- Email: [email protected]
Better prognosis of elderly patients with infectious endocarditis in the era of routine echocardiography and nonrestrictive indications for valve surgery
Better Prognosis of Elderly Patients With Infectious Endocarditis in the Era of Routine Echocardiography and Nonrestrictive Indications for Valve Surgery Jose´ Zamorano, MD, FESC, Javier Sanz, MD, Rau´l Moreno, MD, Carlos Almerı´a, MD, Jose´ Luis Rodrigo, MD, Ester de Marco, MD, Viviana Serra, MD, Miriam Samedi, MD, and Luis Sa´nchez-Harguindey, MD, Madrid, Spain
Objective: It has been reported that endocarditis in the elderly may have a poor outcome. Our aim was to assess the different features and prognosis, if any, in the present time. Methods: Of 103 patients with proven endocarditis, 31 were 65 years or older and 72 were younger than 65 years. Degenerative heart disease was seen more frequently in the elderly (22.5% vs 2.7%, P ⴝ .003). Drug abuse and immunodeficiency virus infection were more common in the younger group, as was tricuspid endocarditis (26.3% vs 0%, P < .001). At clinical presentation cardiac failure (41.9 vs 19.4%, P ⴝ .02) and leukocytosis (61.2% vs 40.2%, P ⴝ .049) were seen more frequently in the elderly. Results: Despite other similar clinical features, it
E
lderly patients with infective endocarditis (IE) have traditionally been considered to constitute a subgroup with higher risk of complications and worse prognosis.1-6 Nevertheless, recent studies have shown that such classic poor outcomes might be changing.7,8 One possible reason for this may be an earlier diagnosis because of the generalized and precocious use of both transthoracic (TTE) and transesophageal (TEE) echocardiographic modalities. The latter has demonstrated higher sensitivity for the diagnosis of IE and its complications.9-12 Other possible causes might be the development of more accurate diagnostic criteria,13 newer antibiotic therapies, or well-defined indications for operation.14,15 The aim of this study was to compare the epidemiologic, clinical, echocardiographic, and prognostic features of elderly patients with IE with those of a younger population in the present time,
From the Echocardiography Laboratory of the Hospital Clı´nico San Carlos, Madrid, Spain. Reprint requests: Jose´ Zamorano, Director of Echo Laboratory, Hospital Clı´nico San Carlos, Plaza de Cristo Rey, 28040 Madrid, Spain (E-mail: [email protected]). Copyright 2002 by the American Society of Echocardiography. 0894-7317/2002/$35.00 ⫹ 0 27/1/118927 doi:10.1067/mje.2002.118927
702
took longer to diagnose older patients (7.2 ⴞ 6.2 vs 3.2 ⴞ 3.5 days, P < .001). Enterococcus infected the aged more often (32.2% vs 13.1%, P ⴝ .001). During hospitalization, heart failure and embolization tended to be more common in the elderly and the younger group, respectively. There were no significant differences in the incidence of anatomic complications, the need for operation, and overall mortality. Conclusion: Although a worse prognosis has been reported in elderly patients with infective endocarditis, the early use of transesophageal echocardiographic examinations and equal therapeutic options provides a similar outcome when compared with younger subjects. (J Am Soc Echocardiogr 2002;15: 702-7.)
and to assess any possible differences between groups.
METHODS Study Population This study was performed in Hospital Clı´nico San Carlos de Madrid, which is both a primary hospital attending a total population of more than 500,000 people and a referral center for cardiac diagnostic tests and surgical procedure. The patients included in the study were primarily selected by reviewing the clinical files of all the patients admitted to our hospital between 1991 and 1999 whose final diagnosis was IE. Either pathological (in the operating room or in a postmortem study) or clinical confirmations of the diagnosis (fulfilling the Duke criteria13) were required as entry criteria. We used the Duke criteria because they have proven both more specific and sensitive than Von Reyn’s.16-19 In our hospital, every patient in whom IE is suspected systematically undergoes at least one TTE and also TEE if indicated14,20 independently on blood cultures results. Because of this, the clinical records were matched with the records in the echocardiographic laboratory. Clinical files of patients with equivocal findings on echocardiographic examinations, which might have been because of IE, were also
Journal of the American Society of Echocardiography Volume 15 Number 7
reviewed to confirm that the diagnosis had been ruled out. If so, such patients were excluded from analysis. Echocardiographic Studies All echocardiographic studies were performed by experienced members of the Echocardiography Laboratory. Bidimensional, M-mode, and Doppler studies (pulsed, continuous, and color modalities) were systematically performed on every patient, using left and right paraesternal, apical, subxyphoid, and suprasternal transducer positions. Whenever a TEE was performed, patient’s consent was obtained. In every case, before introduction of the probe, local anesthesia of the oropharynx with 10% lidocaine spray and sedation with 1 mg intravenous diazepam plus 25 mg intravenous meperidine hydrochloride were carried out. Definitions Predisposing factors to IE may be both cardiac and extracardiac. In the first case, the term “degenerative heart disease” was used to indicate not only the presence of anatomic and pathologic changes related to aging but also certain tissue abnormalities that lead to accelerated distortion of the cardiac valves as in the case of mitral valve prolapse disease. Patients with congenital heart disease included cases of bicuspid aortic valve and others such as ventricular or atrial septal defect. Among the extracardiac factors, we included diabetes mellitus because, though there is not strong evidence for enhanced predisposition to infections, when infections occur they tend to be more severe and have a higher rate of complications than in nondiabetic patients.21 Increased susceptibility for bacterial infections, including IE, has also been described in chronic liver disease.22 Fever was defined as the presence of a confirmed temperature of 38°C or higher. The term “vascular phenomena” included the presence of petechiae, splinter hemorrhages, Osler’ s nodes, Janeway’s lesions, and Roth’s spots; some of these manifestations being considered immunologic phenomena in the Duke criteria. Embolic episodes to skin were not included in the category of embolism, as they are not usually associated with the outcome. Leukocytosis was defined as the presence of a mean leukocyte count higher than 10.5 ⫻ 103 cells/dL. Duration since the onset of symptoms to hospital admission was estimated by the patient and specified on the clinical record. Time to diagnosis was defined as the period from hospital admission to the confirmation of diagnosis. With respect to echocardiographic definitions, a patient was said to have a “vegetation” when any echogenic, mobile mass attached to a valve, its supporting structures, the endocardial surface (usually in the path of regurgitant jets), or a prosthetic intracardiac device was detected. An “abscess” was diagnosed if either an abnormal paravalvular echogenic or a relatively echo-free space was seen. When there was evidence of blood flow inside it (detected by means of Doppler modalities) or continuity between it
Zamorano et al 703
and the vascular lumen, the patient was said to have a “pseudoaneurysm.” A “fistula” was defined as the presence of an abnormal anatomic pathway communicating 2 different cavities. A systolic displacement of 1 or more leaflets beyond the valve annulus was required for the diagnosis of “prolapse.” A case of IE was considered to have negative blood cultures when at least 2 different cultures had been obtained and all of them were negative by the time of hospital discharge or as recorded on clinical files.23 Statistical Analysis Quantitative variables are expressed as mean ⫾ standard deviation and qualitative variables as proportions (percentages). The comparison of 2 media was studied with the Student t test, and comparison of proportions with the chi-square test (Fisher exact test correction when necessary). Associations were considered significant in presence of a P value ⬍ .05, although all P values ⬍ .10 are reported.
