International Journal of Infectious Diseases (2007) 11, 430—433

http://intl.elsevierhealth.com/journals/ijid

Epidemiology of infective endocarditis in : a 10-year multicenter retrospective study

Amel Letaief a,*, Essia Boughzala b, Naoufel Kaabia a, Samia Ernez c, Fekria Abid d, Taoufik Ben Chaabane e, Mounir Ben Jemaa f, Rachid Boujnah g, Mohamed Chakroun h, Moncef Daoud i, Rafika Gaha j, Naceur Kafsi d, Ali Khalfallah k, Lotfi Slimane g, Mohamed Zaouali d a Infectious Diseases Department, Farhat Hached University Hospital, Avenue Ibn El Jazzar, 4000, Tunisia b Cardiology, Sahloul Hospital, Sousse, Tunisia c Cardiology, Farhat Hached Hospital, , Tunisia d Cardiology, La Rabta Hospital, Tunis, Tunisia e Infectious Diseases, La Rabta Hospital, Tunis, Tunisia f Infectious Diseases, Hedi Chaker Hospital, , Tunisia g Cardiology, Hospital, Tunis, Tunisia h Infectious Diseases, Fattouma Bourguiba Hospital, Monastir, Tunisia i Cardiology, Hedi Chaker Hospital, Sfax, Tunisia j Epidemiology, Farhat Hached Hospital, Sousse, Tunisia k Cardiology, Menzel Bourguiba, , Tunisia

Received 28 May 2006; received in revised form 25 October 2006; accepted 27 October 2006 Corresponding Editor: J. Peter Donnelly, Nijmegen, The Netherlands

KEYWORDS Summary Infective endocarditis; Background: Since the first description of infective endocarditis, the profile of the disease has Epidemiology; evolved continuously with stable incidence. However, epidemiological features are different in Native valve; developing countries compared with western countries. Rheumatic fever; Objective: To describe epidemiological, microbiological and outcome characteristics of infective Staphylococcus; endocarditis in Tunisia. Streptococcus; Patients and methods: This was a descriptive multicenter retrospective study of inpatients Negative blood cultures; treated for infective endocarditis from 1991 to 2000. Charts of patients with possible or definite Mortality infective endocarditis according to the Duke criteria were included in the study. Results: Four hundred and forty episodes of infective endocarditis among 435 patients (242 males, 193 females; mean (SD) age = 32.4 (16.8) years, range 1—78 years) were reviewed. The most common predisposing heart disease was rheumatic valvular disease (45.2%). Infective endocarditis occurred on prosthetic valves in 17.3% of cases. Causative microorganisms were identified in 50.2% of cases: streptococci (17.3%), enterococci (3.9%), staphylococci (17.9%), and

* Corresponding author. Tel.: +216 73 21 11 83; fax: +216 73 21 11 83. E-mail address: [email protected] (A. Letaief).

1201-9712/$32.00 # 2007 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2006.10.006 Epidemiology of infective endocarditis in Tunisia 431

