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Vegetation size at diagnosis in infective endocarditis: Influencing factors and prognostic implications
76
Letters to the Editor
Vegetation size at diagnosis in infective endocarditis: Influencing factors and prognostic implications María Luaces a,⁎, Isidre Vilacosta b , Cristina Fernández b , Cristina Sarriá c , José Alberto San Román d , Catherine Graupner a , Iván J. Núñez-Gil b a
Cardiología, Fuenlabrada University Hospital, Camino del Molino, 2. 28942 Fuenlabrada, Spain b Cardiology, Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain c Infectious Diseases, La Princesa University Hospital, Madrid, Spain d Cardiology, ICICOR, Valladolid University Hospital, Valladolid, Spain Received 30 January 2008; Accepted 3 May 2008 Available online 9 August 2008
Abstract The role of vegetation as the key feature of infective endocarditis is universally recognized. Nowadays, the wide availability of transesophageal echocardiography has made of it the most employed technique to establish the diagnosis by visualizing vegetations. However, the factors which influence the size of vegetation when first detected are not clearly determined. Furthermore, there is considerable controversy regarding the prognostic implications of the size of vegetation. This is of paramount significance to early identify patients at high risk for complications, which might benefit from aggressive attitudes. We present a study based on TEE. Our results show that the size of vegetation at admission is mostly determined by anatomical and not microbiological factors, and the prognostic influence of vegetations on the risk of embolisms, need of surgery, persistent infection and septic shock. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Endocarditis; Transesophageal echocardiography; Prognosis
1. Introduction
2. Methods
Despite all advances in diagnostic tools and therapeutic armamentarium, infective endocarditis (IE) still remains a serious entity with high in-hospital mortality [1,2]. The vegetation is the cornerstone of the diagnosis and echocardiography is used to detect it. Notwithstanding, some controversial issues are pending about the determinants of vegetation size. Furthermore, the prognostic value of vegetation size is open to debate. Many efforts have been made to early identify a high-risk subgroup of patients which might benefit from aggressive attitudes [3,4]. Different studies yielded varied results, due to a scarce number of patients, use of transthoracic echocardiography, or different diagnostic criteria [5–9]. Taking all these considerations in mind, we conducted a study based on the first transesophageal echocardiogram (TEE) with a double aim: 1) to know, if any, the determinant factors of vegetation size at admission; 2) to establish the prognostic influence of vegetation size at admission in adverse events and final outcomes.
Clinical, multicenter, prospective study. All the patients admitted to 5 tertiary hospitals meeting criteria for definite IE with vegetations found and measured in the first TEE were prospectively included [10]. For each case, epidemiological, clinical, microbiological and echocardiographic data were collected, along with the clinical course, adverse events, need of cardiac surgery and mortality. Baseline characteristics were related to vegetation size by single univariate analysis. In order to find the factors determining vegetation size at admission, variables shown to have a statistical significance by univariate analysis and those clinically relevant were included to build a linear regression model. Prognostic implications of vegetation size were addressed by multivariate analysis. Events included need of surgery, embolisms, persistent infection, septic shock, and mortality (Table 1).
⁎ Corresponding author. Tel.: +34 91 600 6455; fax: +34 91 600 6186. E-mail address: [email protected] (M. Luaces).
3. Results Our clinical cohort consisted of 330 episodes. Of those, 281 were left-sided IE, and 49 were right-sided IE. Most cases involved the mitral valve (41.8%). There were 93 prosthetic IE. Mean vegetation size at admission was 14.45 ± 7.66 mm (range, 0.5 to 47 mm). By univariate analysis, we found larger
Letters to the Editor
77
Table 1 Prognostic implications of vegetation size at admission. Event
Adjusted relative risk (95% CI a)
p
Persistent infection
1.03 (0.99–1.07) Adjusted by age, acute course, S. aureus, S. viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment, heart failure. 1.08 (1.02–1.15) Adjusted by age, acute course, S.aureus, S.viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment, heart failure, persistent infection. 1.08 (1.03–1.12) Adjusted by age, acute course, underlying heart disease, S.aureus, S.viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment. 1.04 (1.00–1.09) Adjusted by age, S. aureus, S. viridans, metallic prostheses, position, grade of mobility.
