UDC:  616.11-002-089 
EXUDАTIVE  PERICARDITIS:  EIGHT  YEARS 
OF CLINICAL EXPERIENCE. 
PART I: INFORMATION OBTAINED
  FROM  CLINICAL TRIALS AND  STATISTICAL  STUDIES 
1Telepov V.V., 1Salo S.V., 1Trembovetskaya E.M., 1Rudenko E.V.,  
2Ganul V.L., 2Borisyuk B.O., 3Starosyla D.B., 4Sokoliuk M.A.

¹ M.Amosov National Institute of Cardiovascular Surgery of National Academy of Medical Sciences of Ukraine (Kyiv)
² State enterprise «National Cancer Institute of the Ministry of Health of Ukraine» (Kyiv)
³ L.V.Gromashevskiy Institute of Epidemiology & Infectious Diseases National Academy of Medical Sciences of Ukraine (Kyiv)
4 Municipal Institution of Kyiv Regional Counsil “Kyiv Regional 4Oncology Dispensary”, Department of Abdominal Surgery (with urology beds)

The aim of this review is to analyze and to discuss the methods of exudative pericarditis (EP) research including also new ones, being important for the understanding of this problem on the territory of Ukraine. For this purpose, we have chosen the most “popular” EP types; they were investigated in our country during 29 years, i.e. during 21 years before the introduction of new technologies and 8 years following this event; we describe here comparative qualitative and quantitative characteristics of different EP types.
Key words: exudative pericarditis, two-stage intra-pericardial chemotherapy, isolation and identification of viruses, dot-ELISA, sclerosing of the pericardium, research methods, cis-platinum, proteflazidum.

The influence of different teratogenic, carcinogenic, chemical, physical, and other negative factors leads often to the decrease of  organism’s immunity as well as to immune deficiency and development of different diseases, the E belonging to one of such consequences.
Lately we become witnesses of the impetuous growth of this condition in Ukraine, the absence of annual preventive medical examinations leading to its belated diagnostics. Now the EP is among the leaders not only as a result of some underlying diseases, but also as an independent myocardium ailment. 

