment aimed at achieving stable euthyroidism. In addition to antithyroid drugs, NSAIDs, #colchicine, and/or glucocorticoids can be used [87].

7.3 Pericardial involvement in oncological diseases

Malignant tumors are the most common cause of effusive pericarditis with a hemodynamically significant amount of pericardial fluid. Early diagnosis and treatment of malignant pericarditis can significantly improve patient prognosis. On the other hand, untreated malignant pericardial effusion is a potentially fatal complication of cancer [110].

The prevalence of oncological diseases in exudative pericarditis ranges from 12 to 23% [111]. In cancer patients, pericardial effusion develops in 5–15% of patients and is more often a manifestation of late-stage disease [111]. The pericardium can be affected by direct tumor extension or metastasis via the lymphatic or blood vascular system. Pericardial effusion may also develop as a result of chemotherapy, radiation therapy, or opportunistic infections [112]. Pericardial tumors include primary and secondary malignancies, as well as benign neoplasms. Primary pericardial tumors are rare and account for about 10% of all primary cardiac tumors, with their prevalence in the general population ranging from 0.001 to 0.007% [113]. Secondary tumors or direct invasion of the pericardium are approximately 1000 times more frequent [114].

Malignant pericardial mesothelioma accounts for 2–3% of all pericardial tumors, and its prevalence in the general population is <0.002%. The disease has a poor prognosis with a median survival of 6 months [115]. Other pericardial malignancies include lymphomas and sarcomas. Sarcomas are rare, and their subtypes include angiosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, and undifferentiated sarcoma. The prognosis for this tumor is poor—less than 1 year for all patients [114].

Pericardial involvement by secondary malignant tumors is most frequently observed in lung cancer (29%), breast cancer (up to 10%), malignant melanoma, lymphomas, acute myeloid leukemia, and much less frequently in gastrointestinal cancer, genitourinary cancer, acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma [116].

Pericardial cysts (mesothelial cysts) and lipomas are the most common benign pericardial masses and are often asymptomatic. Symptoms, when they occur, are related to compression and may in such situations require surgical removal. Other rare and usually benign pericardial tumors include lipoblastomas, paragangliomas, germ cell tumors, hemangiomas, and fibromas [117]. Pericarditis can be a marker of occult cancer. According to the Danish Registry, more than 10% of 13,759 individuals with pericarditis were subsequently diagnosed with cancer [114].

7.4 Pericardial diseases associated with cancer treatments

Chemotherapy-induced pericardial involvement typically manifests as pericarditis, with or without associated myocarditis. The development of pericarditis as a complication of chemotherapy is possible with the following agents: anthracyclines and related compounds: doxorubicin**; nitrogen mustard analogues: cyclophosphamide**; antineoplastic antibiotics: mitomycin**; alkyl sulfonates: busulfan**; antimetabolites: clofarabine, cytarabine**, fluorouracil** [118, 119]; protein kinase inhibitors (small-molecule tyrosine kinase inhibitors: dasatinib**, imatinib**); monoclonal antibodies: nivolumab**; anthracyclines and related compounds: doxorubicin** [120].

Effusive or constrictive pericarditis may also occur in 6–30% of patients after radiation therapy [121]. Acute pericarditis may occur within days or months after radiation therapy; it is more frequently constrictive pericarditis. Chronic radiation pericarditis is often constrictive-effusive [122].

Specific diagnostic features of pericardial involvement in oncological diseases

Diagnosis of pericardial involvement in cancer is carried out using imaging methods, cytological examination of the pericardial fluid, and biopsy. Transthoracic echocardiography is the method of choice for the initial evaluation of patients with suspected pericardial disease. In most cases, it not only allows diagnosing the condition but also serves as a guide during pericardiocentesis. Three-dimensional echocardiography is the preferred method for monitoring LV function and detecting pericarditis in cancer patients. Advantages include higher accuracy in determining left ventricular ejection fraction, better reproducibility, and lower temporal variability compared to two-dimensional echocardiography in cancer patients receiving chemotherapy [118]. The use of other imaging methods, such as contrast-enhanced cardiac computed tomography and contrast-enhanced cardiac magnetic resonance imaging, can be a useful adjunct to the echocardiographic evaluation. They should be particularly considered when evaluating primary cardiac tumors, with or without pericarditis, or in cases where the diagnosis of constrictive pericarditis remains uncertain after thorough echocardiographic evaluation [118].

