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A multicenter study on experience of 13 tertiary hospitals in Turkey in patients with infective endocarditis/Turkiye'de 13, ucuncu basamak hastanenin katildigi cok merkezli enfektif endokardit calismasi.

Introduction

Despite great medical progress, infective endocarditis (IE) remains a life-threatening condition with a high mortality rate (1, 2). In developed countries, the epidemiological features of IE are changing as a result of new predisposing factors, higher frequency of nosocomial cases and increasing longevity (3, 4). New developments in the diagnosis and management of IE have influenced the pattern of disease seen in developed countries, particularly as related to early surgical intervention and reduced mortality (5-8).

Although rheumatic heart disease is still a major risk factor for IE in most developing countries, acute rheumatic fever has declined sharply and degenerative valvular lesions have become the most frequent anatomic abnormalities predisposing to infection in the west (5, 9). IE is frequently associated with rheumatic valvular disease resulting in high morbidity and mortality in Turkey (10). In fact, most studies on IE from the developing world with few exceptions are single center studies (11, 12).

The aim of this multicenter study was to investigate the clinical manifestations, microbiological profile, echocardiography findings and management strategies of IE in Turkey.

Methods

Study design

The study was designed as a retrospective observational multicenter trial.

Study population

The study population consisted of 248 consecutive Turkish patients with IE treated at 13 major hospitals in seven geographical areas of Turkey from 2005 to 2012 respectively. All hospitals are tertiary referral centers, which receive patients from surrounding hospitals. These hospitals were located in different cities throughout Turkey. We analyzed the medical files of all patients hospitalized with the diagnosis of IE. Inclusion criteria were definite IE, according to modified Duke Criteria (13). All patients had undergone transthoracic echocardiography (TTE) on admission and at regular intervals thereafter or whenever there was a change in the clinical status. Echocardiographic data included routine parameters and presence, number, maximal diameter and mobility of any vegetation. Transesophageal echocardiography (TEE) was considered in patients with a high clinical suspicion of IE with a nondiagnostic TTE and in those with a suspected mechanical complication. Patients with possible IE were excluded.

The study was approved by the local Medical Ethics Committee.

Data collection

Data on demographic characteristics, age, sex, underlying heart disease, presenting signs and symptoms, diabetes mellitus and other co-morbidities, results of laboratory and microbiological investigations, echocardiographic findings, treatment given during hospitalization, surgical requirements, cardiac and extra-cardiac complications were collected. The patients were also analyzed for factors associated with recurrent episodes of IE. The antibiotic regimen, aspects related to the surgical approach, and in-hospital outcome were also recorded. Complete blood count, C-reactive protein, erythrocyte sedimentation rates, serum chemistry, and urine analysis comprised the routine laboratory investigations that were recorded.

Statistical analysis

Statistical Package for Social Sciences software (SPSS 12, Chicago, IL, USA) was used for analysis. Descriptive statistics are presented as mean [+ or -] standard deviation or percentages.

Results

Baseline characteristics of the patients are shown in Table 1. The mean age of patients was 47 [+ or -] 18 years (range 13-87). One hundred thirty seven of the patients were males. The most common symptom at presentation was fever 189 (76%). Native valves endocarditis (NVE) was involved in 158 patients while in 75 participants there was prosthetic valve endocarditis (PVE) (Table 2). Seven of PVE were early PVE (onset of clinical manifestations within 12 months from valvular heart surgery), the other 68 of PVE were late PVE (onset of clinical manifestations later than 12 months from surgery). The remaining 15 patients had pacemaker endocarditis. Vegetations were detected in 223 patients (89%) and 52 patients had multiple vegetations. The most common valvular pathology was mitral regurgitation, which was detected in 142 patients (56%). The most common predisposing factors were rheumatic valvular disease (n = 69, 28%). Mitral valve was the most common site of vegetation; 107 patients (43%) which were followed by the aortic valve in 77 patients (32%) and both mitral and aortic valves in 23 patients (9%) (Table 3).