RESULTS According to the aforementioned criteria, we identified 103 consecutive cases of clinically or pathologically proven IE. These patients constituted the study population. Of them, 31 (30.1%) were 65 years old or older and were defined as the elderly population. The remaining 72 patients (69.9%) were defined as younger (Table 1). Clinical Presentation Elderly patients were less often male than were younger patients (54.8% vs 76.3%, P ⫽ .036). With regard to predisposing factors, we found a higher proportion of men in the younger population (97.2% vs 64.5%, P ⬍ .001), mainly because of the higher prevalence of immunodeficiency virus infection, drug abuse, and liver diseases. On the contrary, as expected, degenerative heart disease was seen more frequently in the elderly (22.5% vs 2.7%, P ⫽ .003). The elderly also had a higher frequency of pacemakers (9.6% vs 1.3%, P ⫽ .059) and diabetes mellitus (12.9% vs 2.7%, P ⫽ .065). The other predisposing factors for IE were not differently distributed between groups. There was no difference in duration of symptoms before hospitalization between groups. Importantly, however, time to diagnosis was significantly longer in elderly patients (7.2 ⫾ 6.2 vs 3.2 ⫾ 3.5 days, P ⬍ .001). Regarding the clinical presentation, heart failure (41.9% vs 19.4%, P ⫽ .02) and leukocytosis (61.2% vs 40.2%, P ⫽ .049) were more frequently seen in elderly patients. On the contrary, there was a lower frequency of splenomegaly in older patients (6.4% vs 19.4%, P ⫽ .073). Other clinical data, such as fever, murmur, and embolisms, appeared as frequently in the elderly as in the younger population.
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704 Zamorano et al
Table 1 Clinical, epidemiologic, and echocardiographic data of the study population n Male gender Predisposing factors Rheumatic heart disease Congenital heart disease Degenerative heart disease Cardiac prosthesis Pacemaker leads Drug abuse (iv) HIV infection Prior IE Liver disease Diabetes mellitus Liver or renal transplantation Duration of symptoms (days) Clinical presentation Fever Embolism Heart failure Murmur Splenomegaly Vascular phenomena Leukocytosis Time to diagnosis (days)
Elderly
Younger
P
31 (30%) 17 (54.8%) 20 (64.5%) 7 (22.5%) 3 (9.6%) 7 (22.5%) 10 (32.2%) 3 (9.6%) 0 0 3 (9.6%) 0 4 (12.9%) 1 (3.2%) 20.3 ⫾ 22.9
72 (69.9%) 55 (76.3%) 70 (97.2%) 12 (16.6%) 9 (12.5%) 2 (2.7%) 24 (33.3%) 1 (1.3%) 31 (43%) 22 (30.5%) 4 (5.5%) 13 (18%) 2 (2.7%) 2 (2.7%) 26.1 ⫾ 8.8
.036 ⬍.001 NS NS .003 NS NS ⬍.001 ⬍.001 NS .011 .065 NS NS
23 (74.2%) 7 (22.5%) 13 (41.9%) 22 (71%) 2 (6.4%) 3 (9.6%) 19 (61.2%) 7.2 ⫾ 6.2
54 (75%) 19 (26.3%) 14 (19.4%) 56 (77.7%) 14 (19.4%) 3 (4.1%) 29 (40.2%) 3.2 ⫾ 3.5
NS NS .020 NS .073 NS ⬍.050 .001
iv, Intravenous; IE, infective endocarditis.
