Research
Original Investigation
Prognostic Value of Skin Manifestations of Infective Endocarditis Amandine Servy, MD; Laurence Valeyrie-Allanore, MD; François Alla, MD, PhD; Catherine Lechiche, MD; Pierre Nazeyrollas, MD, PhD; Christian Chidiac, MD, PhD; Bruno Hoen, MD, PhD; Olivier Chosidow, MD, PhD; Xavier Duval, MD, PhD; for the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group
IMPORTANCE Infective endocarditis (IE) is a rare disease with poor prognosis. When IE is suspected, skin examination is mandatory to look for a portal of entry and classic skin lesions to help diagnose and manage the condition.
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OBJECTIVES To describe the prevalence of and factors associated with dermatological manifestations in patients with definite IE. DESIGN Observational, prospective, population-based epidemiological study between January 1 and December 31, 2008. Subsequently, collected dermatological data were subjected to post hoc analysis. SETTING AND PARTICIPANTS Patients (n = 497) diagnosed in 7 French regions and hospitalized in France for definite IE satisfying modified Duke criteria. MAIN OUTCOMES AND MEASURES Patient and disease epidemiological information was collected, focusing on the most classic dermatological manifestations of IE (Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages). Disease outcome was also recorded. RESULTS Among 497 definite IE cases, 487 had known dermatological status. Of 487 cases, 58 (11.9%) had skin manifestations, including 39 (8.0%) with purpura, 13 (2.7%) with Osler nodes, 8 (1.6%) with Janeway lesions, and 3 (0.6%) with conjunctival hemorrhages (5 patients had 2 skin manifestations). Patients with skin manifestations had a higher rate of IE-related extracardiac complications than patients without skin manifestations, particularly cerebral emboli (32.8% vs 18.4%, P = .01), without increased mortality. Patients with purpura had larger cardiac vegetations (18.1 vs 13.7 mm, P = .01), and Janeway lesions were associated with more extracerebral emboli (75.0% vs 31.8%, P = .02). CONCLUSIONS AND RELEVANCE Specific skin manifestations of IE are associated with a higher risk of complications and should alert physicians to examine for extracardiac complications, notably with cerebral imaging.
Author Affiliations: Author affiliations are listed at the end of this article. Group Information: The Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group investigators are listed at the end of this article.
JAMA Dermatol. 2014;150(5):494-500. doi:10.1001/jamadermatol.2013.8727 Published online February 5, 2014. 494
Corresponding Author: Amandine Servy, MD, Department of Dermatology, Centre Hospitalier Universitaire Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris, 51 Avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil CEDEX, France ([email protected]). jamadermatology.com
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
I
nfective endocarditis (IE) affects 2 to 6 individuals per 100 000 person-years in industrialized countries. Inpatient mortality approaches 20%, particularly due to septic shock, heart failure, or stroke.1 The epidemiological profile of IE has evolved progressively, with increasing percentages of health care–associated IE, Staphylococcus aureus involvement, and prosthetic and degenerative native valve IE.2-4 A complete dermatological physical examination is essential for the management of IE. Indeed, a cutaneous portal of entry is found for more than 20% of the cases,5 and dermatological lesions suggestive of septicemia (Osler nodes, Janeway lesions, purpura, and splinter and conjunctival hemorrhages) may help physicians reach a clinical diagnosis. Nevertheless, it can be difficult to discriminate among these classic dermatologic al lesions (Figure) and nonspec ific descriptions. Distinguishing between Janeway lesions and Osler nodes is not that obvious.6 Osler nodes are described as purple painful nodes, mainly localized on fingertips, pulp of the toes, palms, soles, or sometimes on the ears.6 Lesions disappear within a few days without sequelae, occasionally in a few hours. Janeway lesions are often small, nontender, erythematous, and painless macules or papules on the palms or soles, sometimes purpuric or hemorrhagic.5,7 They tend to last days to weeks before healing completely. Histological findings for both lesions, described in case reports,8-15 include septic emboli with inflammatory reactions, and culture of lesions can grow pathologic microorganisms. Vascular purpura, usually necrotic, is more frequent and typical. Purpura is most often localized on lower parts of the body (legs and back) and sometimes on mucosa (conjunctivae and mouth) or near the clavicles. The findings on histological examination of purpura have been shown to be primarily septic emboli or leukocytoclastic vasculitis.16 Splinter (longitudinal striations along the major nail axis) and conjunctival hemorrhages are also observed in IE but are not pathognomonic of it. Despite the importance of the skin for positive and etiological IE diagnosis, few nondermatological investigations have analyzed the manifestations of cutaneous IE, the prevalence of
which remains unclear. Therefore, using data from a large French general population–based epidemiological study, we analyzed the prevalence of the 4 main dermatological manifestations of IE (Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages) and their possible associated factors.
Methods Study Design The study was approved by an institutional review board (Comité de Protection des Personnes, Besançon, France, December 2007). In accord with French law at that time, patients were informed of the study orally but did not have to provide written individual consent. Between January 1 and December 31, 2008, the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group17,18 conducted an exhaustive observational and prospective analysis of all IE cases occurring in 7 French regions (Franche-Comté, Ille-et-Vilaine, LanguedocRoussillon, Lorraine, Marne, Île-de-France, and Rhône-Alpes).17 The 15 million inhabitants of these regions account for 32% of the French population (http://www.insee.fr/fr/themes /document.asp?ref_id=ip1220). Only definite IE cases satisfying Duke criteria revised by Li et al19 (eTable in the Supplement) among patients 18 years or older and living in one of the study regions were considered for this analysis. All hospital physicians usually managing IE (ie, cardiologists [P.N. and X.D.], cardiac surgeons, infectious disease specialists [C.L., C.C., and B.H.], intensivists, and internists) were aware of this epidemiological study and notified all their patients. Then, Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse investigators transferred collected data from medical records to standardized case report forms. The following information was collected for each patient: sex, age, medical history, procedures and at-risk factors for IE, clinical signs and symptoms, portal of entry, laboratory and microbiology test results, imaging findings, medical and surgical treat-
Figure. Classic Lesions Associated With Infective Endocarditis A
B
A, Osler nodes on the right thumb characterized by a painful distal erythematous and hemorrhagic bullous lesion. B, Extensive distal infiltrated purpura evolving to necrosis of the legs. C, Erythematous purpuric macules of
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C
the sole corresponding to a Janeway lesion. From the collection of the Department of Dermatology, Centre Hospitalier Universitaire Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris, Créteil, France.
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ment, and complications. A dermatological examination was not systematically performed. Among clinical data, the following 4 classic dermatological manifestations of IE were diagnosed according to each physician’s personal experience with IE and recorded: Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages. All case report forms were checked by an adjudication committee composed of an infectious disease specialist, a cardiologist, a microbiologist, and a cardiac surgeon and were classified according to modified Duke criteria. Then, one of us (A.S.) examined case report forms to extract information for a post hoc analysis of collected dermatological data. Concordance between data collection and medical records was checked for 10.0% of patients with IE having skin lesions.
Statistical Analysis All statistical analyses were performed using commercially available software (SAS, version 8.02; SAS Institute Inc). P < .05 defined significance. The prevalences of dermatological manifestations of definite IE cases were calculated. After elimination of 10 patients with unknown dermatological status, factors associated with cutaneous lesions were subjected to univariate analysis. First, we compared all definite IE cases according to the presence or absence of at least 1 of 4 cutaneous IE lesions considered. Then, we performed another analysis with each dermatological manifestation individually vs all other patients having IE in the cohort without it. Quantitative variables, expressed as means (SDs) with 95% CIs, were analyzed using t test or Wilcoxon rank sum test. Qualitative variables, expressed as numbers (percentages), were compared using χ2 test or Fisher exact test for all comparisons.