All patients had blood culture studies, but only 156 (62%) had positive blood cultures for bacteremia. Staphylococci were the most frequent causative microorganisms isolated in both NVE (n = 45, 28%) and PVE (n = 23, 30%) cases, with an overall involvement of 68 cases (27%) (Table 4). Methicillin-resistant staphylococci were isolated in 15 patients. Streptococci were isolated in 27 (10%) of subjects with positive blood cultures followed by gram-negative microorganisms in eleven patients. Enterococcus endocarditis were found in 28 patients (n = 28, 11.3%). Streptococci were the causative agents in 27 cases (14.5%), mostly affected by S. viridans (n = 22, 8.9%). Fungal endocarditis (Candida albicans) was found in two patients.

Congestive heart failure was the most common complication, which was detected in 88 patients (33%) during the disease course. Systemic embolism occurred in 71 patients (29%). Septic shock occurred in 43 patients (17%). The mean duration of antibiotic treatment was 28 [+ or -] 18 days. One hundred sixteen patients (47%) had undergone combined medical and surgical treatment. Surgical intervention was performed in 86 patients (54%) for NVE (total 158 patients) and in 30 patients (40%) for PVE (total 75 patients). Eighty-one patients died during hospital follow-up. In-hospital mortality rate was 33%. Forty-seven patients (36%) who were treated only with medical therapy died. The mortality rate was 29% (34 patients) with surgical treatment. The mortality rate was 57% in patients with early PVE and 31% in patients with late PVE.

Discussion

The current study provides several important comprehensions into IE in tertiary hospitals in Turkey. Despite advances in diagnostic methods, antibiotic treatment, blood culture techniques and surgical therapy techniques, IE is still associated with high mortality rate. According to current study, rheumatic valvular disease remains the most common underlying heart disease of IE.

Several studies related to the epidemiology of infective endocarditis in Turkey have been published in the literature. However, these were single center studies and lack general trend and characteristics (14). For the first time, the present multicenter study has provided important data on the epidemiology, etiology, clinical, microbiology, treatment characteristics and the current perspective on IE in Turkey. Despite advances in diagnostic imaging methods, antibiotic therapy, blood culture techniques, and the surgical approach, IE is still associated with a high mortality rate. The most important finding of the current study was the relatively high rate of mortality. Despite higher rates of antibiotic therapy and surgical interventions, the overall in-hospital mortality rates for both native valve and prosthetic valve IE remained high (33%), which is higher than that observed in other countries, including some developing countries (1, 5, 15).

The epidemiologic characteristics of IE have shifted over the last decades in developed countries. In west populations, IE is commonly diagnosed in patients older than 50 years (16, 17). These changes are mainly being attributed to a number of factors including a marked reduction in the incidence of acute rheumatic disease and congenital heart disease, increase in cases of degenerative valvular disease, increasing patient longevity, increased use of invasive procedures and implanted medical devices (prosthetic valves, pacemaker, ICD and central vascular catheters etc.) (5, 12). In a recent study conducted by Leblebicioglu et al. (14) from Turkey the mean age for IE was 45 years (112 adult patients), and in a study from Turkey by Cetinkaya et al. (10) the patients were under the age of 40 years (228 patients). In our study, the mean age of the patients was 47 years (range 13 to 87 years) and rheumatic heart disease still was the most common underlying heart disease for IE. Transthoracic echocardiography and TEE was utilized in the vast majority of patients (95%). The use of TEE was 37% in the whole population.

In the present study, positive culture rate was 65%. The proportion of negative blood cultures was high in our study, which was 10% higher than the rates reported in recently published studies (1, 13). Culture negative endocarditis in the present study was more frequent in patients with IE mainly referred from peripheral hospitals, where a large spectrum of empiric antibiotic therapy had been administered before the definite diagnosis.

In previous studies, when blood cultures were positive, staphylococci and streptococci were the most commonly isolated causative agents of IE (36% and 35%, respectively). These two microorganisms have been reported as main etiological agents in 13-49% and 20-63% of the cases with native valve endocarditis, respectively (5, 10, 12). However, in our study cohort staphylococci and enterococci were the most frequently isolated causative agents in IE with the incidences of 29% and 11%, respectively. The rate of enterococci infection was among the highest when compared with the literature data (3-20%) (10, 12, 14, 18). It is well known that enterococcal bacteremia is a serious infection, associated with mortality rates between 23% and 46% (19-22). But in our study mortality of enterococcal endocarditis was highest compared with other agents (46%).

Study limitations

The main limitation of this study is its retrospective design. TEE was performed in only 37% of the cohort; which might have influenced the results related to the echocardiographic findings and their association with the outcome.