Table 2 Location of infective endocarditis in elderly and younger patients Native mitral Native aortic Native tricuspid Native pulmonary Prosthetic mitral Prosthetic aortic Prosthetic tricuspid Pacemaker leads
Elderly
Younger
P
11 (35.4%) 10 (32.2%) 0 0 6 (19.3%) 4 (12.9%) 0 3 (9.6%)
17 (23.6%) 16 (22.2%) 19 (26.3%) 1 (1.3%) 15 (20.8%) 8 (11.1%) 1 (1.3%) 1 (1.3%)
NS NS ⬍.001 NS NS NS NS NS
Location and Etiologic Germ The most frequent location was native mitral and native tricuspid valve in elderly and younger patients, respectively (Table 2). There was a much higher frequency of tricuspid location among younger patients (26% vs 0%, P ⬍ .001), probably because of the higher prevalence of intravenous drug abuse. On the contrary, there was a higher frequency of pacemaker-leads IE in elderly patients. Mitral and aortic locations were not significantly more frequent in elderly patients. Simultaneous infection in 2 native valves (mitral and aortic) was seen 3 times in each group. There were also 3 cases of infection in mitral and aortic prosthesis in the younger group. The prevalence of negative blood cultures IE was 12.9% and 22.2% in elderly and younger groups, respectively (P ⫽ NS). In 5 cases, blood cultures
Table 3 Causative germs of infective endocarditis and their distribution in the study population Elderly
Negative blood cultures 4 (12.9%) Staphylococcus aureus 7 (22.5%) Staphylococcus coagulase-negative 5 (16.1%) Streptococcus pyogenes 0 Enterococcus 10 (32.2%) Streptococcus bovis 2 (6.4%) Streptococcus viridans 1 (3.2%) Streptococcus pneumoniae 1 (3.2%) Streptococcus milleri 0 Neisseria spp 0 Corynebacterium 0 Escherichia coli 1 (3.2%) Candida spp 0
Younger
P
16 (22.2%) NS 23 (31.9%) NS 12 (16.6%) NS 3 (4.1%) NS 5 (13.1%) .001 1 (1.3%) NS 10 (13.8%) NS 0 NS 1 (1.3%) NS 1 (1.3%) NS 1 (1.3%) NS 1 (1.3%) NS 3 (4.1%) NS
yielded results suggestive of double infection in the same patient; and in another patient with intravenous drug abuse, 3 germs were isolated from blood. There were 2 additional positive blood cultures diagnosed, but the causative micro-organism was not specified in the clinical file. The main differences between both age groups were seen in the case of Enterococcus, which appeared more frequently in the elderly (32.2% vs 13.1%, P ⫽ .001). Staphylococcus aureus and Streptococcus viridans infected younger patients more often, but not significantly (Table 3).
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Inhospital outcome Although not significantly, mortality (16.1% vs 12.5%) and need for valve operation (58.1% vs 45.8%) were more frequent in elderly patients (Table 4). The combined end point of death or operation tended to be more frequent in elderly patients (71% vs 53%, P ⫽ .082). The perioperative mortality in elderly and younger patients was 5.6% and 12.1%, respectively (P ⫽ NS). Heart failure tended to occur more often in elderly patients (35% vs 18%, P ⫽ .061). On the contrary, embolic events tended to occur more frequently among younger patients (49% vs 29%, P ⫽ .062). The incidence of other complications, such as renal failure, abscesses, pseudoaneurysms, and valve rupture or perforation was not significantly different between groups.
DISCUSSION In the current study, IE was diagnosed in elderly patients later, and the elderly had cardiac failure at presentation more frequently. However, mortality rate was not statistically higher and this was probably because of 2 reasons: (1) Despite their advanced age, elderly patients were referred for a valve operation more frequently than younger patients; and (2) their perioperative mortality tended to be, surprisingly, lower than in younger patients. Increased susceptibility to IE in the elderly may be attributed to different factors. First, predisposing conditions such as malnutrition, diabetes mellitus, chronic diseases, and diagnostic and therapeutic manipulations, which may lead to transient bacteremia, tend to be more common in the aged.24,25 Second, evidence exists for a decline in immune response with advanced age. Although neutrophil blood counts and marrow reserves do not change substantially, a diminished ability to recruit them from bone marrow to circulation has been described.26 Moreover, certain nonspecific neutrophil immune functions, such as chemotactic response and bactericidal activity, may be decreased in very old individuals.27 Anomalies in both humoral and cellular immune responses have also been reported.28-30 Finally, cardiac changes associated with aging, such as valve calcification and fibrosis, may also increase the risk of suffering IE.24 Necropsy studies have shown a high prevalence of valvular heart disease in very old individuals.31,32 In addition, there is an improved life expectancy at present, and therefore IE tends to occur more and more frequently among the elderly. The percentage of patients with IE older than 60 years has progressively increased along the century.4 Currently, in most series, approximately 40% to 50% of subjects suffering IE are elderly individuals.3-5,7,8 Neverthe-
Zamorano et al 705
Table 4 Inhospital clinical course of elderly and younger patients with infective endocarditis Renal failure Heart failure Embolic events Abscess/pseudoaneurysm Rupture/perforation Fistulae Prolapse Surgery Mortality Time to surgery (days) Death or surgery
Elderly
Younger
P
4 (12.9%) 11 (35.4%) 9 (29.0%) 5 (16.1%) 7 (22.5%) 0 3 (9.6%) 18 (58.1%) 5 (16.1%) 20.6 ⫾ 18.3 22 (71.0%)
10 (13.8%) 13 (18%) 35 (48.6%) 19 (26.3%) 9 (12.5%) 1 (1.3%) 5 (6.9%) 33 (45.8%) 9 (12.5%) 18.1 ⫾ 20.4 38 (52.8%)
NS .061 .062 NS NS NS NS NS NS NS .082