Results
though transthoracic echocardiography diagnosed IE in almost half of the patients, transesophageal echocardiography was almost always performed to confirm the diagnosis and to identify heart complications. Time to IE diagnosis was similar regardless of dermatological manifestation status (P = .90), usually less than 1 month. However, compared with patients having IE without skin lesions, those with dermatological manifestations had significantly more extracardiac complications (75.9% vs 54.8%, P = .002), and their manifestations were associated with a higher rate of cerebral complications (41.4% vs 25.4%, P = .01), mainly cerebral emboli (32.8% vs 18.4%, P = .01), while only a trend was found for a subgroup with symptomatic cerebral complications (Table 2). Compared with patients having IE without cerebral emboli, those with this complication had significantly higher percentages of IE-associated skin signs (Table 3). Despite significantly higher complication rates for patients with dermatological manifestations of IE, mortality and hospital length of stay were comparable to those for patients without dermatological manifestations (Table 2). Considering patients with each type of cutaneous lesion individually vs those without, purpura was significantly associated with larger initial cardiac vegetations (18.1 vs 13.7 mm, P = .01). Janeway lesion was significantly associated with extracerebral emboli (75.0% vs 31.8%, P = .02) and often with symptomatic emboli in lung, spleen, heart, kidney, liver, or peripheral localizations. Bicuspid aortic valve was significantly associated with Osler node (23.0% vs 4.0%, P = .01). No other characteristics were associated with the presence of each type of cutaneous lesion (data not shown). Concordance was good (80.0%) between case report forms and medical records. Although some symptomatological or differential diagnoses can be discussed, no patient was excluded because of incomplete or imprecise medical records.
Prevalence of Dermatological Manifestations of IE Among 497 definite IE cases, 487 had known dermatological status (presence or absence of a classic IE-associated cutaneous lesion). Four hundred twenty-nine patients (88.1%) had no skin manifestation. Fifty-eight patients (11.9%) had at least 1 of 4 skin manifestations of IE considered, including 39 (8.0%) with purpura, 13 (2.7%) with Osler nodes, 8 (1.6%) with Janeway lesions, and 3 (0.6%) with conjunctival hemorrhages. Five patients had 2 skin manifestations.
Factors Associated With Dermatological Manifestations of IE The main characteristics of patients with IE according to the presence or absence of dermatological manifestations are summarized in Table 1. Patients with cutaneous lesions were younger, while no differences were observed for the frequencies of intravenous drug use or associated comorbidities except for a lower percentage of patients with type 1 diabetes mellitus among patients with skin manifestations. In particular, the frequency of previously known underlying heart disease, including a prosthetic valve, did not differ significantly between patients with vs without skin manifestations. Comparable numbers of patients with or without skin signs had heart murmurs (new or previously known) at IE diagnosis. Al496
Discussion Based on the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse prospective population study of patients with definite IE, 11.9% had dermatological manifestations. According to the literature,20 the frequency of cutaneous lesions varies widely (5%-25% of IE cases) across investigations. In a 1973 review article21 covering 1927 to 1967, the frequencies were 10% to 23% of patients with IE having Osler nodes22,23 and 19% to 40% of patients with IE having purpura.24,25 These manifestations seem to be reported less frequently (approximately 10% of cases) in more recent studies.5,7 The prevalence rates may be underestimated in the absence of systematic dermatological examination and photographs for retrospective assessment. We found the IE dermatological manifestations to be significantly associated with symptomatic and asymptomatic cerebral embolic events. Consequently, the presence of these cutaneous lesions might attest to an active embolic process responsible for systemic complications and thus a sign of IE severity, which is in agreement with reported septic emboli in Osler nodes, Janeway lesions, and purpura.8-15 Moreover, we observed the largest cardiac
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
Table 1. Characteristics of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa Dermatological Manifestations of IE None ≥1 (n = 429) (n = 58)
IE-Associated Characteristic Characteristics of Patients Age, mean (SD), y
63.1 (15.5)
Male-female ratio
320:109
Intravenous drug users, No. (%)
P Valueb
57.0 (17.3)
.01
42:16
.73
22 (5.1)
6 (10.3)
.13
≥1
210 (49.0)
23 (39.7)
.18
Hypertension
207 (48.3)
21 (36.2)
.09
Diabetes mellitus
103 (24.0)
8 (13.8)
.08
53 (12.4)
2 (3.4)
.04
Comorbidities, No. (%)
Type 1 diabetes mellitus Heart disease, No. (%) Underlying, previously known Prosthetic valve
201 (46.9)
29 (50.0)
.65
94 (21.9)
10 (17.2)
.65 .65
Congenital heart disease
18 (4.2)
3 (5.2)
Native valve disease
84 (19.6)
16 (27.6)
.16
Previous IE
27 (6.3)
5 (8.6)
.57
Intracardiac devices
60 (14.0)
4 (6.9)
.13
Community
307 (71.6)
47 (81.0)
Nosocomial
99 (23.1)
9 (15.5)
Health care related
14 (3.3)
0
Dental
34 (7.9)
2 (3.4)
.29
Indwelling central catheter
30 (7.0)
5 (8.6)
.60
Microbiological Characteristics Source of acquisition, No. (%)
.14
At-risk procedures, No. (%)
Cardiac catheter
12 (2.8)
0
.38
Digestive
19 (4.4)
4 (6.9)
.51
Urinary
6 (1.4)
1 (1.7)
.60
Gynecological
0
1 (1.7)
.12
Portal of entry, No. (%) Cutaneous
74 (17.2)
10 (17.2)
.97
Active intravenous drug use
22 (5.1)
6 (10.3)
.13
Buprenorphine hydrochloride injection
15 (3.5)
5 (8.6)
.08
Microorganisms, No. (%)
.56
Streptococcaceae
206 (48.0)
31 (53.4)
.44
Streptococci
154 (35.9)
23 (39.7)
.58
Staphylococcaceae Staphylococcus aureus Other microorganism
154 (35.9)
21 (36.2)
.96
108 (25.2)
20 (34.5)
.13
37 (8.6)
3 (5.2)
.61
7 (1.6)
2 (3.4)
.29
25 (5.8)
1 (1.7)
.36
26 (6.1)
3 (5.2)
3 mo
33 (7.7)
6 (10.3)
>1 Microorganism No pathogen identified Time to IE diagnosis, No. (%) First symptom to hospitalization interval Appeared after admission
.90
Heart murmur at diagnosis, No./total No. (%) Yes
238/375 (63.5)
36/54 (66.7)
.65
New murmur
180/375 (48.0)
30/54 (55.6)
.30
Previous murmur unchanged
63/375 (16.8)
8/54 (14.8)
.71
Previous murmur modified
41/375 (10.9)
5/54 (9.3)
.71 (continued)
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Table 1. Characteristics of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa (continued)
Abbreviations: TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.
Dermatological Manifestations of IE None ≥1 (n = 429) (n = 58)
IE-Associated Characteristic Echocardiographic IE findings, No./total No. (%) TTE
392 (91.4)
TEE
54 (93.1)
.80
376 (87.6)
51 (87.9)
.95
174/393 (44.3)
24/53 (45.3)
.89
396 (92.3)
55 (94.8)
.79
c
Vegetation
371 (86.5)
55 (94.8)
.08
Perforation
80 (18.6)
8 (13.8)
.37
Cardiac abscess
70 (16.3)
10 (17.2)
.85
16/94 (17.0)
3/10 (30.0)
.39
161 (37.5)
28 (48.3)
.13
TTE alone diagnosed IE Echocardiographic abnormality
Dehiscenced Severe regurgitation
a
Osler node, Janeway lesion, purpura, or conjunctival hemorrhage.
b
χ2 Test or Fisher exact test for qualitative variables; t test or Wilcoxon rank sum test for quantitative variables.
c
The mean (SD) vegetation sizes were 14.4 (11.0) mm for patients without dermatological manifestations (n = 297) and 15.8 (9.1) mm for patients with at least 1 dermatological manifestation (n = 44) (P = .19).
d
Exclusively for IE developing on prosthetic valves.