0.059
Septic shock
Need for surgery
Embolisms a
0.009
b0.001
0.045
CI denotes confidence interval.
vegetations in native mitral endocarditis (15.36 ± 7.93 vs 13.71 ± 7.34 mm, p = 0.05), in pacemaker IE (17.85 ± 8.76 vs 14.15 ± 7.51 mm, p = 0.01), and when an embolism occurred before admission (16.46 ± 9.13 mm, vs 13.99 ± 7.21 mm, p = 0.02). Vegetations were shorter in metallic prosthetic IE (11.42 ± 6.44 mm vs 15.09 ± 7.83 mm, p = 0.001) and when a new atrio-ventricular (AV) block was present (11.22 ± 4.96 mm vs 14.74 ± 7.79 mm, p = 0.02). There were no differences in vegetation size according to the causative microorganism (p = 0.45). Embolisms were associated to larger vegetations (15.82 ± 8.56 vs 13.93 ± 7.23 mm, p = 0.04), particularly when they involved the liver, kidneys or spleen. Other clinical adverse events were associated to the size of vegetations in the univariate analysis. That is the case of septic shock (18.94 ± 8.79 vs 13.85 ± 7.30 mm, p b 0.001), and signs of persistent infection (15.66 ± 7.72 vs 13.74 ± 7.54 mm, p = 0.02). In-hospital mortality rate was 29%. Linear regression analysis revealed the following as determinants of the size of vegetation at admission: the aortic position (mean difference − 2.3 mm, p = 0.01), the metallic prosthetic infection (mean difference − 5.11 mm, p = 0.001),
Fig. 1. Determinant factors of vegetation size at admission (linear regression model).
and embolism before admission (mean difference 3.3 mm, p b 0.001) (Fig. 1). By multivariate analysis, vegetation size at admission was associated to a higher risk of total embolisms (relative risk 1.04), need of surgery (relative risk 1.08), persistent infection (relative risk 1.03) and septic shock (relative risk 1.08). 4. Discussion We present a large series of vegetations measured at admission by TEE. Our data show how the mean size of vegetation has increased when compared to the classical series, probably due to improvements in technology. This is a significant finding, since to date vegetations are considered as “large” if they are ≥ 10 mm in length [5]. This concept arises from a classical work in which the mean vegetation size was 10 mm and larger vegetations correlated by univariate analysis with adverse events. In our work, we considered all the possible factors influencing vegetation size. Much has been published about the characteristics of the episode and vegetation size. Interestingly, although most of our episodes were caused by S. aureus (22.42%), classically associated to large vegetations [11], we failed to find such a relationship. Conversely, we found that vegetation size is mostly influenced by anatomical factors: aortic involvement and metallic prostheses. Probably, the anatomy of the aortic root and the high velocity flows at the left ventricular outflow tract limit the growth of large vegetations. As per metallic prostheses, the unique features of the metallic IE — periannulitis rather than valve infection, explain these results. An important finding was the association between large vegetation and embolisms prior to admission. So it shows that even after losing a piece of them, embolic vegetations retain large sizes. The role of vegetation size as an indication for surgery remains controversial [12–14]. In our series, there was an independent association between them, suggesting the need of an aggressive attitude when large vegetations are encountered. More studies are needed to show the benefit
78
Letters to the Editor
of surgery in this context. Although we found a higher risk of total embolisms with increasing vegetation size, we could not demonstrate a higher risk for new embolic episodes. This fact is probably explained by the dramatic drop of embolic risk after two weeks of successful treatment [15,16]. Finally, we did not find an independent relationship between vegetation size at admission and in-hospital mortality, mostly influenced by heart failure, prosthetic IE and septic shock. Moreover, we performed a new analysis considering vegetations N 20 mm, and we did not find a higher risk of death. There are conflicting opinions about this issue, influenced by different study designs [17,18]. 5. Conclusions The size of vegetation size at admission measured by TEE is determined by anatomical factors, and vegetations which have already embolized still retain large sizes. The size of vegetation at admission is independently associated to a higher risk of total embolisms, but not to new embolic events. It predicts also a higher probability of cardiac surgery, persistent infection and septic shock, but not an increased risk of death. References [1] Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Eng J Med 2001 Nov 1;345:1318–30. [2] Hoen B, Alla F, Selton-Suty C, et al. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA 2002;288: 75–81. [3] Chu V, Cabell C, Benjamin D, et al. Early predictors of in-hospital death in infective endocarditis. Circulation 2004;109:1745–9. [4] San Roman JA, Lopez J, Vilacosta I, et al. Prognostic stratification of patients with left-sided endocarditis determined at admission. Am J Med 2007;120(369):e1–7. [5] Mügge A, Daniel WG, Frank G, Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach. J Am Coll Cardiol 1989;14:631–8.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.05.011