less, the definition of elderly is not well established and different reports have used different ages (older than 60, 65, or 70 years). In our study, in which we defined older individuals as those 65 years or older, the total proportion was 30%. We must take into account that our hospital is situated in an area of high prevalence of drug abuse. IE in intravenous drug abusers may have particular epidemiologic, bacteriologic, clinical, echocardiographic, and therapeutic features, so that they constitute a distinct subpopulation.15,33,34 After excluding this subset, the total percentage of older individuals was 43%, similar to what others have previously reported. In our series, the younger group had predisposing factors for IE more often than the elderly did. This was mainly because of a higher prevalence of immunodeficiency virus infection, intravenous drug abuse, and liver diseases. On the contrary, certain valve conditions such as degenerative diseases were more frequent in the aged. However, prostheses were not more common in this population, in contrast with other previous observations.4,6,7 The rest of predisposing factors were similarly seen in both groups. With regard to site of infection, the native tricuspid IE was the predominant finding in the younger patients, probably because of the high proportion of intravenous drug abusers in this subset. After exclusion of this population, there were no other significant differences regarding the site of infection, similar to other reports.3,6-8 Although previous series reported a higher incidence of aortic involvement in the aged,1,2,35 in more recent ones, and in ours, mitral valve was the most common primary site of infection both in elderly and younger patients.4,6-8 Although not significantly, the aortic valve was most frequently involved among the younger patients. This has also been observed by some authors,4,6 although others have reported opposite findings.7,8 Cardiac failure and leukocytosis appeared more frequently among the elderly. We do not have an explanation for the higher frequency of leukocytosis in elderly patients, and controversial data have been
706 Zamorano et al
reported in other series.4,7 Other clinical data took place similarly in both populations. The same was observed with regard to anatomic complications as detected by echocardiography. Infective organisms showed few differences between the 2 groups. As reported by previous authors,3,4,6,24,36 Enterococcus, a germ that usually comes from the urinary tract or a colonic source, was isolated more frequently in the elderly. Consistently with other studies, a nonsignificantly higher frequency for Streptococcus viridans to be found in younger individuals was observed.24 Surprisingly, duration of symptoms was similar between both groups, but time to diagnosis was approximately twice as long with elderly patients. Terpenning et al4 also reported an increased frequency of inadequate diagnosis in these patients. In our study there seems to be no explanation other than a low level of clinical suspicion from the responsible physicians. Despite the delay in diagnosis and the higher frequency of cardiac failure in elderly patients, mortality was not significantly higher, probably because of 2 reasons: (1) Despite their more advanced age, elderly patients were referred for surgical valve replacement more frequently than younger patients. This reflects that similar therapeutic criteria were used for older and younger patients, which is also shown by the fact that time from diagnosis to surgical procedure in those operated was approximately the same, regardless of the patient’s age. Terpenning et al4 and Selton-Suty et al6 reported a higher proportion of death in the aged, but in both series surgical procedure was used less frequently in this population. On the contrary, in the study by Gagliardi et al,8 in which surgical treatment was equally distributed, no differences in mortality were found. The same was observed by Werner et al,7 who reported no differences in survival in global terms but a relatively high mortality in medically treated older individuals. (2) The perioperative mortality in elderly patients was, surprisingly, lower than in younger patients. In other series, perioperative mortality in patients with IE was higher in elderly patients.4
CONCLUSIONS Despite elderly patients with infective endocarditis having cardiac failure at clinical presentation more frequently, the early use of both TTE and TEE examinations, and the same treatment options, results in an improved outcome, which does not differ from that observed in younger individuals. This suggests that similar diagnostic and therapeutic modalities should be used in both populations.
Journal of the American Society of Echocardiography July 2002
REFERENCES 1. Applefeld MM, Hornick RB. Infective endocarditis in patients over age 60. Am Heart J 1974;88:90-4. 2. Robbins N, DeMaria A, Miller MH. Infective endocarditis in the elderly. South Med J 1980;73:1335-8. 3. Steckelberg JM, Melton LJ 3rd, Ilstrup DM, Rouse MS, Wilson WR. Influence of referral bias on the apparent clinical spectrum of infective endocarditis. Am J Med 1990;88:582-8. 4. Terpenning MS, Buggy BP, Kauffman CA. Infective endocarditis: clinical features in young and elderly patients. Am J Med 1987;83:626-34. 5. Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980-1990: a review of 210 episodes. Medicine Baltimore 1993;72:90-120. 6. Selton-Suty C, Hoen B, Grentzinger A, Houplon P, Maignan M, Juilliere Y, et al. Clinical and bacteriological characteristics of infective endocarditis in the elderly. Heart 1997;77:260-3. 7. Werner GS, Schulz R, Fuchs JB, Andreas S, Prange H, Ruschewski W, et al. Infective endocarditis in the elderly in the era of transesophageal echocardiography: clinical features and prognosis compared with younger patients. Am J Med 1996; 100:90-7. 8. Gagliardi JP, Nettles RE, McCarty DE, Sanders LL, Corey GR, Sexton DJ. Native valve infective endocarditis in elderly and younger adult patients: comparison of clinical features and outcomes with use of the Duke criteria and the Duke endocarditis database. Clin Infect Dis 1998;26:1165-8. 9. Shiveley BK, Gurule FT, Roldan CA, Leggett JH, Schiller NB. Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis. J Am Coll Cardiol 1991;18:391-7. 10. Birmingham GD, Rahko PS, Ballantyne F 3rd. Improved detection of infective endocarditis with transesophageal echocardiography. Am Heart J 1992;123:774-81. 11. Daniel WG, Mugge A, Grote J, Hausmann D, Nikutta P, Laas J, et al. Comparison of transthoracic and transesophageal echocardiography for detection of abnormalities of prosthetic and bioprosthetic valves in the mitral and aortic position. Am J Cardiol 1993;71:210-5. 12. Daniel WG, Mugge A, Martin RP, Lindert O, Hausmann D, Nonnast-Daniel B, et al. Improvement in the diagnosis of abscesses associated with endocarditis by transesophageal echocardiography. N Engl J Med 1991;324:795-800. 13. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200-9. 14. Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer AW, et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98: 2936-48. 15. Farmer JA, Torre G. Endocarditis. Curr Opin Cardiol 1997; 12:123-30. 16. Hoen B, Be´ guinot I, Rabaud C, Jaussaud R, Selton-Suty C, May T, et al. The Duke criteria for diagnosing infective endocarditis are specific: analysis of 100 patients with acute fever or fever of unknown origin. Clin Infect Dis 1996;23: 298-302. 17. Bayer AS, Ward JI, Ginzton LE, Shapiro SM. Evaluation of new clinical criteria for the diagnosis of infective endocarditis. Am J Med 1994;96:211-9. 18. Cecchi E, Parrini I, Chinaglia A, Pomari F, Brusasco G, Bobbio M, et al. New diagnostic criteria for infective endocar-