P Valueb
Table 2. Complications and Outcomes of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa Dermatological Manifestations of IE None (n = 429)
≥1 (n = 58)
P Valuea
Heart failure, No. (%)
143 (33.3)
20 (34.5)
.86
Extracardiac complications, No. (%)
235 (54.8)
44 (75.9)
.002
22 (5.1)
6 (10.3)
.13
109 (25.4)
24 (41.4)
.01
81 (18.9)
17 (29.3)
.06
43 (10.0)
7 (12.1)
.63
Cerebral embolism
79 (18.4)
19 (32.8)
.01
Cerebral hemorrhage
24 (5.6)
3 (5.2)
>.99
129 (30.1)
30 (51.7)
61 (14.2)
13 (22.4)
.07
31 (7.2)
7 (12.1)
.20
188 (43.8)
39 (67.2)
.01
34 (7.9)
24 (41.4)
.99
27 (7.0)
12 (11.8)
.11
31 (7.5)
8 (11.0)
.30
Osler node
8 (2.1)
5 (4.9)
.16
9 (2.2)
4 (5.5)
.11
Janeway lesion
6 (1.6)
2 (2.0)
.67
6 (1.4)
2 (2.7)
Microorganisms
a
0
.16
.34 .05
Streptococcaceae
187 (48.6)
50 (49.0)
.94
204 (49.3)
33 (45.2)
.52
Staphylococcaceae
138 (35.8)
37 (36.3)
.94
143 (34.5)
32 (43.8)
.13
2
χ Test or Fisher exact test.
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
vebetations in patients with purpura, and other authors have reported vegetation size to be associated with cerebral emboli.20,26,27 Janeway lesions were directly associated with embolic events other than cerebral emboli, and Osler nodes were associated with bicuspid aortic valves. Embolic events are one of the most frequent (20%-50% of cases20) and severe complications of IE. Their incidence is the highest during the first 2 weeks after beginning an antibiotic regimen.20,27,28 Approximately 30% of emboli are silent,29 but they may affect prognosis. The identification of patients with the highest frequency of cerebral emboli may justify cerebral magnetic resonance imaging and affect patient care.29 Physicians should be aware of this association, which might identify new predictive factors. Early systematic dermatological examination, preferably by a dermatologist or an experienced physician alert to these skin manifestations and their appearance, could shorten the time to reach a specific diagnosis, even for small and transient lesions. No clear relationship has been established between the onset of specific IE dermatological lesions and a responsible microorganism. As did Arber et al,30 we observed fewer coagulasenegative staphylococci infections in patients having IE with skin signs. Although Martínez-Marcos et al31 recently reported that dermatological manifestations occurred frequently in patients with enterococcal IE, few studies8,9,11,15,32 have reported the presence of S aureus in needle aspirate or biopsy cultures of Osler nodes or Janeway lesions and blood. Microbiological cultures of classic dermatological lesions can
ARTICLE INFORMATION Accepted for Publication: September 14, 2013. Published Online: February 5, 2014. doi:10.1001/jamadermatol.2013.8727. Author Affiliations: Department of Dermatology, Centre Hospitalier Universitaire (CHU) Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Créteil, France (Servy, Valeyrie-Allanore, Chosidow); Centre d’Investigation Clinique–Epidémiologie Clinique, CHU de Nancy, Nancy, France (Alla); Department of Infectious and Tropical Diseases, CHU de Caremeau, Nîmes, France (Lechiche); Departments of Cardiology and Therapeutics, CHU de Reims, Faculté de Médecine, Reims, France (Nazeyrollas); Department of Infectious and Tropical Diseases, CHU Hôpital de la Croix Rousse, Lyon, France (Chidiac); Department of Infectious and Tropical Diseases, CHU de Besançon, Unité Mixte de Recherche Centre Nationale de Recherche Scientifique 6249 Chrono-Environnement, Université de Franche-Comté, Besançon, France (Hoen); Université Paris–Est Créteil Val-de-Marne, Institut National de la Santé et de la Récherche Médicale (INSERM), Centre d’Investigation Clinique (CIC) 006, Créteil, France (Chosidow); INSERM CIC 007, AP-HP, CHU Bichat, INSERM Unité 738, Université Paris Diderot, Unité de Formation et de Recherche de Médecine, Site Bichat, Paris, France (Duval). Author Contributions: Drs Alla and Duval had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Valeyrie-Allanore
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be performed to assist in therapeutic management and to improve our knowledge. This study has some limitations. Because of the exploratory nature of the associated factors sought, collected dermatological data were subjected only to post hoc analysis, and systematic dermatological physical and histological examinations were not conducted, thereby limiting the certainty of the diagnosis of dermatological lesions and their characterization. Consequently, the prevalence of dermatological manifestations of IE could differ slightly. Nevertheless, the absence of systematic dermatological examination reflects real clinical practice and enhances the pertinence of our findings concerning factors associated with cutaneous manifestations of IE. Moreover, differentiating between dermatological lesions is often complex, and it was important to simplify the main message and clinical practice that any classic manifestation of IE is a sign of disease severity. In addition, Osler nodes and Janeway lesions are so similar clinically and histologically that their distinction is debatable.
Conclusions Classic skin manifestations of IE are signs of infection severity, associated with a higher risk of complications that should alert physicians to look for secondary complications, notably with cerebral imaging. In addition to their diagnostic contribution, dermatological manifestations may have a prognostic role in IE and influence therapeutic decisions.
and Alla contributed equally to this work, and Drs Chosidow and Duval contributed equally to this work. Study concept and design: Lechiche, Hoen, Alla, Chosidow, Duval. Analysis and interpretation of data: Servy, Valeyrie-Allanore, Alla, Chosidow, Duval. Drafting of the manuscript: Servy, Valeyrie-Allanore. Critical revision of the manuscript for important intellectual content: Alla, Nazeyrollas, Chidiac, Hoen, Chosidow, Duval. Statistical analysis: Alla. Administrative, technical, or material support: Servy. Study supervision: Chosidow, Duval. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by a research grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2007), by grants from the Société Française de Cardiologie, by the European Society of Clinical Microbiology and Infectious Diseases, and by Novartis France. The sponsor was the Délégation à la Recherche Clinique et au Développement, Centre Hospitalier Universitaire de Besançon. Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information: The Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group (AEPEI) investigators were as follows: AEPEI Study Group on Infective Endocarditis: Principal
investigators: B. Hoen and X. Duval. Other members: F. Alla, A. Bouvet, S. Briançon, E. Cambau, M. Celard, C. Chirouze, N. Danchin, T. Doco-Lecompte, F. Delahaye, J. Etienne, B. Iung, V. Le Moing, J. F. Obadia, C. Leport, C. Poyart, M. Revest, C. Selton-Suty, C. Strady, P. Tattevin, and F. Vandenesch. Region study coordinating investigators: Y. Bernard, S. Chocron, C. Chirouze, B. Hoen, P. Plesiat, I. Abouliatim, C. De Place, P. Tattevin, M. Revest, P. Y Donnio, F. Alla, J. P. Carteaux, T. Doco-Lecompte, C. Lion, N. Aissa, C. Selton-Suty, B. Baehrel, R. Jaussaud, P. Nazeyrollas, C. Strady, V. Vernet, E. Cambau, X. Duval, B. Iung, P. Nataf, C. Chidiac, M. Celard, F. Delahaye, J. F. Obadia, F. Vandenesch, H. Aumaître, J. M. Frappier, V. Le Moing, E. Oziol, A. Sotto, and C. Sportouch. Centre National de Référence des Streptocoques: C. Poyart and A. Bouvet. Centre National de Référence des Staphylocoques: F. Vandenesch, M. Celard, and M. Bes. Investigators: P. Abassade, E. Abrial, C. Acar, N. Aissa, J. F. Alexandra, N. Amireche, D. Amrein, P. André, M. Appriou, M. A. Arnould, P. Assayag, A. Atoui, F. Aziza, N. Baille, N. Bajolle, P. Battistella, S. Baumard, A. Ben Ali, J. Bertrand, S. Bialek, M. Bois Grosse, M. Boixados, F. Borlot, A. Bouchachi, O. Bouche, S. Bouchemal, J. L. Bourdon, A. Bouvet, L. Brasme, F. Bricaire, E. Brochet, J. F. Bruntz, A. Cady, J. Cailhol, M. P. Caplan, B. Carette, J. P. Carteaux, O. Cartry, C. Cazorla, M. Celard, H. Chamagne, H. Champagne, G. Chanques, J. Chastre, B. Chevalier, C. Chirouze, F. Chometon, C. Christophe, A. Cohen, N. Colin de Verdiere, N. Danchin, V. Daneluzzi, L. David, P. De Lentdecker, F. Delahaye, V. Delcey, P. Deleuze, E. Donal, X. Duval, B. Deroure, V. Descotes-Genon, K. Didier Petit, A. Dinh, V. Doat, F. Duchene, F. Duhoux, M. Dupont, S. Ederhy, O.