[6] Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic value of echocardiography. Ann Intern Med 1991;114:635–40. [7] Sanfilippo AJ, Picard MH, Newell JB, et al. Echocardiographic assessment of patients with infectious endocarditis: prediction of risk of complications. J Am Coll Cardiol 1991;18:1191–9. [8] Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 2001;37: 1069–76. [9] Tischler MD, Vaitkus PT. The ability of vegetation size on echocardiography to predict clinical complications: a meta-analysis. J Am Soc Echocardiogr 1997;10:562–8. [10] Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994;96:200–9. [11] Erbel R, Liu F, Ge J, Rohmann S. Identification of high-risk subgroups in infective endocarditis and the role of echocardiography. Eur Heart J 1995;16:588–602. [12] Baddour LM, Wilson WR, Bayer AS, et al. Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394–434. [13] Horstkotte D, Follath F, Gutschik E, et al. Guidelines on Prevention, Diagnosis and Treatment of Infective Endocarditis Executive Summary. Eur Heart J 2004;25:267–76. [14] Tleyjeh IM, Ghomrawi HM, Steckelberg JM, et al. The impact of valve surgery on 6-month mortality in left-sided infective endocarditis. Circulation 2007;115:1721–8. [15] Vilacosta I, Graupner C, San Roman JA, et al. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 2002;39:1489–95. [16] Dickerman SA, Abrutyn E, Barsic B. The relationship between the initiation of antimicrobial therapy and the incidence of stroke in infective endocarditis: an analysis from the ICE Prospective Cohort Study (ICE-PCS). Am Heart J 2007;154:1086–94. [17] Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005;112:69–75. [18] Martin-Davila P, Navas E, Fortun J, et al. Analysis of mortality and risk factors associated with native valve endocarditis in drug users: the importance of vegetation size. Am Heart J 2005;150:1099–106.
Letters to the Editor
Vegetation size at diagnosis in infective endocarditis: Influencing factors and prognostic implications María Luaces a,⁎, Isidre Vilacosta b , Cristina Fernández b , Cristina Sarriá c , José Alberto San Román d , Catherine Graupner a , Iván J. Núñez-Gil b a
Cardiología, Fuenlabrada University Hospital, Camino del Molino, 2. 28942 Fuenlabrada, Spain b Cardiology, Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain c Infectious Diseases, La Princesa University Hospital, Madrid, Spain d Cardiology, ICICOR, Valladolid University Hospital, Valladolid, Spain Received 30 January 2008; Accepted 3 May 2008 Available online 9 August 2008
Abstract The role of vegetation as the key feature of infective endocarditis is universally recognized. Nowadays, the wide availability of transesophageal echocardiography has made of it the most employed technique to establish the diagnosis by visualizing vegetations. However, the factors which influence the size of vegetation when first detected are not clearly determined. Furthermore, there is considerable controversy regarding the prognostic implications of the size of vegetation. This is of paramount significance to early identify patients at high risk for complications, which might benefit from aggressive attitudes. We present a study based on TEE. Our results show that the size of vegetation at admission is mostly determined by anatomical and not microbiological factors, and the prognostic influence of vegetations on the risk of embolisms, need of surgery, persistent infection and septic shock. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Endocarditis; Transesophageal echocardiography; Prognosis
1. Introduction
2. Methods
Despite all advances in diagnostic tools and therapeutic armamentarium, infective endocarditis (IE) still remains a serious entity with high in-hospital mortality [1,2]. The vegetation is the cornerstone of the diagnosis and echocardiography is used to detect it. Notwithstanding, some controversial issues are pending about the determinants of vegetation size. Furthermore, the prognostic value of vegetation size is open to debate. Many efforts have been made to early identify a high-risk subgroup of patients which might benefit from aggressive attitudes [3,4]. Different studies yielded varied results, due to a scarce number of patients, use of transthoracic echocardiography, or different diagnostic criteria [5–9]. Taking all these considerations in mind, we conducted a study based on the first transesophageal echocardiogram (TEE) with a double aim: 1) to know, if any, the determinant factors of vegetation size at admission; 2) to establish the prognostic influence of vegetation size at admission in adverse events and final outcomes.