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ditis: a study of sensitivity and specificity. Eur Heart J 1997; 18:1149-56. Dodds GA, Sexton DJ, Durack DT, Bushore TM, Corey GR, Kisslo J. Negative predictive value of the Duke criteria for infective endocarditis. Am J Cardiol 1996;77:403-7. Lindner JR, Case A, Dent JM, Abbott RD, Scheld WM, Kaul S. Diagnostic value of echocardiography in suspected endocarditis: an evaluation based on the pre-test probability of disease. Circulation 1996;93:730-6. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med 1999; 341:1906-12. McCashland TM, Sorrell MF, Zetterman RK. Bacterial endocarditis in patients with chronic liver disease. Am J Gastroenterol 1994;89:924-7. Zamorano J, Sanz J, Moreno R, Almeria C, Rodrigo JL, Samedi M, et al. Comparison of outcome in patients with culture-negative versus culture-positive active infective endocarditis. Am J Cardiol 2001;87:1423-5. Ribera JM. Endocarditis infecciosa en el anciano. Rev Esp Cardiol 1998;51(suppl 2):64-70. Schneider EL. Infectious diseases in the elderly. Ann Intern Med 1983;98:395-400. Chatta GS, Price TH, Stratton JR, Dale DC. Aging and marrow neutrophil reserves. J Am Geriatr Soc 1994;42:77-81. Corberand J, Ngyen F, Laharrague P, Fontanilles AM,
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Gleyzes B, Gyrard E, et al. Polymorphonuclear functions and aging in humans [abstract]. J Am Geriatr Soc 1981;29:391-7. Saltzman RL, Peterson PK. Immunodeficiency of the elderly. Rev Infect Dis 1987;9:1127-39. Murasko DM, Nelson BJ, Silver R, Matour D, Kaye D. Immunologic response in an elderly population with a mean age of 85. Am J Med 1986;81:612-8. Pahwa SG, Pahwa RN, Good RA. Decreased in vitro humoral response in aged humans [abstract]. J Clin Invest 1981;67: 1094-102. Shirani J, Yousefi J, Roberts WC. Major cardiac findings at necropsy in 366 American octogenarians. Am J Cardiol 1995; 75:151-6. Roberts WC. Ninety-three hearts ⬎90 years of age. Am J Cardiol 1993;71:599-604. Durack DT. Infective endocarditis. In: Alexander RW, Schlant RC, Fuster V, editors. Hurst’s: the heart, arteries and veins. 9th ed. New York, NY: McGraw-Hill; 1998. p. 2205-39. San Roman JA, Vilacosta I, Zamorano JL, Almerı´a C, Sa´ nchez-Harguindey L. Transesophageal echocardiography in right sided endocarditis. J Am Coll Cardiol 1993;21:122630. Thell R, Martin FH, Edwards JE. Bacterial endocarditis in subjects 60 years of age and older. Circulation 1975;51:17482. Crossley KB, Peterson PK. Infections in the elderly. Clin Infect Dis 1996;22:209-14.
Objective: It has been reported that endocarditis in the elderly may have a poor outcome. Our aim was to assess the different features and prognosis, if any, in the present time. Methods: Of 103 patients with proven endocarditis, 31 were 65 years or older and 72 were younger than 65 years. Degenerative heart disease was seen more frequently in the elderly (22.5% vs 2.7%, P ⴝ .003). Drug abuse and immunodeficiency virus infection were more common in the younger group, as was tricuspid endocarditis (26.3% vs 0%, P < .001). At clinical presentation cardiac failure (41.9 vs 19.4%, P ⴝ .02) and leukocytosis (61.2% vs 40.2%, P ⴝ .049) were seen more frequently in the elderly. Results: Despite other similar clinical features, it
E
lderly patients with infective endocarditis (IE) have traditionally been considered to constitute a subgroup with higher risk of complications and worse prognosis.1-6 Nevertheless, recent studies have shown that such classic poor outcomes might be changing.7,8 One possible reason for this may be an earlier diagnosis because of the generalized and precocious use of both transthoracic (TTE) and transesophageal (TEE) echocardiographic modalities. The latter has demonstrated higher sensitivity for the diagnosis of IE and its complications.9-12 Other possible causes might be the development of more accurate diagnostic criteria,13 newer antibiotic therapies, or well-defined indications for operation.14,15 The aim of this study was to compare the epidemiologic, clinical, echocardiographic, and prognostic features of elderly patients with IE with those of a younger population in the present time,
From the Echocardiography Laboratory of the Hospital Clı´nico San Carlos, Madrid, Spain. Reprint requests: Jose´ Zamorano, Director of Echo Laboratory, Hospital Clı´nico San Carlos, Plaza de Cristo Rey, 28040 Madrid, Spain (E-mail: [email protected]). Copyright 2002 by the American Society of Echocardiography. 0894-7317/2002/$35.00 ⫹ 0 27/1/118927 doi:10.1067/mje.2002.118927
702
took longer to diagnose older patients (7.2 ⴞ 6.2 vs 3.2 ⴞ 3.5 days, P < .001). Enterococcus infected the aged more often (32.2% vs 13.1%, P ⴝ .001). During hospitalization, heart failure and embolization tended to be more common in the elderly and the younger group, respectively. There were no significant differences in the incidence of anatomic complications, the need for operation, and overall mortality. Conclusion: Although a worse prognosis has been reported in elderly patients with infective endocarditis, the early use of transesophageal echocardiographic examinations and equal therapeutic options provides a similar outcome when compared with younger subjects. (J Am Soc Echocardiogr 2002;15: 702-7.)
and to assess any possible differences between groups.