According to the data of the European Society of Cardiology (ESC 2015), about 50% of all EP cases in developed countries are thought to be idiopathic; in other 50% of cases the EP leading causes are tumor diseases (10–25%), infections (15–30%), iatrogenic factors (15–20%), and connective tissue pathologies (5–15%). As earlier, in a lot of developing countries tuberculosis continues to persist as a leading cause of pericardial exudation (above 60%) [1–4].
To carry out comparative characterization of different EP types, we examine here a body of clinical data obtained during 8 years due to the use of different research approaches including also the newest ones.
The aim of this work is the analysis of the data obtained and of the results reached due to the newest approaches for diagnostics and treatment of patients with different EP types during 8 years in order to improve patients’ life quality and duration.
Materials and methods.  From the 2nd of January 2008 up to the 1st of January 2016, 399 EP patients (100%) were examined at the M.Amosov National Institute of Cardiovascular Surgery of National Academy of Medical Sciences of Ukraine. 
On the base of disease etiological features, the patients were divided on five clinical groups, namely.
the I group of EP patients – patients with infection processes; n=162; 40.6% (15–30%); 
the II group – EP patients with tumor processes; n=152; 38.1% (10–15%);
the III group – EP patients with autoimmune conditions: n=36; 9% (5–15%);
the IV group – other EP cases; n=35; 8.8% (5–10%);
the V group – patients with intra-pericardial exudates (trans-sudates) of different origin [due to diabetes, cardiomyopathies, stagnated heart failure (HF) etc.]: n=14; 3.5% (5–10%).
The I group (n=162) includes:
1) EP of viral etiology (EPVE) – 137 (84.6%)*, including EP cases due to infections caused by:
– herpes simplex virus type I and type II (HSV½) – 31 (22.6%),
– herpes zoster virus (HZV) – 4 (2.9%),
– cytomegalovirus (CMV) – 11 (8.1%),
– Epstein-Barr virus (EBV) – 32 (23.4%),
– human herpes virus type 6 (ННV6) – 7 (5.1%),
– adenovirus – 24 (17.5%),
– influenza viruses  (H1N1 and H3N2) – 17 (12.4%),
– hepatitis C virus (HCV) – 1 (0.7%),
– EP associated with human immunodeficiency virus (HIV) and AIDS (HIV/AIDS/EP) – 10 (7.3%)*.
The myopericarditis (MP) was found in 23 (16.8%)* EPVE patients, this condition being associated with EBV infection (11 patients, 7.4%) infection, HSV½ infections  (3 persons, 2%) as well as with adenoviral infection  (5 patients,   3.4%), and influenza virus H1N1  (4 patients, 2,7%).
2) EP of bacterial etiology (EPBE) – 18 (11.1%)*, including:
– EP caused by Chlamidiae (ChEP) – 1 (5.6%),
– EP caused by Pseudomonas aeruginosa – 2 (11.1%),
– EP due to Staphylococcus aureus infections – 4 (22.2%),
– EP caused by  Staphylococcus epidermidis – 5 (27.8%),
– EP developed during Enterococcus faecalis infection – 3 (17.7%),
– EP of tuberculosis origin (TbcEP) – 3 (16.7%);
3) cases of fungal EP (FEP) due to Candida spp. – 6 (3.7%)*;
4) EP caused by a parasitic organism Toxoplasma gondii (PEP) – 1 (0.6%)*.
Purulent EP was found in 8 (4.9%)* patients.
The II group (n=152) contains:
1)	neoplasm-caused EP (NCEP) – 4 (2.6%)*;
2)	paraneoplasm-caused EP (PNCEP) – 148 (97.4%)*,  including:
– anterior mediastinum tumors – 32 (21.6%),
– mammary gland tumors – 43 (29.1%),
– lung cancer – 51 (34.5%),
– malignant heart tumors – 4 (2.7%),
– malignant blood conditions – 7 (4.7%),
– other EP cases – 11 (7.4%).
In 8 (5.4 %) PNCEP patients we observed the tumor penetration into myocardium, in 58 (39.2%) of them metastatic pericarditis was found; in 17 (11.5%) patients secondary metastatic tumors developed, in 4 (2.7%) persons the products of tumor disintegration were present in the pericardium cavity.
The III group (n=36) contains:
1) EP associated with systemic conditions (EPASC) – 16 (44.5%)*,
2) autoimmune EP (AIEP) – 12 (33.3%)*,
3) allergic EP (AEP) – 8(22.2%)*.
In patients with the AIEP the autoimmune process was due to earlier infection, earlier surgical intervention etc.
The IV group (n=35) includes:
1) toxic EP (TEP) – 16 (45.7%)*,
2) post-infarct EP cases (PIEP) – 1 (2.9%)*,
3) radiation-associated EP (RAEP) – 7 (20%)*,
4) cholesterol-due EP (ChDEP) – 10 (28.5%)*,
5) gout-due EP (GDEP) – 1 (2.9%)*.
In one patient (14.3%)* the RAEP developed due to direct ionizing radiation effect (in the zone of Chernobyl atomic electric station), the RAEP in other patients was caused by multiple courses of radiation therapy (these patients are not included to the PNCEP group).
The TEP patients toxemia was due to drug effects (6 cases, 37.5%)*, inhalation of toxic vapors (5 cases, 31.3%), alcohol consumption (3 patients, 18.7%), and direct chemical compounds influence (2 cases, 12.5%).
The  V group (n=14) (3,5%) includes patients with intra-pericardial   exudates due to:
1) diabetes mellitus ( 8 cases, 57.1%)*,
2) dilated cardiomyopathy (DCMP) – 2 (14.3%)*,