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Epaulard, M. Evest, J. F. Faucher, B. Fantin, E. Fauveau, T. Ferry, M. Fillod, T. Floch, T. Fraisse, J. M. Frapier, L. Freysz, B. Fumery, B. Gachot, S. Gallien, I. Gandjbach, P. Garcon, A. Gaubert, J.L. Genoud, S. Ghiglione, C. Godreuil, A. Grentzinger, L. Groben, D. Gherissi, P. Guéret, A. Hagege, N. Hammoudi, F. Heliot, P. Henry, S. Herson, B. Hoen, P. Houriez, L. Hustache-Mathieu, O. Huttin, S. Imbert, B. Iung, S. Jaureguiberry, M. Kaaki, A. Konate, J. M. Kuhn, S. Kural Menasche, A. Lafitte, B. Lafon, F. Lanternier, V. Le Chenault, V. Le Moing, C. Lechiche, S. Lefevre, Thibaut, A. Lefort, A. Leguerrier, J. Lemoine, L. Lepage, C. Leport, C. Lepousé, J. Leroy, P. Lesprit, L. Letranchant, D. Loisance, G. Loncar, C. Lorentz, P. Mabo, I. Magnin-Poull, T. May, A. Makinson, H. Man, M. Mansouri, O. Marçon, J. P. Maroni, V. Masse, F. Maurier, M. C. Meyohas, P. L. Michel, C. Michelet, F. Mechaï, O. Merceron, D. Messika-Zeitoun, Z. Metref, V. Meyssonnier, C. Mezher, S. Micheli, M. Monsigny, S. Mouly, B. Mourvillier, O. Nallet, P. Nataf, P. Nazeyrollas, V. Noel, J. F. Obadia, E. Oziol, T. Papo, B. Payet, A. Pelletier, P. Perez, J. S. Petit, F. Philippart, E. Piet, C. Plainvert, B. Popovic, J. M. Porte, P. Pradier, R. Ramadan, M. Revest, J. Richemond, M. Rodermann, M. Roncato, I. Roigt, O. Ruyer, M. Saada, J. Schwartz, C. Selton-Suty, M. Simon, B. Simorre, S. Skalli, F. Spatz, C. Strady, J. Sudrial, L. Tartiere, A. Terrier De La Chaise, M. C. Thiercelin, D. Thomas, M. Thomas, L. Toko, F. Tournoux, A. Tristan, J. L. Trouillet, L. Tual, A. Vahanian, F. Verdier, V. Vernet Garnier, V. Vidal, P. Weyne, M. Wolff, A. Wynckel, N. Zannad, and P. Y. Zinzius. Additional Contributions: Janet Jacobson provided editorial assistance. We thank the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group for sharing their data. These individuals did not receive compensation for their help. REFERENCES 1. Hoen B, Duval X. Clinical practice: infective endocarditis. N Engl J Med. 2013;368(15):14251433. 2. Moreillon P, Que YA. Infective endocarditis. Lancet. 2004;363(9403):139-149. 3. Que YA, Moreillon P. Infective endocarditis. Nat Rev Cardiol. 2011;8(6):322-336. 4. Miro JM, Anguera I, Cabell CH, et al; International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis. Clin Infect Dis. 2005;41(4):507-514. 5. Hoen B, Alla F, Selton-Suty C, et al; Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse (AEPEI) Study Group. Changing profile of infective endocarditis. JAMA. 2002;288(1):75-81.
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6. Farrior JB, Silverman ME. A consideration of the differences between a Janeway’s lesion and an Osler’s node in infectious endocarditis. Chest. 1976;70(2):239-243. 7. Murdoch DR, Corey GR, Hoen B, et al; International Collaboration on Endocarditis– Prospective Cohort Study (ICE-PCS) Investigators. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century. Arch Intern Med. 2009;169(5):463-473. 8. Espinosa Parra FJ, Ramos Rincón JM, Herrero Huerta F, Pretel Serrano L, Lorenzo AA. Diagnostic utility of Osler’s nodules in infectious endocarditis among parenteral drug users [in Spanish]. An Med Interna. 2002;19(6):299-301. 9. Alpert JS, Krous HF, Dalen JE, O’Rourke RA, Bloor CM. Pathogenesis of Osler’s nodes. Ann Intern Med. 1976;85(4):471-473. 10. Lin CS, Lee RL, Kuo CM, Lee LC. Positive culture of the Janeway lesion in acute bacterial endocarditis. Taiwan Yi Xue Hui Za Zhi. 1980;79(1):99-102.
Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009. Eur Heart J. 2009;30(19):23692413. 21. Weinstein L, Rubin RH. Infective endocarditis: 1973. Prog Cardiovasc Dis. 1973;16(3):239-274. 22. Geraci JE, Martin WJ. Antibiotic therapy of bacterial endocarditis, VI: subacute enterococcal endocarditis: clinical, pathologic and therapeutic consideration of 33 cases. Circulation. 1954;10(2):173-194. 23. Newman W, Torres JH, Guck JK. Bacterial endocarditis; an analysis of fifty-two cases. Am J Med. 1954;16(4):535-542. 24. Kaipainen WJ, Seppala K. Endocarditis lenta; a review of 118 patients treated during the ten-year period 1945 to 1954. Acta Med Scand. 1956;155(1):71-81. 25. Vogler WR, Dorney ER, Bridges HA. Bacterial endocarditis. Am J Med. 1962;32:910-921.
11. Vinson RP, Chung A, Elston DM, Keller RA. Septic microemboli in a Janeway lesion of bacterial endocarditis. J Am Acad Dermatol. 1996;35(6):984-985.
26. Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37(4):1069-1076.
12. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345(18):1318-1330.
27. Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis. Circulation. 2005;112(1):69-75.
13. Matsui Y, Okada N, Nishizawa M, et al. An Osler’s node and a Janeway lesion. Intern Med. 2009;48(16):1487-1488.
28. Dickerman SA, Abrutyn E, Barsic B, et al; ICE Investigators. The relationship between the initiation of antimicrobial therapy and the incidence of stroke in infective endocarditis. Am Heart J. 2007;154(6):1086-1094.