To confirm the malignant nature of the disease, cytological examination of the pericardial fluid is justified [123,124]. Malignant cells are identified by pericardial fluid analysis in only about 40% of cases [124]. When malignant cells cannot be identified by cytological analysis, other mechanisms must be suspected. Pericardial effusion may be associated with mediastinal lymphatic obstruction due to tumor infiltration or radiation-induced fibrosis. Other possible causes include opportunistic infections (cytomegalovirus, tuberculosis, Candida and Aspergillus pericarditis), systemic treatments such as alkylating agents, local inflammation, chest radiation-induced pericarditis, or fluid retention caused by certain chemotherapeutic agents [124].

To differentiate between benign and malignant effusion, it is advisable to measure blood levels of the adenocarcinoma-associated antigens CA 19-9 and CA 72-4 [123].

The diagnostic value of tumor markers is not high enough, as none of them (carcinoembryonic antigen, CYFRA 21-1, neuron-specific enolase, CA 19-9, CA 72-4, SCC, GATA-3, vascular endothelial growth factor) has shown sufficient sensitivity and specificity in distinguishing between benign and malignant effusions [123].

In addition, to confirm malignant disease of the pericardium, pericardial and epicardial biopsy should be considered [123,124].

Management of pericarditis in cancer.

Treatment of pericarditis in cancer is generally conducted in accordance with standard pericarditis treatment guidelines.

However, it must be taken into account that many cancer patients may have a predisposition to bleeding due to hemostatic disorders secondary to their disease or treatment. Thus, routine therapy such as NSAIDs may be difficult to administer. As a result, a broader and earlier use of other drugs, such as #colchicine and glucocorticoids, is frequently observed, although this may not alter outcomes [112].

All patients with pericarditis and cancer require appropriate systemic anti-tumor treatment [124].

In cardiac tamponade, pericardiocentesis is indicated for all patients with malignant effusion to relieve symptoms and establish the diagnosis of malignant effusion [114,125].

In addition, in patients with suspected and confirmed malignant effusion, prolonged pericardial drainage is advisable to prevent recurrence and allow intraperitoneal/intrapericardial treatment, which reduces the recurrence rate to approximately 10-20% [126].

For patients with radiosensitive tumors, such as lymphomas and leukemias, radiation therapy is indicated to control malignant effusions [114].

It should be noted that cardiac radiation therapy itself can cause myocarditis and pericarditis.

For patients in whom pericardiocentesis cannot be performed, as well as in cases of pericardial constriction or complications of previous procedures, pericardiectomy is indicated [124].

In practice, the treatment of pericarditis in cancer is usually palliative, aimed at symptom relief rather than curing the underlying oncological process. However, situations may arise where treating pericarditis in cancer can have a positive impact on the patient's prognosis [126].

The presence of pericardial effusion is associated with high mortality in cancer patients. The presence of symptomatic pericardial effusion indicates more advanced carcinomatous disease (especially in the case of solid tumors) with direct cardiac invasion or severe mediastinal infiltration. Pericardial effusion can be diagnosed in the absence of any previously detected metastases in one-third of patients, and it may be a stronger prognostic factor for outcomes than metastasis [124].

7.5 Chylopericardium

Chylopericardium is the accumulation of chylous fluid (serous chyle effusion) in the pericardial cavity. The condition affects men and women equally and can occur at any age, starting from the newborn period. Data on the prevalence of chylopericardium are not presented in the literature. The incidence of chylous effusion in newborns is 1 case per 15,000 births and is accompanied by a high mortality rate of 15-50% [127-130].