3) stagnated HF – 4 (28,6%)*.
The approaches taken for diagnostics are the following:
а) clinical: anamnesis (patients life style, his/her diseases, family anamnesis), auscultation, percussion, evaluation of circulation impairment (CI) severity;
b) instrumental: ECG (electrocardiography), EchoCG (trans-thoracic echocardiography), plan survey radiography, computer tomography of thoracic and peritoneum cavity organs, magnetic resonance tomography (MRT), positron-emission tomography (PET), roentgen-vascular examination;
c) laboratory analyses data: common blood analysis, biochemical blood analysis, methods of microbiology and immunology, ELISA including also dot-ELISA, study of virus cytopathogenic effect, polymerase chain reaction (PCR), methods of interferon level determination, immunohistochemical approach, specific approaches for systemic disease detection, culturing of Mycobacterium tuberculosis, troponin test, determination of thyroid hormones etc.;
d)  cytological examination of cell elements present in intra-pericardial fluid, of blood cells and atypical cells (AC);
д) histological investigation of biopsy material or excised pericardium areas.
These investigations were made using both blood sera and intra-pericardial fluids.
Pericardiocentesis  (PCC) was carried out for all patients (n=399) including 200 (50.1%) males and 199 (49.9%) women; the pericardium cavity drainage and passive exudation was made during 48 h.
Pericardectomy (PCE) was realized for `31 (7.8%) patients following the diagnostic PCC. Thirty-two patients (8%) were admitted to the emergency department because of heart tamponade and almost a half of patients (211 persons, 52.9%) – because of heart tamponade threat; other 156 (39.1%) persons were taken to the hospital according to planned hospitalizations.
Almost all patients (379 cases, 95%) were treated according to etiology of their underlying disease; new approaches were also used. The patients were taken for next consultations (fluid level control in pericardium) in 1 month (1st consultation), in 2 months (2nd consultation), and in 6 months (3rd consultation) following surgical intervention; later they were examined once per year. 
In cases of metastatic PNCEP or/and tumor penetration into the pericardium, the neoplasm-origin exudates were found; AC presence having been confirmed, two-stage intra-pericardial chemotherapy (TSIPCh) was carried out (n=69; 46.6%) using cys-platin, a brand platinum-containing drug of the “Ebewe” firma (Austria) in optimal volume and doses. In addition, intrapleural, intravenous or intra-arterial chemotherapy was made if necessary [6, 7].  For the treatment of EP cases associated with tumors (n=15; 9.9%), with viral infections (n=11; 6.8%) and autoimmune processes (n=8; 2.2%), glucocorticosteroids (dexamethasone phosphate, 12-40 mg) were introduced into the pericardium [5].
For the management of all EP patients excluding HIV/AIDS persons, the sympthomatolytic therapy was accompanied by the use of proteflasidum, a brand preparation being produced by the firma “EcoPharm” (Ukraine), according to the standard treatment scheme [5].
To compare the results obtained, control groups were organized for two main nosologic EP forms.
They contain:
1)	EPVE patients (without HIV/AIDS/EP) – 137 persons, including:
The I group: patients treated using new approaches – 117 (85.4%),
The II group: patients without treatment – 20 (14.6%);
2) PNCEP patients – 148 including:  
The Ia group – patients with neoplastic cells in exudates having been treated be the TSIPCh –   69 (46.6%),
The IIa group – patients with neoplastic cells in exudates without such treatment – 58 (39.2%).
We organized also an experimental group including 6 (4.05%) patients (5–20 years old) with recurrent tumor processes and 6 (4.05%) persons with primary tumor processes without AC in exudates.
No cytostatic drugs were introduced into pericardium of 9 (6.1%) patients with primary tumor processes and without AC in their exudates; the tumor EP nature was confirmed by the AC detection following repeated PCC.
Results and discussion. In our clinic all the EP patients survived and were discharged following adequate management, EchoCG control, and prescription of further treatment course depending on each patient’s underlying disease. No relapse was detected in any patient from the I group; however, repeated PCC was carried out for all the II group patients.
Among persons having received dexamethasone phosphate, positive results (cessation of fluid exudation) was seen only in EPVE and EPASC patients.
The survival median (Ме) in patients of the Ia group  was 31.8±4.4 months (partial remission) with further development of adhesive pericarditis,   the Me of the IIа group being 3.7±1.2 months. 
Prolonged remissions in the study group were achieved for all patients; no repetitive relapses were seen in patients both with recurring and primary tumor processes due to endolymphatic outflow. 