METHODS Study Population This study was performed in Hospital Clı´nico San Carlos de Madrid, which is both a primary hospital attending a total population of more than 500,000 people and a referral center for cardiac diagnostic tests and surgical procedure. The patients included in the study were primarily selected by reviewing the clinical files of all the patients admitted to our hospital between 1991 and 1999 whose final diagnosis was IE. Either pathological (in the operating room or in a postmortem study) or clinical confirmations of the diagnosis (fulfilling the Duke criteria13) were required as entry criteria. We used the Duke criteria because they have proven both more specific and sensitive than Von Reyn’s.16-19 In our hospital, every patient in whom IE is suspected systematically undergoes at least one TTE and also TEE if indicated14,20 independently on blood cultures results. Because of this, the clinical records were matched with the records in the echocardiographic laboratory. Clinical files of patients with equivocal findings on echocardiographic examinations, which might have been because of IE, were also
Journal of the American Society of Echocardiography Volume 15 Number 7
reviewed to confirm that the diagnosis had been ruled out. If so, such patients were excluded from analysis. Echocardiographic Studies All echocardiographic studies were performed by experienced members of the Echocardiography Laboratory. Bidimensional, M-mode, and Doppler studies (pulsed, continuous, and color modalities) were systematically performed on every patient, using left and right paraesternal, apical, subxyphoid, and suprasternal transducer positions. Whenever a TEE was performed, patient’s consent was obtained. In every case, before introduction of the probe, local anesthesia of the oropharynx with 10% lidocaine spray and sedation with 1 mg intravenous diazepam plus 25 mg intravenous meperidine hydrochloride were carried out. Definitions Predisposing factors to IE may be both cardiac and extracardiac. In the first case, the term “degenerative heart disease” was used to indicate not only the presence of anatomic and pathologic changes related to aging but also certain tissue abnormalities that lead to accelerated distortion of the cardiac valves as in the case of mitral valve prolapse disease. Patients with congenital heart disease included cases of bicuspid aortic valve and others such as ventricular or atrial septal defect. Among the extracardiac factors, we included diabetes mellitus because, though there is not strong evidence for enhanced predisposition to infections, when infections occur they tend to be more severe and have a higher rate of complications than in nondiabetic patients.21 Increased susceptibility for bacterial infections, including IE, has also been described in chronic liver disease.22 Fever was defined as the presence of a confirmed temperature of 38°C or higher. The term “vascular phenomena” included the presence of petechiae, splinter hemorrhages, Osler’ s nodes, Janeway’s lesions, and Roth’s spots; some of these manifestations being considered immunologic phenomena in the Duke criteria. Embolic episodes to skin were not included in the category of embolism, as they are not usually associated with the outcome. Leukocytosis was defined as the presence of a mean leukocyte count higher than 10.5 ⫻ 103 cells/dL. Duration since the onset of symptoms to hospital admission was estimated by the patient and specified on the clinical record. Time to diagnosis was defined as the period from hospital admission to the confirmation of diagnosis. With respect to echocardiographic definitions, a patient was said to have a “vegetation” when any echogenic, mobile mass attached to a valve, its supporting structures, the endocardial surface (usually in the path of regurgitant jets), or a prosthetic intracardiac device was detected. An “abscess” was diagnosed if either an abnormal paravalvular echogenic or a relatively echo-free space was seen. When there was evidence of blood flow inside it (detected by means of Doppler modalities) or continuity between it
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and the vascular lumen, the patient was said to have a “pseudoaneurysm.” A “fistula” was defined as the presence of an abnormal anatomic pathway communicating 2 different cavities. A systolic displacement of 1 or more leaflets beyond the valve annulus was required for the diagnosis of “prolapse.” A case of IE was considered to have negative blood cultures when at least 2 different cultures had been obtained and all of them were negative by the time of hospital discharge or as recorded on clinical files.23 Statistical Analysis Quantitative variables are expressed as mean ⫾ standard deviation and qualitative variables as proportions (percentages). The comparison of 2 media was studied with the Student t test, and comparison of proportions with the chi-square test (Fisher exact test correction when necessary). Associations were considered significant in presence of a P value ⬍ .05, although all P values ⬍ .10 are reported.
RESULTS According to the aforementioned criteria, we identified 103 consecutive cases of clinically or pathologically proven IE. These patients constituted the study population. Of them, 31 (30.1%) were 65 years old or older and were defined as the elderly population. The remaining 72 patients (69.9%) were defined as younger (Table 1). Clinical Presentation Elderly patients were less often male than were younger patients (54.8% vs 76.3%, P ⫽ .036). With regard to predisposing factors, we found a higher proportion of men in the younger population (97.2% vs 64.5%, P ⬍ .001), mainly because of the higher prevalence of immunodeficiency virus infection, drug abuse, and liver diseases. On the contrary, as expected, degenerative heart disease was seen more frequently in the elderly (22.5% vs 2.7%, P ⫽ .003). The elderly also had a higher frequency of pacemakers (9.6% vs 1.3%, P ⫽ .059) and diabetes mellitus (12.9% vs 2.7%, P ⫽ .065). The other predisposing factors for IE were not differently distributed between groups. There was no difference in duration of symptoms before hospitalization between groups. Importantly, however, time to diagnosis was significantly longer in elderly patients (7.2 ⫾ 6.2 vs 3.2 ⫾ 3.5 days, P ⬍ .001). Regarding the clinical presentation, heart failure (41.9% vs 19.4%, P ⫽ .02) and leukocytosis (61.2% vs 40.2%, P ⫽ .049) were more frequently seen in elderly patients. On the contrary, there was a lower frequency of splenomegaly in older patients (6.4% vs 19.4%, P ⫽ .073). Other clinical data, such as fever, murmur, and embolisms, appeared as frequently in the elderly as in the younger population.