Congenital chylothorax is often associated with non-immune hydrops fetalis, hereditary diseases and genetic syndromes (Turner, Down, Noonan syndromes, etc.), thoracic neoplasms growing into or compressing the thoracic duct (congenital goiter, lung tumors), and congenital malformations of the lymphatic system (tumors developing from lymphatic vessels, thoracic duct atresia, vessel or vessel wall hypoplasia), and lung malformations [127,128,130-132]. In newborns, chylopericardium may occur against the background of intrauterine infection (congenital cytomegalovirus infection) [128].

Compression or invasion of the thoracic duct leads to the formation of chylous effusion in the pericardium, frequently caused by mediastinal neoplasms (lymphangioma, dysgerminoma, teratoblastoma, thymoma, etc.) and gastric carcinoma [129].

Other causes of chylopericardium may include tuberculosis, pulmonary hypertension, subclavian vein thrombosis, and Gorham-Stout syndrome.

Injury to the thoracic duct during cardiothoracic surgery (central venous catheterization, removal of lung and mediastinal tumors, correction of congenital heart defects, valve replacement, CABG, heart transplantation) can lead to chylopericardium. Chylopericardium may occur due to blunt or penetrating chest trauma, in which case it is usually combined with chylothorax. Furthermore, in 56% of cases, chylopericardium may be idiopathic.

The mechanism of chylopericardium development varies depending on the causative factor. Normally, pericardial fluid drains into the lymphatic collectors of the anterior mediastinum, then into the bronchopulmonary lymph nodes, and further into the thoracic duct. Chyle accumulates in the pericardium secondarily, either due to damage to the lymphatic pathways (disruption of the connection between the thoracic duct and pericardial lymphatic vessels). Right heart overload and increased superior vena cava pressure can cause elevated pressure in the thoracic duct, leading to chyle reflux into the pericardial lymphatic vessels [1,129]. Less commonly, in congenital malformations of the lymphatic system, chyle can enter the pericardial sac due to transudation through an altered vessel wall or via an abnormal connection between the thoracic duct and the pericardium [130-132].

Clinical presentation of chylopericardium.

The initial clinical signs of chylopericardium are fatigue, dizziness, dry cough, and a feeling of retrosternal pressure. As the volume of chyle increases, dyspnea, chest discomfort or pain, and palpitations join the clinical picture. Attacks of asphyxia, cyanosis, syncopal episodes, peripheral edema, and ascites may occur. In patients with pulmonary lymphangiectasia, coughing up chyle clots in the form of bronchial casts (plastic bronchitis) may be observed. Based on physical examination findings, patients with chylopericardium are often initially diagnosed with exudative pericarditis. Too rapid accumulation of chyle with limited pericardial compliance can lead to cardiac tamponade accompanied by tachypnea, tachycardia, arterial hypotension, pulsus paradoxus, and shock [125-129].

All patients with suspected chylopericardium undergo the following instrumental examinations: targeted chest X-ray, echocardiography (EchoCG), and contrast-enhanced computed tomography of the heart [1, 129].

Lymphangiography/lymphoscintigraphy are extremely rare and can be used to identify injury or obstruction of the thoracic duct in order to visualize the source of chyle leakage [1].

Targeted chest X-ray typically reveals cardiomegaly. Chest CT helps identify the causes of impaired lymphatic drainage, including mediastinal malignancies, tuberculosis, etc. EchoCG assists in detecting pericardial effusion and impaired diastolic venous filling of the heart chambers. EchoCG is mandatory when performing a transthoracic puncture.

To confirm the diagnosis, patients with chylopericardium undergo a diagnostic puncture with cytological analysis of the drainage fluid (exudates, transudates) [1].

Pericardial effusion in chylopericardium has a cloudy white or milky color. Chylous exudate is an opaque, milky fluid containing suspended microscopic fat droplets, a high triglyceride content (>500 mg/dL), protein (>3 g/L), a cholesterol-to-triglyceride ratio of less than 1, and a predominance of lymphocytes.

Differential diagnosis of chylopericarditis.