14. Kerr A Jr, Tan JS. Biopsies of the Janeway lesion of infective endocarditis. J Cutan Pathol. 1979;6(2):124-129.
16. Lévesque H, Marie I. Infection and vascular purpura [in French]. J Mal Vasc. 1999;24(3):177-182.
29. Duval X, Iung B, Klein I, et al. IMAGE (Resonance Magnetic Imaging at the Acute Phase of Endocarditis) Study Group. Effect of early cerebral magnetic resonance imaging on clinical decisions in infective endocarditis. Ann Intern Med. 2010;152(8):497-504, W175.
17. Selton-Suty C, Célard M, Le Moing V, et al; AEPEI Study Group. Preeminence of Staphylococcus aureus in infective endocarditis. Clin Infect Dis. 2012;54(9):1230-1239.
30. Arber N, Militianu A, Ben-Yehuda A, Krivoy N, Pinkhas J, Sidi Y. Native valve Staphylococcus epidermidis endocarditis. Am J Med. 1991;90(6):758-762.
18. Duval X, Delahaye F, Alla F, et al; AEPEI Study Group. Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications. J Am Coll Cardiol. 2012;59(22):1968-1976.
31. Martínez-Marcos FJ, Lomas-Cabezas JM, Hidalgo-Tenorio C, et al; Grupo Para el Estudio de las Infecciones Cardiovasculares de la Sociedad Andaluza de Enfermedades Infecciosas. Enterococcal endocarditis. Enferm Infecc Microbiol Clin. 2009;27(10):571-579.
15. Cardullo AC, Silvers DN, Grossman ME. Janeway lesions and Osler’s nodes. J Am Acad Dermatol. 1990;22(6, pt 1):1088-1090.
19. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-638. 20. Habib G, Hoen B, Tornos P, et al; ESC Committee for Practice Guidelines; Endorsed by the European Society of Clinical Microbiology and
32. Thadepalli H, Francis CK. Diagnostic clues in metastatic lesions of endocarditis in addicts. West J Med. 1978;128(1):1-5.
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Original Investigation
Prognostic Value of Skin Manifestations of Infective Endocarditis Amandine Servy, MD; Laurence Valeyrie-Allanore, MD; François Alla, MD, PhD; Catherine Lechiche, MD; Pierre Nazeyrollas, MD, PhD; Christian Chidiac, MD, PhD; Bruno Hoen, MD, PhD; Olivier Chosidow, MD, PhD; Xavier Duval, MD, PhD; for the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group
IMPORTANCE Infective endocarditis (IE) is a rare disease with poor prognosis. When IE is suspected, skin examination is mandatory to look for a portal of entry and classic skin lesions to help diagnose and manage the condition.
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OBJECTIVES To describe the prevalence of and factors associated with dermatological manifestations in patients with definite IE. DESIGN Observational, prospective, population-based epidemiological study between January 1 and December 31, 2008. Subsequently, collected dermatological data were subjected to post hoc analysis. SETTING AND PARTICIPANTS Patients (n = 497) diagnosed in 7 French regions and hospitalized in France for definite IE satisfying modified Duke criteria. MAIN OUTCOMES AND MEASURES Patient and disease epidemiological information was collected, focusing on the most classic dermatological manifestations of IE (Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages). Disease outcome was also recorded. RESULTS Among 497 definite IE cases, 487 had known dermatological status. Of 487 cases, 58 (11.9%) had skin manifestations, including 39 (8.0%) with purpura, 13 (2.7%) with Osler nodes, 8 (1.6%) with Janeway lesions, and 3 (0.6%) with conjunctival hemorrhages (5 patients had 2 skin manifestations). Patients with skin manifestations had a higher rate of IE-related extracardiac complications than patients without skin manifestations, particularly cerebral emboli (32.8% vs 18.4%, P = .01), without increased mortality. Patients with purpura had larger cardiac vegetations (18.1 vs 13.7 mm, P = .01), and Janeway lesions were associated with more extracerebral emboli (75.0% vs 31.8%, P = .02). CONCLUSIONS AND RELEVANCE Specific skin manifestations of IE are associated with a higher risk of complications and should alert physicians to examine for extracardiac complications, notably with cerebral imaging.
Author Affiliations: Author affiliations are listed at the end of this article. Group Information: The Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group investigators are listed at the end of this article.
JAMA Dermatol. 2014;150(5):494-500. doi:10.1001/jamadermatol.2013.8727 Published online February 5, 2014. 494
Corresponding Author: Amandine Servy, MD, Department of Dermatology, Centre Hospitalier Universitaire Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris, 51 Avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil CEDEX, France ([email protected]). jamadermatology.com
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
I
nfective endocarditis (IE) affects 2 to 6 individuals per 100 000 person-years in industrialized countries. Inpatient mortality approaches 20%, particularly due to septic shock, heart failure, or stroke.1 The epidemiological profile of IE has evolved progressively, with increasing percentages of health care–associated IE, Staphylococcus aureus involvement, and prosthetic and degenerative native valve IE.2-4 A complete dermatological physical examination is essential for the management of IE. Indeed, a cutaneous portal of entry is found for more than 20% of the cases,5 and dermatological lesions suggestive of septicemia (Osler nodes, Janeway lesions, purpura, and splinter and conjunctival hemorrhages) may help physicians reach a clinical diagnosis. Nevertheless, it can be difficult to discriminate among these classic dermatologic al lesions (Figure) and nonspec ific descriptions. Distinguishing between Janeway lesions and Osler nodes is not that obvious.6 Osler nodes are described as purple painful nodes, mainly localized on fingertips, pulp of the toes, palms, soles, or sometimes on the ears.6 Lesions disappear within a few days without sequelae, occasionally in a few hours. Janeway lesions are often small, nontender, erythematous, and painless macules or papules on the palms or soles, sometimes purpuric or hemorrhagic.5,7 They tend to last days to weeks before healing completely. Histological findings for both lesions, described in case reports,8-15 include septic emboli with inflammatory reactions, and culture of lesions can grow pathologic microorganisms. Vascular purpura, usually necrotic, is more frequent and typical. Purpura is most often localized on lower parts of the body (legs and back) and sometimes on mucosa (conjunctivae and mouth) or near the clavicles. The findings on histological examination of purpura have been shown to be primarily septic emboli or leukocytoclastic vasculitis.16 Splinter (longitudinal striations along the major nail axis) and conjunctival hemorrhages are also observed in IE but are not pathognomonic of it. Despite the importance of the skin for positive and etiological IE diagnosis, few nondermatological investigations have analyzed the manifestations of cutaneous IE, the prevalence of
which remains unclear. Therefore, using data from a large French general population–based epidemiological study, we analyzed the prevalence of the 4 main dermatological manifestations of IE (Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages) and their possible associated factors.