Clinical implications

The present study brings a new insight to our clinical practice. We hope these findings may be helpful to develop new strategies against IE in Turkey

Conclusion

The present study demonstrated that IE remains a severe disease with a high mortality rate. Younger age, higher prevalence of rheumatic heart disease, more frequent enterococci infection and higher rates of culture negativity were other important aspects of IE epidemiology in Turkey.

Conflict of interest: None declared.

Peer-review: Externally peer-reviewed.

Authorship contributions: Concept--M.A.E.; Design--M.A.E., M.E.K.; Supervision--M.A.E., S.A., M.G.K.; Resource--M.A.E.; Material--S.A., M.E.K.; Data collection&/or Processing--M.R.S., H. K., S.B., T.U.; Analysis&/or interpretation--M.A.E., M.G.K., M.A.A., M.E.K.; Literature search--M.A.E., M.E.K., H.K.E., A.A.; Writing--M.A.E.; Critical review--M.E.K., M.A.E.; Other--A.A., T.U., S.B., H.K.

Acknowledgements

Collaborator list in alphabetical order

1. Ataturk University School of Medicine, Department of Cardiology, Erzurum, Turkey (Enbiya Aksakal, Selim Topcu).

2. Bulent Ecevit University School of Medicine, Department of Cardiology, Zonguldak, Turkey (Mustafa Aydin, M. Rasit Sayin).

3. Cumhuriyet University School of Medicine, Department of Cardiology, Sivas, Turkey (Hekim Karapinar, Zekeriya Kucukdurmaz).

4. Dicle University School of Medicine, Department of Cardiology, Diyarbakir, Turkey (Siddik Ulgen, Sait Alan, Serdar Soydinc).

5. Duzce University School of Medicine, Department of Cardiology, Duzce, Turkey (Ismail Ekinozu, Yusuf Aslantas).

6. Erciyes University School of Medicine, Department of Cardiology, Kayseri, Turkey (Mehmet G. Kaya, Mahmut Akpek).

7. Eskisehir Osmangazi University School of Medicine Department of Cardiology, Eskisehir, Turkey (Taner Ulus).

8. Gaziosman Pasa University School of Medicine, Department of Cardiology, Tokat, Turkey (Fatih Koc, Kerem Ozbek).

9. Kahramanmaras Sutcu Imam University School of Medicine, Department of Cardiology, Kahramanmaras, Turkey (Cemal Tuncer, Gurkan Acar).

10. Kartal Kosuyolu Education and Research Hospital, Clinical Cardiology, Istanbul, Turkey (Ali Metin Esen).

11. Izmir Ataturk Education and Research Hospital, Clinical Cardiology, Izmir, Turkey (Nihan Kahya Eren).

12. Suleyman Demirel University School of Medicine, Department of Cardiology. Isparta, Turkey (Abdullah Dogan, Fatih Kahraman).

13. Yuzuncu Yil University School of Medicine, Department of Cardiology, Van, Turkey (Serkan Akdag).

References

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Mehmet Ali Elbey, Serkan Akdag [1], Mehmet Emin Kalkan [2], Mehmet G. Kaya [3], M. Rasit Sayin [4], Hekim Karapinar [5], Serkan Bulur [6], Taner Ulus [7], M. Ata Akil, Hatice Kopru Elbey *, Abdurrahman Akyuz

Department of Cardiology and * Ophthalmology, Faculty of Medicine, Dicle University, Diyarbakir--Turkey

[1] Department of Cardiology, Faculty of Medicine, Yuzuncu Yil University, Van-Turkey

[2] Clinic of Cardiology, Kartal Kosuyolu Education and Research Hospital, Istanbul-Turkey

[3] Department of Cardiology, Faculty of Medicine, Erciyes University, Kayseri-Turkey

[4] Department of Cardiology, Faculty of Medicine, Bulent Ecevit University, Zonguldak-Turkey

[5] Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas-Turkey

[6] Department of Cardiology, Faculty of Medicine, Duzce University, Duzce-Turkey

[7] Department of Cardiology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir-Turkey

Address for Correspondence/Yazisma Adresi: Dr. Mehmet Ali Elbey, Dicle Universitesi Tip Fakultesi, Kardiyoloji Anabilim Dali, 21280, Diyarbakir-Turkiye Phone: +90 412 248 80 01 Fax: +90 412 248 85 23 E-mail: elbeymali@hotmail.com