During diagnostics, it is important to verify the nature of the pericardial effusion and identify the cause of its accumulation. Therefore, the following conditions must be ruled out: hydropericardium, hemopericardium, purulent pericarditis, cholesterol pericarditis, and metastatic pericarditis. Cholesterol pericarditis develops in tuberculous pericarditis, rheumatoid arthritis, and trauma, and is characterized by a higher cholesterol level with a cholesterol-to-triglyceride ratio greater than 1 [1, 18].

Treatment of chylopericarditis.

Conservative treatment includes diet and correction of electrolyte and protein imbalances. The therapeutic diet excludes long-chain and medium-chain triglycerides, or patients with symptomatic chylopericardium and uncontrolled pericardial effusion are completely switched to parenteral nutrition [1, 18].

In patients with symptomatic chylopericardium, pericardial drainage is advisable [1].

The safest and most effective surgical approach is considered to be thoracoscopic ligation of the thoracic duct above the level of the diaphragm combined with partial pericardiectomy [1].

To reduce chyle production, patients with symptomatic chylopericardium are indicated for administration of #octreotide** [1].

Therapy with #octreotide** is prescribed for 2 weeks, administered subcutaneously at a dose of 100 mcg 3 times a day [1]. If pericardial effusion persistently reaccumulates and radical treatment is not feasible, a pericardio-peritoneal shunt is placed or thoracic duct embolization is performed. In addition to eliminating abnormal lymphatic drainage, it is necessary to treat the cause of secondary chylopericardium (removal of a mediastinal tumor, treatment of tuberculosis and other infections) [1].

7.6 Idiopathic recurrent pericarditis

Recurrent pericarditis (RP) is pericarditis whose etiology has not yet been identified, and the course of the disease is characterized by recurrent attacks of acute pericardial inflammation.

After the initial episode resolves and remission lasts for 4–6 weeks, acute pericarditis may recur, leading to the development of recurrent pericarditis (RP) in approximately 15–30% of adult patients [14, 25] and 35% of children [11]. Recurrences are generally less severe than the initial attack.

The registered incidence of acute pericarditis in the general population is 30–150/10^5 person-years [9, 10]. Considering the likelihood of recurrence and alternative etiologies, the incidence of IRP can be estimated at approximately 5–35/10^5 per year [9, 10].

This pathology is listed in the European registry of rare diseases, orpha.net, under the code ORPHA: 251307 in the section for systemic and rheumatological diseases in adults and children [133].

Following the first recurrence, up to 50% of patients experience repeated attacks of pericarditis [14, 134].

IRP is a diagnosis of exclusion that can only be made after a thorough and comprehensive workup [48, 135].

Although the term "idiopathic" often reflects that the etiology of the condition has not yet been identified, in recent years preference has been given to autoinflammatory/autoimmune mechanisms of disease development.

Three phenotypes of IRP are distinguished [48]:

• Recurrent attacks of pericarditis combined with serositis, accompanied by high fever and a sharp increase in acute-phase inflammatory markers. This phenotype is most common in children [52] and responds well to therapy with drugs blocking the effect of interleukin-1 (IL-1), such as #anakinra** [53]. Clinical manifestations similar to autoinflammatory diseases suggest a similar pathogenesis.

• Recurrent attacks with a subacute course and a moderate or high increase in acute-phase inflammatory markers. Antinuclear antibodies (ANA) and clinical manifestations associated with systemic autoimmune diseases, such as arthralgia, xerophthalmia, Raynaud's phenomenon, discoid lupus, and uveitis, are frequently detected. Autoimmune mechanisms are believed to play an important role in pathogenesis, although autoantibodies are not specific markers of autoimmune pathogenesis since they can be an epiphenomenon of pericardial inflammation.

• Patients with mild attacks, a subacute course, a slight increase in inflammatory markers, and no positive autoantibodies.

Pathogenesis of idiopathic recurrent pericarditis.

IRP is the result of the interaction between environmental triggers, genetic predisposition, and the immune system. The causes of recurrence remain to be elucidated.