other pathogens (11.1%). Blood cultures were negative in 53.6% and no microorganism was identified in 49.8%. Early valve surgery was performed in 51.2% of patients. The in-hospital mortality was 20.6%. Conclusion: Infective endocarditis is still frequently associated with rheumatic disease among young adults in Tunisia, with a high frequency of negative blood cultures and high in-hospital mortality, given that the population affected is relatively young. # 2007 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction The mean (SD) duration of hospital stay was 37.6 (21.2) days (range 0—99, median 39 days). Predisposing heart dis- Despite great medical progress, infective endocarditis (IE) eases are listed in Table 1. Rheumatic valve disease was remains a serious infection with stable incidence. However, noted in 45.2% of native valve IE, with a stable rate in the profound changes have occurred in the epidemiological pro- last two years of 41.6%. No case of IE was associated with IV file of the disease, especially in developed countries where IE drug use. IE locations were: mitral valve in 45.7%, aortic in more frequently affects older patients or IV addicts with a 33.2%, mitral and aortic in 13.4%, and tricuspid in 4.5%. A decline in underlying rheumatic valvular disease and a larger total of 218 cases (49.5%) had a confirmed or probable portal spectrum of causative microorganisms.1—6 These changes of entry. Dental procedures/poor dental condition was the have not been noted in developing countries.7,8 most frequent cause of the bacteremia (n = 110), followed by In Tunisia, epidemiological data are fragmentary and show cutaneous route (n = 43), percutaneous iatrogenic proce- that IE is frequently associated with rheumatic valvular dures and cardiac surgery (n = 23), and miscellaneous other disease resulting in high morbidity and mortality.9,10 The conditions (n = 42). aim of this multicenter study was to describe the epidemio- The median number of blood cultures drawn was three. logical characteristics of IE in Tunisia. The causative microorganisms were identified by blood cul- tures in 204 cases (46.4%) and by other methods in 17 (3.9%) additional cases (six cultures of valve, six serological tests Patients and methods and five in a metastatic location). Blood cultures remained negative in 53.6% of cases and no microorganism was identi- This descriptive study was conducted retrospectively for a fied in 49.8%. Overall, streptococci, enterococci and staphy- 10-year period, from 1991 to 2000, in almost all regions of lococci were the most commonly isolated — 78% of the Tunisia.We analyzed the charts of all patients hospitalized, in identified causative microorganisms (Table 2). Congestive 13 (from 18) cardiology or infectious diseases units, with a heart failure and neurological complications were observed diagnosis of IE. Inclusion criteria were definite or possible IE, in 45.2% and 20.2%, respectively (Table 3). according to modified Duke criteria.11 The following data were collected from those cases included: age, sex, under- lying heart disease, predisposing conditions for bacteremia, complications, echocardiographic and microbiological data, surgical treatment, and outcome. For blood cultures, con- ventional manual systems were used with at least three aerobic and anaerobic bottles inoculated with blood, for at least 14 days. Serological tests for brucella and coxiella infections were performed in 17% and 12%, respectively, of IE patients with negative blood cultures. However, antibodies anti-bartonella, legionella and mycoplasma were not per- formed. Early surgery was undertaken, if indicated, up to two months following the IE diagnosis. Since it was a retrospec- Figure 1 Incidence of infective endocarditis by age and sex. tive study, only intra-hospital mortality was considered. Statistical interpretation of data was performed using the computerized software program SPSS version 13 (SPSS, Inc., Table 1 Distribution of underlying heart disease in 440 Chicago, IL, USA). cases of infective endocarditis

Underlying heart disease No. (%) Results Native valve disease 364 (82.7) Among 510 notifications during the study period, 440 epi- Rheumatic valve disease 199 (45.2) sodes of IE among 435 patients were retained (242 males, 193 Not previously known 100 (22.7) females; mean (SD) age 32.4 (16.8) years) (Figure 1). Tunisia Congenital heart disease 39 has a population of 8 million; assuming that all cases are Degenerative 24 reported, there would be 55 cases/1 000 000 inhabitants. Other 2 The incidence of IE was also stable during the 10-year period Prosthetic valve 76 (17.3) of the study with at least 46 new cases per year. 432 A. Letaief et al.