Methods Study Design The study was approved by an institutional review board (Comité de Protection des Personnes, Besançon, France, December 2007). In accord with French law at that time, patients were informed of the study orally but did not have to provide written individual consent. Between January 1 and December 31, 2008, the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group17,18 conducted an exhaustive observational and prospective analysis of all IE cases occurring in 7 French regions (Franche-Comté, Ille-et-Vilaine, LanguedocRoussillon, Lorraine, Marne, Île-de-France, and Rhône-Alpes).17 The 15 million inhabitants of these regions account for 32% of the French population (http://www.insee.fr/fr/themes /document.asp?ref_id=ip1220). Only definite IE cases satisfying Duke criteria revised by Li et al19 (eTable in the Supplement) among patients 18 years or older and living in one of the study regions were considered for this analysis. All hospital physicians usually managing IE (ie, cardiologists [P.N. and X.D.], cardiac surgeons, infectious disease specialists [C.L., C.C., and B.H.], intensivists, and internists) were aware of this epidemiological study and notified all their patients. Then, Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse investigators transferred collected data from medical records to standardized case report forms. The following information was collected for each patient: sex, age, medical history, procedures and at-risk factors for IE, clinical signs and symptoms, portal of entry, laboratory and microbiology test results, imaging findings, medical and surgical treat-
Figure. Classic Lesions Associated With Infective Endocarditis A
B
A, Osler nodes on the right thumb characterized by a painful distal erythematous and hemorrhagic bullous lesion. B, Extensive distal infiltrated purpura evolving to necrosis of the legs. C, Erythematous purpuric macules of
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C
the sole corresponding to a Janeway lesion. From the collection of the Department of Dermatology, Centre Hospitalier Universitaire Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris, Créteil, France.
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ment, and complications. A dermatological examination was not systematically performed. Among clinical data, the following 4 classic dermatological manifestations of IE were diagnosed according to each physician’s personal experience with IE and recorded: Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages. All case report forms were checked by an adjudication committee composed of an infectious disease specialist, a cardiologist, a microbiologist, and a cardiac surgeon and were classified according to modified Duke criteria. Then, one of us (A.S.) examined case report forms to extract information for a post hoc analysis of collected dermatological data. Concordance between data collection and medical records was checked for 10.0% of patients with IE having skin lesions.
Statistical Analysis All statistical analyses were performed using commercially available software (SAS, version 8.02; SAS Institute Inc). P < .05 defined significance. The prevalences of dermatological manifestations of definite IE cases were calculated. After elimination of 10 patients with unknown dermatological status, factors associated with cutaneous lesions were subjected to univariate analysis. First, we compared all definite IE cases according to the presence or absence of at least 1 of 4 cutaneous IE lesions considered. Then, we performed another analysis with each dermatological manifestation individually vs all other patients having IE in the cohort without it. Quantitative variables, expressed as means (SDs) with 95% CIs, were analyzed using t test or Wilcoxon rank sum test. Qualitative variables, expressed as numbers (percentages), were compared using χ2 test or Fisher exact test for all comparisons.
Results
though transthoracic echocardiography diagnosed IE in almost half of the patients, transesophageal echocardiography was almost always performed to confirm the diagnosis and to identify heart complications. Time to IE diagnosis was similar regardless of dermatological manifestation status (P = .90), usually less than 1 month. However, compared with patients having IE without skin lesions, those with dermatological manifestations had significantly more extracardiac complications (75.9% vs 54.8%, P = .002), and their manifestations were associated with a higher rate of cerebral complications (41.4% vs 25.4%, P = .01), mainly cerebral emboli (32.8% vs 18.4%, P = .01), while only a trend was found for a subgroup with symptomatic cerebral complications (Table 2). Compared with patients having IE without cerebral emboli, those with this complication had significantly higher percentages of IE-associated skin signs (Table 3). Despite significantly higher complication rates for patients with dermatological manifestations of IE, mortality and hospital length of stay were comparable to those for patients without dermatological manifestations (Table 2). Considering patients with each type of cutaneous lesion individually vs those without, purpura was significantly associated with larger initial cardiac vegetations (18.1 vs 13.7 mm, P = .01). Janeway lesion was significantly associated with extracerebral emboli (75.0% vs 31.8%, P = .02) and often with symptomatic emboli in lung, spleen, heart, kidney, liver, or peripheral localizations. Bicuspid aortic valve was significantly associated with Osler node (23.0% vs 4.0%, P = .01). No other characteristics were associated with the presence of each type of cutaneous lesion (data not shown). Concordance was good (80.0%) between case report forms and medical records. Although some symptomatological or differential diagnoses can be discussed, no patient was excluded because of incomplete or imprecise medical records.
Prevalence of Dermatological Manifestations of IE Among 497 definite IE cases, 487 had known dermatological status (presence or absence of a classic IE-associated cutaneous lesion). Four hundred twenty-nine patients (88.1%) had no skin manifestation. Fifty-eight patients (11.9%) had at least 1 of 4 skin manifestations of IE considered, including 39 (8.0%) with purpura, 13 (2.7%) with Osler nodes, 8 (1.6%) with Janeway lesions, and 3 (0.6%) with conjunctival hemorrhages. Five patients had 2 skin manifestations.
Factors Associated With Dermatological Manifestations of IE The main characteristics of patients with IE according to the presence or absence of dermatological manifestations are summarized in Table 1. Patients with cutaneous lesions were younger, while no differences were observed for the frequencies of intravenous drug use or associated comorbidities except for a lower percentage of patients with type 1 diabetes mellitus among patients with skin manifestations. In particular, the frequency of previously known underlying heart disease, including a prosthetic valve, did not differ significantly between patients with vs without skin manifestations. Comparable numbers of patients with or without skin signs had heart murmurs (new or previously known) at IE diagnosis. Al496
Discussion Based on the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse prospective population study of patients with definite IE, 11.9% had dermatological manifestations. According to the literature,20 the frequency of cutaneous lesions varies widely (5%-25% of IE cases) across investigations. In a 1973 review article21 covering 1927 to 1967, the frequencies were 10% to 23% of patients with IE having Osler nodes22,23 and 19% to 40% of patients with IE having purpura.24,25 These manifestations seem to be reported less frequently (approximately 10% of cases) in more recent studies.5,7 The prevalence rates may be underestimated in the absence of systematic dermatological examination and photographs for retrospective assessment. We found the IE dermatological manifestations to be significantly associated with symptomatic and asymptomatic cerebral embolic events. Consequently, the presence of these cutaneous lesions might attest to an active embolic process responsible for systemic complications and thus a sign of IE severity, which is in agreement with reported septic emboli in Osler nodes, Janeway lesions, and purpura.8-15 Moreover, we observed the largest cardiac
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
Table 1. Characteristics of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa Dermatological Manifestations of IE None ≥1 (n = 429) (n = 58)
IE-Associated Characteristic Characteristics of Patients Age, mean (SD), y
63.1 (15.5)
Male-female ratio
320:109
Intravenous drug users, No. (%)
P Valueb
57.0 (17.3)
.01
42:16
.73
22 (5.1)
6 (10.3)
.13
≥1
210 (49.0)
23 (39.7)
.18
Hypertension
207 (48.3)
21 (36.2)
.09
Diabetes mellitus
103 (24.0)
8 (13.8)
.08
53 (12.4)
2 (3.4)
.04
Comorbidities, No. (%)
Type 1 diabetes mellitus Heart disease, No. (%) Underlying, previously known Prosthetic valve
201 (46.9)
29 (50.0)
.65
94 (21.9)
10 (17.2)
.65 .65
Congenital heart disease
18 (4.2)
3 (5.2)
Native valve disease
84 (19.6)
16 (27.6)
.16
Previous IE
27 (6.3)
5 (8.6)
.57
Intracardiac devices
60 (14.0)
4 (6.9)
.13
Community
307 (71.6)
47 (81.0)
Nosocomial
99 (23.1)
9 (15.5)
Health care related
14 (3.3)
0
Dental
34 (7.9)
2 (3.4)
.29
Indwelling central catheter
30 (7.0)
5 (8.6)
.60
Microbiological Characteristics Source of acquisition, No. (%)
.14
At-risk procedures, No. (%)
Cardiac catheter
12 (2.8)
0
.38
Digestive
19 (4.4)
4 (6.9)
.51
Urinary
6 (1.4)
1 (1.7)
.60
Gynecological
0
1 (1.7)
.12
Portal of entry, No. (%) Cutaneous
74 (17.2)
10 (17.2)
.97
Active intravenous drug use
22 (5.1)
6 (10.3)
.13
Buprenorphine hydrochloride injection
15 (3.5)
5 (8.6)
.08
Microorganisms, No. (%)
.56
Streptococcaceae
206 (48.0)
31 (53.4)
.44
Streptococci
154 (35.9)
23 (39.7)
.58
Staphylococcaceae Staphylococcus aureus Other microorganism
154 (35.9)
21 (36.2)
.96
108 (25.2)
20 (34.5)
.13
37 (8.6)
3 (5.2)
.61
7 (1.6)
2 (3.4)
.29
25 (5.8)
1 (1.7)
.36
26 (6.1)
3 (5.2)
3 mo
33 (7.7)
6 (10.3)
>1 Microorganism No pathogen identified Time to IE diagnosis, No. (%) First symptom to hospitalization interval Appeared after admission
.90
Heart murmur at diagnosis, No./total No. (%) Yes
238/375 (63.5)
36/54 (66.7)
.65
New murmur
180/375 (48.0)
30/54 (55.6)
.30
Previous murmur unchanged
63/375 (16.8)
8/54 (14.8)
.71
Previous murmur modified
41/375 (10.9)
5/54 (9.3)
.71 (continued)
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Table 1. Characteristics of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa (continued)
Abbreviations: TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.