The immune-mediated pathophysiology of IRP is actively studied and may involve both autoinflammatory mechanisms of the innate immune system and autoimmune mechanisms of the adaptive immune system [136, 137, 138].

The inflammatory response of the innate immune system, typical of so-called "autoinflammatory diseases," is predominantly mediated by cytokines, mainly IL-1, whereas the inflammatory response of the adaptive immune system, typical of so-called "autoimmune diseases," is predominantly mediated by autoantibodies or autoreactive T lymphocytes [138].

Recent studies have defined idiopathic recurrent pericarditis as a rare, complex autoinflammatory disease caused by abnormally activated NLRP3 inflammasomes [139, 140, 141].

The innate immune system provides an immediate response to a multitude of diverse damage-associated and pathogen-associated molecular patterns (damage-associated molecular patterns – DAMPs, and pathogen-associated molecular patterns – PAMPs), followed by the activation of inflammasomes—cytosolic macromolecular structures consisting of an adapter protein (ASC – apoptosis-associated speck-like protein containing a caspase recruitment domain), procaspase-1, and a sensor molecule (pattern recognition receptor, or PRR).

Inflammasome activation leads to the excessive synthesis of pro-inflammatory cytokines of the interleukin (IL)-1 family: IL-1β, which is responsible for systemic symptoms (such as polyserositis, fever, and elevated acute-phase reactants) [16], and IL-1α, which is thought to cause a chronic local inflammatory process in the pericardium and, consequently, the development of fibrosis [141].

Given that IRP shows efficacy from therapies targeting the innate immune response, especially IL-1 inhibitors, as well as the similarity between IRP and autoinflammatory diseases, this reinforces the hypothesis that IRP may be a form of autoinflammatory disease.

On the other hand, in some cases, simultaneous activation of the adaptive immune system has been hypothesized, since anti-heart autoantibodies or antibodies to intercalated discs, typically detected in autoimmune diseases, are found in 67.5% of adult patients with IRP [137]. Therefore, it can be assumed that in a subset of patients with IRP, the inflammatory mechanism may also activate an "autoimmune" pathway [136].

Clinical presentation and diagnostic criteria.

In the classical variant of IRP, the clinical picture of a recurrence resembles that of acute pericarditis and may manifest as substernal chest pain, temperature elevation ranging from low-grade to high fever, dry non-productive cough, and general symptoms such as weakness, sweating, fatigue, and decreased appetite. Each subsequent recurrence of pericarditis is identical to the previous one but runs a somewhat milder course, especially in children [4, 15, 48].

In IRP, patients often report prodromal symptoms of exacerbation occurring several days before a new episode.

During patient examination, a pericardial friction rub, pericardial effusion, thickening of the pericardial leaflets due to fibrin deposition, as well as electrocardiographic changes, etc., may be detected [141,142]. Figure 5 shows the criteria for diagnosing idiopathic recurrent pericarditis [143]. The diagnosis can be made in the presence of 2 criteria and in the absence of exclusion criteria.

Figure 5. Criteria for diagnosing IRP [143].

Blood tests often reveal neutrophilic leukocytosis, elevated C-reactive protein, and in some cases, elevated aminotransferases. The levels of myocardial injury markers (troponin I, CK-MB, and myoglobin) remain within normal limits. The levels of rheumatoid factor, complement system, antinuclear factor, and other specific autoantibodies are generally not elevated [143].

An important indicator of autoinflammation and activation of the macrophage arm of immunity, associated with elevated IL-18, is ferritin, which belongs to acute-phase proteins of inflammation. Therefore, ferritin, like C-reactive protein, should be evaluated during an exacerbation [143].

Prognosis for IRP in children.

The prognosis for life is good.

However, due to frequent relapses, drug side effects, or the occurrence of complications such as cardiac tamponade, constrictive pericarditis, and myocardial involvement, morbidity remains high, and children's quality of life is impaired.

Prognostic factors associated with an increased risk of relapses or complications have been identified for adult patients (Table 6).