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Table 1 Clinical, epidemiologic, and echocardiographic data of the study population n Male gender Predisposing factors Rheumatic heart disease Congenital heart disease Degenerative heart disease Cardiac prosthesis Pacemaker leads Drug abuse (iv) HIV infection Prior IE Liver disease Diabetes mellitus Liver or renal transplantation Duration of symptoms (days) Clinical presentation Fever Embolism Heart failure Murmur Splenomegaly Vascular phenomena Leukocytosis Time to diagnosis (days)
Elderly
Younger
P
31 (30%) 17 (54.8%) 20 (64.5%) 7 (22.5%) 3 (9.6%) 7 (22.5%) 10 (32.2%) 3 (9.6%) 0 0 3 (9.6%) 0 4 (12.9%) 1 (3.2%) 20.3 ⫾ 22.9
72 (69.9%) 55 (76.3%) 70 (97.2%) 12 (16.6%) 9 (12.5%) 2 (2.7%) 24 (33.3%) 1 (1.3%) 31 (43%) 22 (30.5%) 4 (5.5%) 13 (18%) 2 (2.7%) 2 (2.7%) 26.1 ⫾ 8.8
.036 ⬍.001 NS NS .003 NS NS ⬍.001 ⬍.001 NS .011 .065 NS NS
23 (74.2%) 7 (22.5%) 13 (41.9%) 22 (71%) 2 (6.4%) 3 (9.6%) 19 (61.2%) 7.2 ⫾ 6.2
54 (75%) 19 (26.3%) 14 (19.4%) 56 (77.7%) 14 (19.4%) 3 (4.1%) 29 (40.2%) 3.2 ⫾ 3.5
NS NS .020 NS .073 NS ⬍.050 .001
iv, Intravenous; IE, infective endocarditis.
Table 2 Location of infective endocarditis in elderly and younger patients Native mitral Native aortic Native tricuspid Native pulmonary Prosthetic mitral Prosthetic aortic Prosthetic tricuspid Pacemaker leads
Elderly
Younger
P
11 (35.4%) 10 (32.2%) 0 0 6 (19.3%) 4 (12.9%) 0 3 (9.6%)
17 (23.6%) 16 (22.2%) 19 (26.3%) 1 (1.3%) 15 (20.8%) 8 (11.1%) 1 (1.3%) 1 (1.3%)
NS NS ⬍.001 NS NS NS NS NS
Location and Etiologic Germ The most frequent location was native mitral and native tricuspid valve in elderly and younger patients, respectively (Table 2). There was a much higher frequency of tricuspid location among younger patients (26% vs 0%, P ⬍ .001), probably because of the higher prevalence of intravenous drug abuse. On the contrary, there was a higher frequency of pacemaker-leads IE in elderly patients. Mitral and aortic locations were not significantly more frequent in elderly patients. Simultaneous infection in 2 native valves (mitral and aortic) was seen 3 times in each group. There were also 3 cases of infection in mitral and aortic prosthesis in the younger group. The prevalence of negative blood cultures IE was 12.9% and 22.2% in elderly and younger groups, respectively (P ⫽ NS). In 5 cases, blood cultures
Table 3 Causative germs of infective endocarditis and their distribution in the study population Elderly
Negative blood cultures 4 (12.9%) Staphylococcus aureus 7 (22.5%) Staphylococcus coagulase-negative 5 (16.1%) Streptococcus pyogenes 0 Enterococcus 10 (32.2%) Streptococcus bovis 2 (6.4%) Streptococcus viridans 1 (3.2%) Streptococcus pneumoniae 1 (3.2%) Streptococcus milleri 0 Neisseria spp 0 Corynebacterium 0 Escherichia coli 1 (3.2%) Candida spp 0
Younger
P
16 (22.2%) NS 23 (31.9%) NS 12 (16.6%) NS 3 (4.1%) NS 5 (13.1%) .001 1 (1.3%) NS 10 (13.8%) NS 0 NS 1 (1.3%) NS 1 (1.3%) NS 1 (1.3%) NS 1 (1.3%) NS 3 (4.1%) NS
yielded results suggestive of double infection in the same patient; and in another patient with intravenous drug abuse, 3 germs were isolated from blood. There were 2 additional positive blood cultures diagnosed, but the causative micro-organism was not specified in the clinical file. The main differences between both age groups were seen in the case of Enterococcus, which appeared more frequently in the elderly (32.2% vs 13.1%, P ⫽ .001). Staphylococcus aureus and Streptococcus viridans infected younger patients more often, but not significantly (Table 3).
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Inhospital outcome Although not significantly, mortality (16.1% vs 12.5%) and need for valve operation (58.1% vs 45.8%) were more frequent in elderly patients (Table 4). The combined end point of death or operation tended to be more frequent in elderly patients (71% vs 53%, P ⫽ .082). The perioperative mortality in elderly and younger patients was 5.6% and 12.1%, respectively (P ⫽ NS). Heart failure tended to occur more often in elderly patients (35% vs 18%, P ⫽ .061). On the contrary, embolic events tended to occur more frequently among younger patients (49% vs 29%, P ⫽ .062). The incidence of other complications, such as renal failure, abscesses, pseudoaneurysms, and valve rupture or perforation was not significantly different between groups.