Dermatological Manifestations of IE None ≥1 (n = 429) (n = 58)
IE-Associated Characteristic Echocardiographic IE findings, No./total No. (%) TTE
392 (91.4)
TEE
54 (93.1)
.80
376 (87.6)
51 (87.9)
.95
174/393 (44.3)
24/53 (45.3)
.89
396 (92.3)
55 (94.8)
.79
c
Vegetation
371 (86.5)
55 (94.8)
.08
Perforation
80 (18.6)
8 (13.8)
.37
Cardiac abscess
70 (16.3)
10 (17.2)
.85
16/94 (17.0)
3/10 (30.0)
.39
161 (37.5)
28 (48.3)
.13
TTE alone diagnosed IE Echocardiographic abnormality
Dehiscenced Severe regurgitation
a
Osler node, Janeway lesion, purpura, or conjunctival hemorrhage.
b
χ2 Test or Fisher exact test for qualitative variables; t test or Wilcoxon rank sum test for quantitative variables.
c
The mean (SD) vegetation sizes were 14.4 (11.0) mm for patients without dermatological manifestations (n = 297) and 15.8 (9.1) mm for patients with at least 1 dermatological manifestation (n = 44) (P = .19).
d
Exclusively for IE developing on prosthetic valves.
P Valueb
Table 2. Complications and Outcomes of 487 Patients Having Definite Infective Endocarditis (IE) With or Without Dermatological Manifestationsa Dermatological Manifestations of IE None (n = 429)
≥1 (n = 58)
P Valuea
Heart failure, No. (%)
143 (33.3)
20 (34.5)
.86
Extracardiac complications, No. (%)
235 (54.8)
44 (75.9)
.002
22 (5.1)
6 (10.3)
.13
109 (25.4)
24 (41.4)
.01
81 (18.9)
17 (29.3)
.06
43 (10.0)
7 (12.1)
.63
Cerebral embolism
79 (18.4)
19 (32.8)
.01
Cerebral hemorrhage
24 (5.6)
3 (5.2)
>.99
129 (30.1)
30 (51.7)
61 (14.2)
13 (22.4)
.07
31 (7.2)
7 (12.1)
.20
188 (43.8)
39 (67.2)
.01
34 (7.9)
24 (41.4)
.99
27 (7.0)
12 (11.8)
.11
31 (7.5)
8 (11.0)
.30
Osler node
8 (2.1)
5 (4.9)
.16
9 (2.2)
4 (5.5)
.11
Janeway lesion
6 (1.6)
2 (2.0)
.67
6 (1.4)
2 (2.7)
Microorganisms
a
0
.16
.34 .05
Streptococcaceae
187 (48.6)
50 (49.0)
.94
204 (49.3)
33 (45.2)
.52
Staphylococcaceae
138 (35.8)
37 (36.3)
.94
143 (34.5)
32 (43.8)
.13
2
χ Test or Fisher exact test.
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Skin Manifestations of Infective Endocarditis
Original Investigation Research
vebetations in patients with purpura, and other authors have reported vegetation size to be associated with cerebral emboli.20,26,27 Janeway lesions were directly associated with embolic events other than cerebral emboli, and Osler nodes were associated with bicuspid aortic valves. Embolic events are one of the most frequent (20%-50% of cases20) and severe complications of IE. Their incidence is the highest during the first 2 weeks after beginning an antibiotic regimen.20,27,28 Approximately 30% of emboli are silent,29 but they may affect prognosis. The identification of patients with the highest frequency of cerebral emboli may justify cerebral magnetic resonance imaging and affect patient care.29 Physicians should be aware of this association, which might identify new predictive factors. Early systematic dermatological examination, preferably by a dermatologist or an experienced physician alert to these skin manifestations and their appearance, could shorten the time to reach a specific diagnosis, even for small and transient lesions. No clear relationship has been established between the onset of specific IE dermatological lesions and a responsible microorganism. As did Arber et al,30 we observed fewer coagulasenegative staphylococci infections in patients having IE with skin signs. Although Martínez-Marcos et al31 recently reported that dermatological manifestations occurred frequently in patients with enterococcal IE, few studies8,9,11,15,32 have reported the presence of S aureus in needle aspirate or biopsy cultures of Osler nodes or Janeway lesions and blood. Microbiological cultures of classic dermatological lesions can
ARTICLE INFORMATION Accepted for Publication: September 14, 2013. Published Online: February 5, 2014. doi:10.1001/jamadermatol.2013.8727. Author Affiliations: Department of Dermatology, Centre Hospitalier Universitaire (CHU) Henri-Mondor Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Créteil, France (Servy, Valeyrie-Allanore, Chosidow); Centre d’Investigation Clinique–Epidémiologie Clinique, CHU de Nancy, Nancy, France (Alla); Department of Infectious and Tropical Diseases, CHU de Caremeau, Nîmes, France (Lechiche); Departments of Cardiology and Therapeutics, CHU de Reims, Faculté de Médecine, Reims, France (Nazeyrollas); Department of Infectious and Tropical Diseases, CHU Hôpital de la Croix Rousse, Lyon, France (Chidiac); Department of Infectious and Tropical Diseases, CHU de Besançon, Unité Mixte de Recherche Centre Nationale de Recherche Scientifique 6249 Chrono-Environnement, Université de Franche-Comté, Besançon, France (Hoen); Université Paris–Est Créteil Val-de-Marne, Institut National de la Santé et de la Récherche Médicale (INSERM), Centre d’Investigation Clinique (CIC) 006, Créteil, France (Chosidow); INSERM CIC 007, AP-HP, CHU Bichat, INSERM Unité 738, Université Paris Diderot, Unité de Formation et de Recherche de Médecine, Site Bichat, Paris, France (Duval). Author Contributions: Drs Alla and Duval had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Valeyrie-Allanore
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be performed to assist in therapeutic management and to improve our knowledge. This study has some limitations. Because of the exploratory nature of the associated factors sought, collected dermatological data were subjected only to post hoc analysis, and systematic dermatological physical and histological examinations were not conducted, thereby limiting the certainty of the diagnosis of dermatological lesions and their characterization. Consequently, the prevalence of dermatological manifestations of IE could differ slightly. Nevertheless, the absence of systematic dermatological examination reflects real clinical practice and enhances the pertinence of our findings concerning factors associated with cutaneous manifestations of IE. Moreover, differentiating between dermatological lesions is often complex, and it was important to simplify the main message and clinical practice that any classic manifestation of IE is a sign of disease severity. In addition, Osler nodes and Janeway lesions are so similar clinically and histologically that their distinction is debatable.