Table 6. Prognostic factors predicting complications or relapses [1].

Cardiac tamponade in idiopathic pericarditis is much less common (about 1-2% of cases) than, for example, in neoplastic pericarditis. Cardiac tamponade more frequently complicates the first episode of pericarditis rather than relapses [144,145].

Pericardial constriction is rare (1-2% over 6 years of follow-up) in patients with idiopathic or viral pericarditis, relatively uncommon (2-13%) in patients with post-traumatic cardiac pericarditis or pericarditis associated with systemic autoimmune diseases, and frequent (20-30%) in tuberculous and purulent pericarditis [144-147].

Treatment of idiopathic recurrent pericarditis.

Hospitalization for recurrent pericarditis is indicated in the presence of severe pain syndrome or poor prognostic factors (Table 3) [1].

The treatment strategy for idiopathic recurrent pericarditis in children is generally carried out in accordance with general recommendations for the treatment of pericarditis (see chapters on the treatment of acute and recurrent pericarditis).

The management of IRP should follow the same tactics as for acute pericarditis, prescribing high-dose NSAIDs combined with #colchicine, except for cases of specific etiology requiring alternative treatment, or in refractory patients [1].

In this case, acceptable options are #Ibuprofen** (30-50 mg/kg per day, divided every 6-8 hours) or #Indometacin (2 mg/kg per day, divided every 6-12 hours, Table 4). Intravenous administration may be useful to achieve rapid pain control in hospitalized patients.

#Colchicine is also effective in pericarditis. Studies have shown that colchicine accelerates the response to treatment and reduces the risk of recurrence by approximately 50% [148]. Unfortunately, there is limited data on the use of #colchicine in children with recurrent pericarditis [148,149]. Nevertheless, a recent observational study demonstrated a 65% reduction in recurrence rate [52]. In addition, the use of #colchicine reduces the risk of pericardial constriction in post-pericardiotomy syndrome [125].

Currently, systemic corticosteroids are used as second-line therapy in adults with severe acute pericarditis or #colchicine-resistant recurrent pericarditis. Although glucocorticoids can demonstrate a rapid effect, they nevertheless promote relapses and steroid dependency, especially when used in high doses [50,150].

In children, systemic corticosteroids can cause growth retardation, rashes, purple striae, and a predisposition to osteoporosis. Therefore, the use of this group of drugs in the treatment of idiopathic recurrent pericarditis in children should be avoided as much as possible. To this end, the following principles should be adhered to: (a) use NSAIDs at the maximum tolerated doses, including in combination with #colchicine;

(b) consider the use of anti-IL-1 therapy after the failure of high doses of NSAIDs in combination with #colchicine.

If the above cannot be followed, glucocorticoid therapy should be initiated at the lowest effective dose and tapered gradually after achieving remission [50,52,148,150].

In cases of IRP, #prednisolone** may be added as triple therapy with #ASA**/NSAIDs and #colchicine; however, the dose should be minimized as much as possible and avoided unless infection has been ruled out [1,8].

Anti-IL-1 therapy with #anakinra** (1–2 mg/kg subcutaneously daily) is the most important advance in this field over the past decade [3]. #Anakinra** is effective in multiple autoinflammatory diseases. Thus, it was initially used in children with refractory IRP. Subsequent experience, including clinical trials, has shown that #anakinra** has a dramatic effect in refractory or steroid-dependent IRP with elevated levels of acute-phase inflammatory markers [51,52,151-154].

Children with idiopathic recurrent pericarditis often have an "autoinflammatory phenotype" [52], which is particularly sensitive to #anakinra**. The drug has a very favorable safety profile due to its short half-life and low risk of infections and tuberculosis reactivation. Severe reactions are rare, but injection site reactions occur frequently in the first month of treatment and subsequently resolve [51].

Therefore, #anakinra** should be considered as a second-line agent for children and adolescents with IRP resistant to NSAIDs and #colchicine.