Table 2 Distribution of causative microorganisms observed over the last decades with the mean age of affected patients being 55 to 60 years.1,3,13—15 This has Microorganism No. % mainly been attributed to a dramatic decrease in the Streptococci 77 17.5 incidence of acute rheumatic disease, increasing patient Oral streptococcus 47 longevity that has given rise to degenerative valvular Group D streptococci 10 lesions, placement of prosthetic valves, and increased S. pneumoniae 4 exposure to nosocomial bacteremia.2,16 Although rheu- S. agalactiae 3 matic disease was the most frequent underlying condition Non-identified streptococci 13 in our study (45%), its incidence had decreased when com- pared to the results of a study conducted in the seventies Enterococci 17 3.9 (67%).9 On the other hand, we noted an increasing propor- Staphylococci 79 17.9 tion of IE in patients with no previously known heart disease S. aureus 52 (27.5% versus 1%). This last pattern change should be Coagulase-negative 27 considered in the diagnosis of IE and the role of degenera- tive valve lesions.1,4,16 Enterobacteria 10 2.3 As described in other series in developing coun- Brucella 5 1.1 tries,7,8,12,15 the most characteristic finding in our study Corynebacterium 5 was the high frequency of IE negative blood cultures Coxiella 3 (50%); in contrast, in series from industrialized countries, Other microorganisms 26 blood cultures were found to be negative in 5—15% of IE Other Gram-negative bacilli 11 cases.1—4,14 The etiologic factors most incriminated in the HACEK group 6 high frequency of IE negative blood cultures are previous Candida albicans 4 antibiotic therapy, lack of optimal conventional culture Others 5 techniques, and lack of systematic investigation for rare 2,17—21 No microorganism identified 219 49.8 and fastidious microorganisms. In a Tunisian study, when sera of IE were tested systematically for fastidious microorganisms associated with blood negative endocarditis, a high prevalence of bartonella endocarditis (9.8% of all IE) Table 3 Main complications observed in 440 cases of infec- was observed.19 tive endocarditis In this study, as in previous reports, when blood cultures were positive, staphylococci and streptococci were the most Complications No. % commonly isolated causative agents of IE (35.7% and 34.5%, Congestive heart failure 199 45.2 respectively). These two microorganisms have been reported as etiological agents in 13—49% and 20—63% of cases of native Neurological complications 89 20.2 valve endocarditis, respectively.7,8,15 Only 1.1% of all IE were Hemorrhagic and ischemic CVA 72 16.4 caused by Brucella spp; this low rate in spite of the ende- Cerebral abscess/meningitis 17 3.9 micity of brucellosis in our country is probably due to the Peripheral vascular emboli, aneurism 23 5.2 difficulty in isolating Brucella spp from blood cultures, in Glomerulonephritis 12 2.7 addition to brucellosis serology not having been performed Spleen abscess/infarction 9 2.0 systematically. As in other reports,22,23 the major complications observed CVA, cerebral vascular accident. in our population were congestive heart failure and cerebral vascular accidents, noted in 45.2% and 16.4%, respectively. During this period, 223 patients underwent valve surgery These major complications have the greatest influence on after a median (interquartile range) 27 (14—50) days follow- the prognosis of IE.24 The usual cause of congestive heart ing admission. Sixteen patients (4%) presented with a further failure in patients with IE is infection-induced valvular episode of IE on the prosthetic valve during the period of damage, especially aortic valve infection.2 In this situation, study. The in-hospital mortality rate was 20.6% (90 patients). surgical therapy is usually the only choice, although timing of surgery continues to be a matter for debate.23 Discussion The overall mortality in the present series was 20.6% compared with 9—35% in others series.7,8,12,15 The mortality The real incidence of IE in our country could not be derived of IE is largely dependent on the underlying conditions of the from this study; however, it has demonstrated that this population and timing of surgery in cases with congestive disease remains frequent and serious with more than 46 heart failure.25 cases per year and a mortality rate of 20.6%. Although not In conclusion, in our multicenter retrospective study, the all Tunisian centers participated, a major strength of our incidence of IE has continued to rise and the clinical pre- study is the low influence of referral bias compared with most sentation, site of valvular infection, and types of etiologic previous studies, which have mainly been based on series in a microorganisms were typical of IE reported from the west. single