DISCUSSION In the current study, IE was diagnosed in elderly patients later, and the elderly had cardiac failure at presentation more frequently. However, mortality rate was not statistically higher and this was probably because of 2 reasons: (1) Despite their advanced age, elderly patients were referred for a valve operation more frequently than younger patients; and (2) their perioperative mortality tended to be, surprisingly, lower than in younger patients. Increased susceptibility to IE in the elderly may be attributed to different factors. First, predisposing conditions such as malnutrition, diabetes mellitus, chronic diseases, and diagnostic and therapeutic manipulations, which may lead to transient bacteremia, tend to be more common in the aged.24,25 Second, evidence exists for a decline in immune response with advanced age. Although neutrophil blood counts and marrow reserves do not change substantially, a diminished ability to recruit them from bone marrow to circulation has been described.26 Moreover, certain nonspecific neutrophil immune functions, such as chemotactic response and bactericidal activity, may be decreased in very old individuals.27 Anomalies in both humoral and cellular immune responses have also been reported.28-30 Finally, cardiac changes associated with aging, such as valve calcification and fibrosis, may also increase the risk of suffering IE.24 Necropsy studies have shown a high prevalence of valvular heart disease in very old individuals.31,32 In addition, there is an improved life expectancy at present, and therefore IE tends to occur more and more frequently among the elderly. The percentage of patients with IE older than 60 years has progressively increased along the century.4 Currently, in most series, approximately 40% to 50% of subjects suffering IE are elderly individuals.3-5,7,8 Neverthe-
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Table 4 Inhospital clinical course of elderly and younger patients with infective endocarditis Renal failure Heart failure Embolic events Abscess/pseudoaneurysm Rupture/perforation Fistulae Prolapse Surgery Mortality Time to surgery (days) Death or surgery
Elderly
Younger
P
4 (12.9%) 11 (35.4%) 9 (29.0%) 5 (16.1%) 7 (22.5%) 0 3 (9.6%) 18 (58.1%) 5 (16.1%) 20.6 ⫾ 18.3 22 (71.0%)
10 (13.8%) 13 (18%) 35 (48.6%) 19 (26.3%) 9 (12.5%) 1 (1.3%) 5 (6.9%) 33 (45.8%) 9 (12.5%) 18.1 ⫾ 20.4 38 (52.8%)
NS .061 .062 NS NS NS NS NS NS NS .082
less, the definition of elderly is not well established and different reports have used different ages (older than 60, 65, or 70 years). In our study, in which we defined older individuals as those 65 years or older, the total proportion was 30%. We must take into account that our hospital is situated in an area of high prevalence of drug abuse. IE in intravenous drug abusers may have particular epidemiologic, bacteriologic, clinical, echocardiographic, and therapeutic features, so that they constitute a distinct subpopulation.15,33,34 After excluding this subset, the total percentage of older individuals was 43%, similar to what others have previously reported. In our series, the younger group had predisposing factors for IE more often than the elderly did. This was mainly because of a higher prevalence of immunodeficiency virus infection, intravenous drug abuse, and liver diseases. On the contrary, certain valve conditions such as degenerative diseases were more frequent in the aged. However, prostheses were not more common in this population, in contrast with other previous observations.4,6,7 The rest of predisposing factors were similarly seen in both groups. With regard to site of infection, the native tricuspid IE was the predominant finding in the younger patients, probably because of the high proportion of intravenous drug abusers in this subset. After exclusion of this population, there were no other significant differences regarding the site of infection, similar to other reports.3,6-8 Although previous series reported a higher incidence of aortic involvement in the aged,1,2,35 in more recent ones, and in ours, mitral valve was the most common primary site of infection both in elderly and younger patients.4,6-8 Although not significantly, the aortic valve was most frequently involved among the younger patients. This has also been observed by some authors,4,6 although others have reported opposite findings.7,8 Cardiac failure and leukocytosis appeared more frequently among the elderly. We do not have an explanation for the higher frequency of leukocytosis in elderly patients, and controversial data have been
706 Zamorano et al
reported in other series.4,7 Other clinical data took place similarly in both populations. The same was observed with regard to anatomic complications as detected by echocardiography. Infective organisms showed few differences between the 2 groups. As reported by previous authors,3,4,6,24,36 Enterococcus, a germ that usually comes from the urinary tract or a colonic source, was isolated more frequently in the elderly. Consistently with other studies, a nonsignificantly higher frequency for Streptococcus viridans to be found in younger individuals was observed.24 Surprisingly, duration of symptoms was similar between both groups, but time to diagnosis was approximately twice as long with elderly patients. Terpenning et al4 also reported an increased frequency of inadequate diagnosis in these patients. In our study there seems to be no explanation other than a low level of clinical suspicion from the responsible physicians. Despite the delay in diagnosis and the higher frequency of cardiac failure in elderly patients, mortality was not significantly higher, probably because of 2 reasons: (1) Despite their more advanced age, elderly patients were referred for surgical valve replacement more frequently than younger patients. This reflects that similar therapeutic criteria were used for older and younger patients, which is also shown by the fact that time from diagnosis to surgical procedure in those operated was approximately the same, regardless of the patient’s age. Terpenning et al4 and Selton-Suty et al6 reported a higher proportion of death in the aged, but in both series surgical procedure was used less frequently in this population. On the contrary, in the study by Gagliardi et al,8 in which surgical treatment was equally distributed, no differences in mortality were found. The same was observed by Werner et al,7 who reported no differences in survival in global terms but a relatively high mortality in medically treated older individuals. (2) The perioperative mortality in elderly patients was, surprisingly, lower than in younger patients. In other series, perioperative mortality in patients with IE was higher in elderly patients.4
CONCLUSIONS Despite elderly patients with infective endocarditis having cardiac failure at clinical presentation more frequently, the early use of both TTE and TEE examinations, and the same treatment options, results in an improved outcome, which does not differ from that observed in younger individuals. This suggests that similar diagnostic and therapeutic modalities should be used in both populations.
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