Intravenous immunoglobulins (IVIG) are used in refractory cases with the possibility of re-administration after 1 month [49,52,153,154]. Since anti-IL-1 therapy has become available for the treatment of IRP, the role of IVIG is largely restricted to patients with autoimmune manifestations in myopericarditis.

Recurrent pericarditis with a specific etiology should be treated according to the underlying disease.

Prevention of recurrences and other complications

After achieving complete remission (absence of symptoms and normalization of acute-phase inflammatory markers), therapy can be gradually tapered. Systemic corticosteroids and high-dose NSAIDs are tapered first. Table 5 shows the systemic corticosteroid tapering schedule that we follow in pediatric patients with IRP [1]. Recurrences are particularly frequent if glucocorticoids are tapered rapidly.

Tapering of #anakinra** should not be initiated earlier than 3–6 months after achieving sustained remission and should be performed very slowly due to the high risk of recurrence.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Vasichkina E.S. – Head of the Working Group, MD, PhD (Saint Petersburg), member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Society of Cardiology (RSC)

2. Groznova O.S. – MD, PhD (Moscow), Secretary of the Working Group, member of the Association of Pediatric Cardiologists of Russia (APCR)

3. Kovalev I.A. MD, PhD (Moscow) – President of the Association of Pediatric Cardiologists of Russia (APCR)

4. Balykova L.A. – Doctor of Medical Sciences, Professor (Saransk), Member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Cardiological Society (RCS), Russian Society of Holter Monitoring and Noninvasive Electrocardiology (ROHMNE), Union of Pediatricians of Russia, European Pediatric Association (EPA/UNEPSA), European Society of Cardiology (ESC).

5. Basargina E.N. – MD, PhD, Professor (Moscow), member of the Association of Pediatric Cardiologists of Russia (APCR)

6. Degtyareva E.A. – MD, PhD, Professor (Moscow), member of the Association of Pediatric Cardiologists of Russia (APCR)

7. Leontieva I.V. – MD, PhD, Professor (Moscow), member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Society of Cardiology (RSC), Russian Society of Holter Monitoring and Noninvasive Electrocardiology (RS HM&NIE)

8. Yakovleva L.V. – MD, PhD, Professor (Ufa), member of the Association of Pediatric Cardiologists of Russia (APCR)

Conflict of interest:

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatricians

2. General practitioners (family physicians)

3. Pediatric cardiologists

4. Medical students, residents, postgraduate students

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines" (Registered on May 8, 2019, No. 54588)

2. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care"

3. Federal Clinical Guidelines "Myocarditis", 2020. https://cr.minzdrav.gov.ru/recomend/153_1

4. Order of the Ministry of Health and Social Development of Russia No. 366n dated April 16, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Pediatric Care" (Registered with the Ministry of Justice of Russia on May 29, 2012, No. 24361)

5. Order of the Ministry of Health of Russia No. 440n dated October 25, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care in the Profile of 'Pediatric Cardiology'" (Registered with the Ministry of Justice of Russia on December 4, 2012, No. 26000)

6. State Register of Medicines https://grls.rosminzdrav.ru/Default.aspx

7. Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations for Epidemic Indications, and the Procedure for Administering Preventive Vaccinations"

8. Baranov A.A. "Federal Clinical Guidelines for Providing Medical Care to Children with Myocarditis" 2015 https://www.pediatr-russia.ru/information/klin-rek/deystvuyushchie-klinicheskie-rekomendatsii/

9. Order of the Ministry of Health of the Russian Federation No. 878n dated October 23, 2019, "On Approval of the Procedure for Organizing Medical Rehabilitation of Children"

10. Order of the Ministry of Labor of Russia No. 374n dated July 26, 2024 "On Approval of Classifications and Criteria Used in Carrying Out Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions" (Registered with the Ministry of Justice of Russia on August 23, 2024, No. 79273)

11. Order of the Ministry of Health of Russia No. 160n dated March 2, 2021, "On Approval of Standards of Medical Care for Adults with Myocarditis" (together with the "Standard of Medical Care for Adults with Myocarditis (Diagnosis and Treatment)", "Standard of Medical Care for Adults with Myocarditis (Dispensary Follow-up)") (Registered with the Ministry of Justice of Russia on April 12, 2021, No. 63068)