tertiary center. Nevertheless, compared to patients with IE in developed The low age of our patients (mean age = 32.4 years) is countries, notable differences in our study population comparable to that found in developing countries.8,12 In included a greater proportion of rheumatic heart disease contrast, in western studies an important shift has been and a higher frequency of negative blood cultures. More Epidemiology of infective endocarditis in Tunisia 433 effort is needed in the areas of rheumatic heart prophylaxis 13. Sandre RM, Shafran SD. Infective endocarditis: review of 135 and negative blood culture IE explorations. cases over 9 years. Clin Infect Dis 1996;22:276—86. Conflict of interest: No conflict of interest to declare. 14. Benn M, Hagelskjaer LH, Tvede M. Infective endocarditis, 1984 through 1993: a clinical and microbiological survey. J Intern Med 1997;242:15—22. References 15. Loupa C, Mavroidi N, Boutsikakis I, Paniara O, Deligarou O, Manoli H, et al. Infective endocarditis in Greece: a changing profile. 1. Hoen B, Alla F, Selton-Suty C, Beguinot I, Bouvet A, Briancon S, Epidemiological, microbiological and therapeutic data. Clin et al. Changing profile of infective endocarditis: results of a Microbiol Infect 2004;10:556—61. 1-year survey in . JAMA 2002;288:75—81. 16. McKinsey DS, Ratts TE, Bisno AL. Underlying cardiac lesions in 2. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N adults with infective endocarditis: the changing spectrum. Am J Engl J Med 2001;345:1318—30. Med 1987;82:681—8. 3. Bouza E, Menasalvas A, Munoz P, Vasallo FJ, Moreno MD, Fer- 17. Brouqui P, Raoult D. Endocarditis due to rare and fastidious nandez MG. Infective endocarditis–—a prospective study at the bacteria. Clin Microbiol Rev 2001;14:177—207. end of the twentieth century. Medicine (Baltimore) 2001;80: 18. Fournier PE, Raoult D. Non-culture laboratory methods for the 298—307. diagnosis of infectious endocarditis. Curr Infect Dis Rep 1999;1: 4. Fefer P,Raveh D, Rudensky B, Schlesinger Y,Yinnon AM. Changing 136—41. epidemiology of infective endocarditis: a retrospective survey of 19. Znazen A, Rolain JM, Hammami N, Kammoun S, Hammami A, 108 cases, 1990—1999. Eur J Clin Microbiol Infect Dis 2002;21: Raoult D. High prevalence of Bartonella quintana endocarditis in 432—7. Sfax, Tunisia. Am J Trop Med Hyg 2005;72:503—7. 5. Pelletier Jr LL, Petersdorf RG. Infective endocarditis: a review of 20. Towns ML, Reller LB. Diagnostic methods. Current best prac- 125 cases from the University of Washington Hospitals, 1963—72. tices and guidelines for isolation of bacteria and fungi in Medicine (Baltimore) 1977;56:287—313. infective endocarditis. Infect Dis Clin North Am 2002;16: 6. YoungSE. Aetiology and epidemiology of infective endocarditis in 363—76. England and Wales. J Antimicrob Chemother 1987;20(Suppl A): 21. Omezzine-Letaief A, Alaoui FZ, Bahri F, Mahdhaoui A, Bough- 7—14. zela E, Jemni L. [Infectious endocarditis with negative blood 7. Cetinkaya Y, Akova M, Akalin HE, Ascioglu S, Hayran M, Uzuns O, cultures.] (In French). Arch Mal Coeur Vaiss 2004;97: et al. A retrospective review of 228 episodes of infective endo- 120—4. carditis where rheumatic valvular disease is still common. Int J 22. Heiro M, Nikoskelainen J, Engblom E, Kotilainen E, Marttila R, Antimicrob Agents 2001;18:1—7. Kotilainen P. Neurologic manifestations of infective endocardi- 8. Tariq M, Alam M, Munir G, Khan MA, Smego Jr RA. Infective tis: a 17-year experience in a teaching hospital in Finland. Arch endocarditis: a five-year experience at a tertiary care hospital in Intern Med 2000;160:2781—7. Pakistan. Int J Infect Dis 2004;8:163—70. 23. Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, 9. Ben Smail M, Hannachi N, Kaabar Z, Rouge JF. Les endocardites Karchmer AW, et al. Diagnosis and management of infective infectieuses a` propos de 120 cas. Info Cardiol 1986:877—904. endocarditis and its complications. Circulation 1998;98:2936— 10. Fekih M, Mahjoub H, Zaouali MR. [Aortic infectious endocarditis 48. on native valve.] (In French). Tunis Med 2004;82:S136—45. 24. Eishi K, Kawazoe K, Kuriyama Y, Kitoh Y, Kawashima Y, Omae T. 11. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of Surgical management of infective endocarditis associated with infective endocarditis: utilization of specific echocardiographic cerebral complications. Multi-center retrospective study in findings. Am J Med 1994;96:200—9. Japan. J Thorac Cardiovasc Surg 1995;110:1745—53. 12. Choudhury R, Grover A, Varma J, Khattri HN, Anand IS, Bidwai PS, 25. Skehan JD, Murray M, Mills PG. Infective endocarditis–—incidence et al. Active infective endocarditis observed in an Indian hospital and mortality in the North East Thames regions. Br Heart J 1981—1991. Am J Cardiol 1992;70:1453—8. 1988;59:62—8.