Conclusions Classic skin manifestations of IE are signs of infection severity, associated with a higher risk of complications that should alert physicians to look for secondary complications, notably with cerebral imaging. In addition to their diagnostic contribution, dermatological manifestations may have a prognostic role in IE and influence therapeutic decisions.
and Alla contributed equally to this work, and Drs Chosidow and Duval contributed equally to this work. Study concept and design: Lechiche, Hoen, Alla, Chosidow, Duval. Analysis and interpretation of data: Servy, Valeyrie-Allanore, Alla, Chosidow, Duval. Drafting of the manuscript: Servy, Valeyrie-Allanore. Critical revision of the manuscript for important intellectual content: Alla, Nazeyrollas, Chidiac, Hoen, Chosidow, Duval. Statistical analysis: Alla. Administrative, technical, or material support: Servy. Study supervision: Chosidow, Duval. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by a research grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2007), by grants from the Société Française de Cardiologie, by the European Society of Clinical Microbiology and Infectious Diseases, and by Novartis France. The sponsor was the Délégation à la Recherche Clinique et au Développement, Centre Hospitalier Universitaire de Besançon. Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information: The Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group (AEPEI) investigators were as follows: AEPEI Study Group on Infective Endocarditis: Principal
investigators: B. Hoen and X. Duval. Other members: F. Alla, A. Bouvet, S. Briançon, E. Cambau, M. Celard, C. Chirouze, N. Danchin, T. Doco-Lecompte, F. Delahaye, J. Etienne, B. Iung, V. Le Moing, J. F. Obadia, C. Leport, C. Poyart, M. Revest, C. Selton-Suty, C. Strady, P. Tattevin, and F. Vandenesch. Region study coordinating investigators: Y. Bernard, S. Chocron, C. Chirouze, B. Hoen, P. Plesiat, I. Abouliatim, C. De Place, P. Tattevin, M. Revest, P. Y Donnio, F. Alla, J. P. Carteaux, T. Doco-Lecompte, C. Lion, N. Aissa, C. Selton-Suty, B. Baehrel, R. Jaussaud, P. Nazeyrollas, C. Strady, V. Vernet, E. Cambau, X. Duval, B. Iung, P. Nataf, C. Chidiac, M. Celard, F. Delahaye, J. F. Obadia, F. Vandenesch, H. Aumaître, J. M. Frappier, V. Le Moing, E. Oziol, A. Sotto, and C. Sportouch. Centre National de Référence des Streptocoques: C. Poyart and A. Bouvet. Centre National de Référence des Staphylocoques: F. Vandenesch, M. Celard, and M. Bes. Investigators: P. Abassade, E. Abrial, C. Acar, N. Aissa, J. F. Alexandra, N. Amireche, D. Amrein, P. André, M. Appriou, M. A. Arnould, P. Assayag, A. Atoui, F. Aziza, N. Baille, N. Bajolle, P. Battistella, S. Baumard, A. Ben Ali, J. Bertrand, S. Bialek, M. Bois Grosse, M. Boixados, F. Borlot, A. Bouchachi, O. Bouche, S. Bouchemal, J. L. Bourdon, A. Bouvet, L. Brasme, F. Bricaire, E. Brochet, J. F. Bruntz, A. Cady, J. Cailhol, M. P. Caplan, B. Carette, J. P. Carteaux, O. Cartry, C. Cazorla, M. Celard, H. Chamagne, H. Champagne, G. Chanques, J. Chastre, B. Chevalier, C. Chirouze, F. Chometon, C. Christophe, A. Cohen, N. Colin de Verdiere, N. Danchin, V. Daneluzzi, L. David, P. De Lentdecker, F. Delahaye, V. Delcey, P. Deleuze, E. Donal, X. Duval, B. Deroure, V. Descotes-Genon, K. Didier Petit, A. Dinh, V. Doat, F. Duchene, F. Duhoux, M. Dupont, S. Ederhy, O.
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Research Original Investigation
Skin Manifestations of Infective Endocarditis
Epaulard, M. Evest, J. F. Faucher, B. Fantin, E. Fauveau, T. Ferry, M. Fillod, T. Floch, T. Fraisse, J. M. Frapier, L. Freysz, B. Fumery, B. Gachot, S. Gallien, I. Gandjbach, P. Garcon, A. Gaubert, J.L. Genoud, S. Ghiglione, C. Godreuil, A. Grentzinger, L. Groben, D. Gherissi, P. Guéret, A. Hagege, N. Hammoudi, F. Heliot, P. Henry, S. Herson, B. Hoen, P. Houriez, L. Hustache-Mathieu, O. Huttin, S. Imbert, B. Iung, S. Jaureguiberry, M. Kaaki, A. Konate, J. M. Kuhn, S. Kural Menasche, A. Lafitte, B. Lafon, F. Lanternier, V. Le Chenault, V. Le Moing, C. Lechiche, S. Lefevre, Thibaut, A. Lefort, A. Leguerrier, J. Lemoine, L. Lepage, C. Leport, C. Lepousé, J. Leroy, P. Lesprit, L. Letranchant, D. Loisance, G. Loncar, C. Lorentz, P. Mabo, I. Magnin-Poull, T. May, A. Makinson, H. Man, M. Mansouri, O. Marçon, J. P. Maroni, V. Masse, F. Maurier, M. C. Meyohas, P. L. Michel, C. Michelet, F. Mechaï, O. Merceron, D. Messika-Zeitoun, Z. Metref, V. Meyssonnier, C. Mezher, S. Micheli, M. Monsigny, S. Mouly, B. Mourvillier, O. Nallet, P. Nataf, P. Nazeyrollas, V. Noel, J. F. Obadia, E. Oziol, T. Papo, B. Payet, A. Pelletier, P. Perez, J. S. Petit, F. Philippart, E. Piet, C. Plainvert, B. Popovic, J. M. Porte, P. Pradier, R. Ramadan, M. Revest, J. Richemond, M. Rodermann, M. Roncato, I. Roigt, O. Ruyer, M. Saada, J. Schwartz, C. Selton-Suty, M. Simon, B. Simorre, S. Skalli, F. Spatz, C. Strady, J. Sudrial, L. Tartiere, A. Terrier De La Chaise, M. C. Thiercelin, D. Thomas, M. Thomas, L. Toko, F. Tournoux, A. Tristan, J. L. Trouillet, L. Tual, A. Vahanian, F. Verdier, V. Vernet Garnier, V. Vidal, P. Weyne, M. Wolff, A. Wynckel, N. Zannad, and P. Y. Zinzius. Additional Contributions: Janet Jacobson provided editorial assistance. We thank the Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse Study Group for sharing their data. These individuals did not receive compensation for their help. REFERENCES 1. Hoen B, Duval X. Clinical practice: infective endocarditis. N Engl J Med. 2013;368(15):14251433. 2. Moreillon P, Que YA. Infective endocarditis. Lancet. 2004;363(9403):139-149. 3. Que YA, Moreillon P. Infective endocarditis. Nat Rev Cardiol. 2011;8(6):322-336. 4. Miro JM, Anguera I, Cabell CH, et al; International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis. Clin Infect Dis. 2005;41(4):507-514. 5. Hoen B, Alla F, Selton-Suty C, et al; Association Pour l’Etude et la Prévention de l’Endocardite Infectieuse (AEPEI) Study Group. Changing profile of infective endocarditis. JAMA. 2002;288(1):75-81.
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