12. Order of the Ministry of Health of Russia No. 918n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Cardiovascular Diseases" (as amended by Orders of the Ministry of Health of the Russian Federation No. 171n dated April 14, 2014, No. 89n dated February 22, 2019, No. 114n dated February 21, 2020)

Appendix B. Physician Action Algorithms

Classification of pericarditis [29]

Stages of diagnostic procedures

Features of pericardial effusion assessment

Recommendations for general diagnostic workup in pericardial diseases [1].

Appendix B 2. Clinical Pathways

Diagnostic and management algorithm for suspected pericarditis [1].

Appendix C. Patient Information

The pericardium is a closed slit-like sac consisting of 2 layers—inner and outer—that surround the heart. Normally, a small amount of fluid is present between these layers.

When the pericardium becomes inflamed, the amount of fluid between its two layers increases, which is known as pericardial effusion. Pericardial effusion can compress the heart, impairing its normal function.

Acute pericarditis is a clinical syndrome of polyetiological origin, typically manifesting with inflammatory symptoms and chest pain, and in some cases with a pericardial friction rub and/or inflammatory pericardial effusion.

Acute pericarditis is most often a complication of a prior infection, various internal organ diseases, and their treatments.

The diagnosis of pericarditis can be established at any age.

It is believed that children with weakened immune systems, those who have undergone heart surgery or chest trauma, and those with autoimmune diseases have an increased risk of developing pericarditis.

The clinical manifestations of myocarditis are also diverse and depend on the child's age. Symptoms of pericarditis can resemble those of other conditions.

Your child may experience sharp, stabbing chest pain that worsens with deep breathing or when lying down. This common symptom often starts on the left side or center of the chest and radiates to the neck and left shoulder. In infants, pain equivalents may include sudden, unmotivated episodes of severe distress, pallor, and sometimes vomiting.

Other symptoms of pericarditis may include: shortness of breath, cough, fever and chills, weakness and fatigue, irritability, loss of appetite, palpitations, and syncope.

In younger children, abdominal pain, dyspeptic phenomena, vomiting, and tenderness upon palpation are frequently observed, necessitating the exclusion of acute abdominal surgical pathology and gastrointestinal tract diseases.

In this case, you should immediately consult a doctor or call emergency medical services.

If pericardial pathology is detected and risk factors for complications are present, the child will be hospitalized. The doctor will assess the severity of the condition, and if necessary, the child may be transferred to the intensive care unit for stabilization.

The child will undergo necessary examinations, including ECG, echocardiography, chest X-ray, and laboratory tests, including a complete blood count (CBC) and general clinical blood chemistry. Depending on the severity of the condition and identified changes, individual therapy will be prescribed for the child.

If the fluid volume increases rapidly, the development of such a formidable complication of pericarditis as cardiac tamponade is possible. This is a condition where the heart is compressed by the accumulated fluid, the heart chambers cannot relax and fill with blood, which leads to a decrease in pumping function and reduced cardiac output.

Treatment of pediatric pericarditis strictly begins with physical activity restriction; in severe cases, a drastic limitation of physical activity and strict bed rest in the first days of the illness may be required.

Drug therapy is generally aimed at eliminating pain, reducing inflammation, and treating the infection if present. In severe, complicated pericarditis, your child may require procedures such as pericardiocentesis or pericardiectomy.

Following discharge from the hospital, the child is monitored by the district pediatrician and the local pediatric cardiologist.

Follow-up dispensary observation is carried out for 3 years from the moment the diagnosis is established or discharge from the hospital, and indefinitely for patients with chronic pericarditis.

Child athletes with pericarditis, regardless of etiology, must be suspended from participation in all sports during the acute stage of the disease for at least 3 months. Athletes may resume sports outside the acute stage of the disease, including the absence of effusion according to echocardiography, provided that inflammatory markers have normalized.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Absent