Clinical, multicenter, prospective study. All the patients admitted to 5 tertiary hospitals meeting criteria for definite IE with vegetations found and measured in the first TEE were prospectively included [10]. For each case, epidemiological, clinical, microbiological and echocardiographic data were collected, along with the clinical course, adverse events, need of cardiac surgery and mortality. Baseline characteristics were related to vegetation size by single univariate analysis. In order to find the factors determining vegetation size at admission, variables shown to have a statistical significance by univariate analysis and those clinically relevant were included to build a linear regression model. Prognostic implications of vegetation size were addressed by multivariate analysis. Events included need of surgery, embolisms, persistent infection, septic shock, and mortality (Table 1).
⁎ Corresponding author. Tel.: +34 91 600 6455; fax: +34 91 600 6186. E-mail address: [email protected] (M. Luaces).
3. Results Our clinical cohort consisted of 330 episodes. Of those, 281 were left-sided IE, and 49 were right-sided IE. Most cases involved the mitral valve (41.8%). There were 93 prosthetic IE. Mean vegetation size at admission was 14.45 ± 7.66 mm (range, 0.5 to 47 mm). By univariate analysis, we found larger
Letters to the Editor
77
Table 1 Prognostic implications of vegetation size at admission. Event
Adjusted relative risk (95% CI a)
p
Persistent infection
1.03 (0.99–1.07) Adjusted by age, acute course, S. aureus, S. viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment, heart failure. 1.08 (1.02–1.15) Adjusted by age, acute course, S.aureus, S.viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment, heart failure, persistent infection. 1.08 (1.03–1.12) Adjusted by age, acute course, underlying heart disease, S.aureus, S.viridans, S. coagulase negative, metallic prostheses, position, embolisms prior to treatment. 1.04 (1.00–1.09) Adjusted by age, S. aureus, S. viridans, metallic prostheses, position, grade of mobility.
0.059
Septic shock
Need for surgery
Embolisms a
0.009
b0.001
0.045
CI denotes confidence interval.
vegetations in native mitral endocarditis (15.36 ± 7.93 vs 13.71 ± 7.34 mm, p = 0.05), in pacemaker IE (17.85 ± 8.76 vs 14.15 ± 7.51 mm, p = 0.01), and when an embolism occurred before admission (16.46 ± 9.13 mm, vs 13.99 ± 7.21 mm, p = 0.02). Vegetations were shorter in metallic prosthetic IE (11.42 ± 6.44 mm vs 15.09 ± 7.83 mm, p = 0.001) and when a new atrio-ventricular (AV) block was present (11.22 ± 4.96 mm vs 14.74 ± 7.79 mm, p = 0.02). There were no differences in vegetation size according to the causative microorganism (p = 0.45). Embolisms were associated to larger vegetations (15.82 ± 8.56 vs 13.93 ± 7.23 mm, p = 0.04), particularly when they involved the liver, kidneys or spleen. Other clinical adverse events were associated to the size of vegetations in the univariate analysis. That is the case of septic shock (18.94 ± 8.79 vs 13.85 ± 7.30 mm, p b 0.001), and signs of persistent infection (15.66 ± 7.72 vs 13.74 ± 7.54 mm, p = 0.02). In-hospital mortality rate was 29%. Linear regression analysis revealed the following as determinants of the size of vegetation at admission: the aortic position (mean difference − 2.3 mm, p = 0.01), the metallic prosthetic infection (mean difference − 5.11 mm, p = 0.001),
Fig. 1. Determinant factors of vegetation size at admission (linear regression model).