Accepted Date/Kabul Tarihi: 09.10.2012 Available Online Date/Cevrimici Yayin Tarihi: 04.07.2013

doi: 10.5152/akd.2013.172
Table 1. Demographic characteristics, clinical signs, symptoms
and biochemical variables on admission

Variables                              Frequency           %

Gender (M/F)                            137/111          55/45
Presenting symptoms
  Fever                                   189            76.2
  Fatigue                                 128            51.6
  Dyspnea                                 122            49.2
  Gastrointestinal symptoms               78             31.5
  Chills                                  43             17.3
  Loss of weight                          37             14.9
  Muscle and joint symptoms               13              5.2
  Skin lesions                             6              2.4
NYHA III/ IV                              126             51
Diabetes mellitus                         35              14
Previous IE                                7               3
Atrial fibrillation                       33              13
Systolic blood pressure, mmHg       113 [+ or -] 16
Diastolic blood pressure, mmHg       70 [+ or -] 10
Mean heart rate, bpm                 90 [+ or -] 14
Hemoglobin, g/dL                     11 [+ or -] 2.2
White blood cell, n/mL            15367 [+ or -] 7428
Sedimentation rate, mm/hour          66 [+ or -] 27
C-reactive protein, mg/dL            71 [+ or -] 61
Creatinine, mg/dL                  1.43 [+ or -] 0.76

Continuous variables are represented as mean [+ or -] SD

Table 2. Echocardiographic manifestations of the patients
with IE

Variables                          Frequency       %

Native valve endocarditis             158          64
  Rheumatic heart disease              69          28
  Degenerative heart disease           57          23
  Congenital heart disease             18           7
  Mitral valve prolapsus               9            4
Prosthetic valve endocarditis          75          30
Pacemaker endocarditis                 15           6
Vegetations                           223          89
Multiple                               52          21
Mobile                                150          60
Diameter, mm                    4.4 [+ or -] 4.9
Aortic regurgitation                   82          33
Mitral regurgitation                  142          56
Ejection fraction                53 [+ or -] 11

Continuous variables were are represented as
mean [+ or -] SD

Table 3. Sites of vegetations detected by echocardiography
in 248 patients with infective endocarditis

Site                                             Number of
                                                patients (%)

Mitral valve                                     107 (43.1)
Aortic valve                                      79 (31.9)
Mitral+aortic valves                              23 (9.3)
Tricuspid valve                                   22 (8.9)
Pulmonic valve                                     6 (2.4)
Bicuspid aortic valve                              5 (2)
Tetralogy of Fallot                                5 (2)
Ventricular septal defect                          4 (1.6)
Aortic coarctation+Ventricular septal defect         1
Atrial septal defect                                 1
Hypertrophic cardiomyopathy                          1
Patent ductus arteriosus                             1
No vegetations on echocardiogram                  23 (10.1)

Table 4. Distribution of causative microorganisms
isolated from blood cultures in patients with
infective endocarditis

Organism                         Number of
                                patients (%)

Staphylococci                     73 (29)
  Staphylococcus aureus           53 (21)
  MRSA                               15
  MSSA                               11
  Coagulase-negative              16 (6)
  Staphylococcus epidermidis       4 (2)
Enterococcus                      28 (11)
Streptococci                      27 (11)
  Viridans streptococci              22
  Streptococcus bovis                1
  Other streptococcal species        4
Gram-negative organisms           25 (10)
  Brucella                        12 (5)
  P. aeruginosa                      3
  E. coli                          4 (2)
  HACEK group                        5
  Klebsiella spp.                    1
Candida albicans                     2
No growth on culture             93 (37.5)
Total                               248

MRSA--methicillin-resistant S. aureus,
MSSA--methicillin-sensitive S. aureus
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Title Annotation:Original Investigation/Ozgun Arastirma
Author:Elbey, Mehmet Ali; Akdag, Serkan; Kalkan, Mehmet Emin; Kaya, Mehmet G.; Sayin, M. Rasit; Karapinar,
Publication:The Anatolian Journal of Cardiology (Anadolu Kardiyoloji Dergisi)
Article Type:Report
Geographic Code:7TURK
Date:Sep 1, 2013
Words:3220
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