Table 1

Etiology	Control group
(21 year, 1987–2007)	Group of study
(8years, 2008–2015)	
Total (n)	
Total, %	
	n	% in a given group	n	% in a given group			
Infection-associated EP	50	12.6	162↑	40.6↑	212	26.6↑	
EP associated with tumor disease	105	26.4	152↑	38.1↑	257	32.3↑	
Autoimmune EP	21	5.3	36↑	9↑	57	7.2↑	
Others (including also intra-peritoneal exudate)	40	10.1	49↑	12.3↑	89	11.2↑	
Idiopathic EP	181	45.6	0↓	0↓	181	22.7↓	
Total	397	100	399	100	796	100	
Lethality	18	4.5	0↓	0↓	18	2.3↓	

Conclusions. Taking our data in consideration, it is seen, the EP frequency in Ukraine increases (Table 1); the EP etiology is extremely diverse; this condition develops mostly on the basis of viral or tumor disease. Such pathologies need specific approaches for their diagnostics and management. Some new techniques used in our clinic demonstrate positive results in four met-analyzed patient groups in cases of both advanced (neglected) and in time diagnosed EP forms. 
All these data impel us to state that it is necessary to organize the All-Ukrainian Registry concerning the pericardium diseases and aiming to improve the future EP study, its detection, management, and prophylaxis. The statistical analysis carried out in our clinic permits to compare the all-world data on this nosology form with those obtained in Ukraine in order to determine the common treatment approach.
In next publications based on our 8-years old clinical experience we are going to describe the criteria of timely EP detection, its differential diagnostics, management, prophylaxis, and follow-up results both in general and for each etiological patient group.

References
1. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association Cardio-Thoracic Surgery (EACTS) // Eur.Heart.J. – 2015. –Vol. 36 (42). – P. 2921–2964.
2. Imazio M., Adler Y. Management of pericardial effusion // Eur. Heart J. – 2013. – Vol. 34. – P. 2232–2237.
3. Imazio M., Mayosi B.M., Brucato A. et al. Triage and management of pericardial effusion // J. Cardiovasc. Med. (Hagerstown). – 2011. – Vol. 11. – P. 928–935.
4. Imazio M. Contemporary management of pericardial diseases // Curr. Opin. Cardiol. – 2012. – Vol. 27. – P. 308–317.
5. Isolation and identification of viruses in exudative pericarditis cases /Telepov V.V., Fedorchenko D.B., Ivanskaya N.V., Salo S.V., Rybalko S.L., Popov V.V. // Bulletin of the A.N.Bakulev Scientific Center of Cardiovascular Surgery of the Russian Academy of Medical Sciences. Cardiovascular Diseases. – 2009. – Т. 10, № 3 (in Russian). 
6.	Significance of target-local intra-pericardial chemotherapy in exudative pericarditis management / Telepov V.V., Knyshov G.V., Popov V.V., Salo S.V., Borisiuk B.O. // Annual issue «Cardiovascular surgery». – Кyiv, 2009. – № 17 (in Russian).
7.	Use of two-stage intra-pericardial chemotherapy in patients with tumor processes in anterior mediastinum accompanied by exudative  pericarditis / Telepov V.V., Popov V.V., Salo S.V., Trembovetskaya E.M., Rudenko E.V. // Annual issue «Cardiovascular surgery». – Kyiv, 2010. – № 18. – P. 594–597 (in Russian).