and embolism before admission (mean difference 3.3 mm, p b 0.001) (Fig. 1). By multivariate analysis, vegetation size at admission was associated to a higher risk of total embolisms (relative risk 1.04), need of surgery (relative risk 1.08), persistent infection (relative risk 1.03) and septic shock (relative risk 1.08). 4. Discussion We present a large series of vegetations measured at admission by TEE. Our data show how the mean size of vegetation has increased when compared to the classical series, probably due to improvements in technology. This is a significant finding, since to date vegetations are considered as “large” if they are ≥ 10 mm in length [5]. This concept arises from a classical work in which the mean vegetation size was 10 mm and larger vegetations correlated by univariate analysis with adverse events. In our work, we considered all the possible factors influencing vegetation size. Much has been published about the characteristics of the episode and vegetation size. Interestingly, although most of our episodes were caused by S. aureus (22.42%), classically associated to large vegetations [11], we failed to find such a relationship. Conversely, we found that vegetation size is mostly influenced by anatomical factors: aortic involvement and metallic prostheses. Probably, the anatomy of the aortic root and the high velocity flows at the left ventricular outflow tract limit the growth of large vegetations. As per metallic prostheses, the unique features of the metallic IE — periannulitis rather than valve infection, explain these results. An important finding was the association between large vegetation and embolisms prior to admission. So it shows that even after losing a piece of them, embolic vegetations retain large sizes. The role of vegetation size as an indication for surgery remains controversial [12–14]. In our series, there was an independent association between them, suggesting the need of an aggressive attitude when large vegetations are encountered. More studies are needed to show the benefit
78
Letters to the Editor
of surgery in this context. Although we found a higher risk of total embolisms with increasing vegetation size, we could not demonstrate a higher risk for new embolic episodes. This fact is probably explained by the dramatic drop of embolic risk after two weeks of successful treatment [15,16]. Finally, we did not find an independent relationship between vegetation size at admission and in-hospital mortality, mostly influenced by heart failure, prosthetic IE and septic shock. Moreover, we performed a new analysis considering vegetations N 20 mm, and we did not find a higher risk of death. There are conflicting opinions about this issue, influenced by different study designs [17,18]. 5. Conclusions The size of vegetation size at admission measured by TEE is determined by anatomical factors, and vegetations which have already embolized still retain large sizes. The size of vegetation at admission is independently associated to a higher risk of total embolisms, but not to new embolic events. It predicts also a higher probability of cardiac surgery, persistent infection and septic shock, but not an increased risk of death. References [1] Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Eng J Med 2001 Nov 1;345:1318–30. [2] Hoen B, Alla F, Selton-Suty C, et al. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA 2002;288: 75–81. [3] Chu V, Cabell C, Benjamin D, et al. Early predictors of in-hospital death in infective endocarditis. Circulation 2004;109:1745–9. [4] San Roman JA, Lopez J, Vilacosta I, et al. Prognostic stratification of patients with left-sided endocarditis determined at admission. Am J Med 2007;120(369):e1–7. [5] Mügge A, Daniel WG, Frank G, Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach. J Am Coll Cardiol 1989;14:631–8.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.05.011
[6] Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic value of echocardiography. Ann Intern Med 1991;114:635–40. [7] Sanfilippo AJ, Picard MH, Newell JB, et al. Echocardiographic assessment of patients with infectious endocarditis: prediction of risk of complications. J Am Coll Cardiol 1991;18:1191–9. [8] Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 2001;37: 1069–76. [9] Tischler MD, Vaitkus PT. The ability of vegetation size on echocardiography to predict clinical complications: a meta-analysis. J Am Soc Echocardiogr 1997;10:562–8. [10] Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994;96:200–9. [11] Erbel R, Liu F, Ge J, Rohmann S. Identification of high-risk subgroups in infective endocarditis and the role of echocardiography. Eur Heart J 1995;16:588–602. [12] Baddour LM, Wilson WR, Bayer AS, et al. Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394–434. [13] Horstkotte D, Follath F, Gutschik E, et al. Guidelines on Prevention, Diagnosis and Treatment of Infective Endocarditis Executive Summary. Eur Heart J 2004;25:267–76. [14] Tleyjeh IM, Ghomrawi HM, Steckelberg JM, et al. The impact of valve surgery on 6-month mortality in left-sided infective endocarditis. Circulation 2007;115:1721–8. [15] Vilacosta I, Graupner C, San Roman JA, et al. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 2002;39:1489–95. [16] Dickerman SA, Abrutyn E, Barsic B. The relationship between the initiation of antimicrobial therapy and the incidence of stroke in infective endocarditis: an analysis from the ICE Prospective Cohort Study (ICE-PCS). Am Heart J 2007;154:1086–94. [17] Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005;112:69–75. [18] Martin-Davila P, Navas E, Fortun J, et al. Analysis of mortality and risk factors associated with native valve endocarditis in drug users: the importance of vegetation size. Am Heart J 2005;150:1099–106.