Tleyjeh IM, Steckelberg JM, Murad HS, Anavekar NS, Ghomrawi HMK, Mirzoyev Z, Moustafa SE, Hoskin TL, Mandrekar JN, Wilson WR, Baddour LM. Temporal Trends in Infective EndocarditisA Population-Based Study in Olmsted County, Minnesota. JAMA. 2005;293(24):3022-3028. doi:10.1001/jama.293.24.3022
Author Affiliations: Department of Medicine
(Drs Tleyjeh, Steckelberg, Anavekar, Mirzoyev, Wilson, and Baddour), Division
of Infectious Diseases (Drs Tleyjeh, Steckelberg, Wilson, and Baddour), Department
of Physiology and Biomedical Engineering (Dr Moustafa), and Division of Biostatistics
(Ms Hoskin and Dr Mandrekar), Mayo Clinic College of Medicine, Mayo Clinic,
Rochester, Minn; Department of Medicine, Michael Reese Hospital/University
of Illinois at Chicago (Dr Murad); Division of Health Services Research and
Policy, University of Minnesota, Minneapolis (Mr Ghomrawi); and Division of
Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario (Dr Moustafa).
Context Limited data exist regarding population-based epidemiologic changes
in incidence of infective endocarditis (IE).
Objective To evaluate temporal trends in the incidence and clinical characteristics
Design, Setting, and Patients Population-based survey using the resources of the Rochester Epidemiology
Project of Olmsted County, Minnesota. One hundred seven IE episodes occurred
in 102 Olmsted County residents between 1970 and 2000. The modified Duke criteria
were used to validate the diagnosis of definite or possible IE.
Main Outcome Measures Incidence of IE, proportion of patients with underlying heart disease,
and causative microorganisms and clinical characteristics.
Results Age- and sex-adjusted incidence of IE ranged from 5.0 to 7.0 cases per
100 000 person-years during the study period and did not change significantly
over time (P = .42 for trend). Infective
endocarditis caused by viridans group streptococci was the most common organism-specific
subgroup, with an annual adjusted incidence of 1.7 to 3.5 cases per 100 000;
in comparison, IE due to Staphylococcus aureus had
an annual adjusted incidence of 1.0 to 2.2 cases per 100 000. No time
trend was detected for either pathogen group (P = .63
and P = .66, respectively). An increasing
temporal trend was observed in the proportions of prosthetic valve IE cases
(P = .09). Among people with underlying
heart disease, there was an increasing temporal trend in mitral valve prolapse
(P = .04) and a decreasing trend in rheumatic
heart disease (P = .08). However, the absolute
numbers were small. There was no time trend in rates of valve surgery or 6-month
mortality during the study period (P = .97
and P = .59, respectively).
Conclusions In this community-based temporal trend study, we found no substantial
change in the incidence of IE over the past 3 decades. Viridans group streptococci
continue to outnumber S aureus as the most common
causative organisms of IE in this population.
The representativeness heuristic of the clinical features of infective
endocarditis (IE) as described by Osler has undergone a significant change
in developed countries.1,2 Previously,
IE was a disease that commonly affected patients with predisposing valvular
abnormalities caused by rheumatic carditis, with viridans group streptococci
the most common causative pathogens.3 This
presentation is currently seen in developing countries, where rheumatic heart
disease is still prevalent. In developed countries, mitral valve prolapse
(MVP) is now thought to be the most common predisposing cardiac condition
in patients with IE.2 Several recent studies
from passively reported case series suggest that Staphylococcus
aureus is now the most frequently identified causative pathogen.1 These more recent clinical observations of IE characteristics,
however, are based on data that come primarily from large, tertiary care centers4,5 and may not reflect true changes in
the epidemiology of IE but rather temporal changes in referral patterns. Thus,
population-based investigations are needed to more accurately characterize
IE in the United States.
Olmsted County, Minnesota, is a setting uniquely qualified for the conduct
of population-based studies of disease epidemiology. The Rochester Epidemiology
Project has been continuously supported by the US federal government for more
than 30 years6 and has played a pivotal role
in the examination of disease epidemiology. Key features of the project and
the county include6 that: (1) the local population
is relatively isolated from other urban centers and receives the majority
of its care from a small number of health care practitioners; (2) medical
care is largely self-contained within the community; (3) medical, surgical,
and pathological diagnoses are identified in a computerized central index
covering essentially all sources of medical care (both inside and outside
of Mayo Clinic) used by county residents; and (4) the original medical records
of all inpatient and outpatient care are readily available for review. Thus,
essentially complete ascertainment of IE cases in Olmsted County is possible
and all details of medical care provided to the residents are available for
study.3 We therefore conducted a community
surveillance study of patients with IE from Olmsted County during the period
1970-2000. We evaluated trends in the incidence and clinical characteristics
of IE that occurred in a population-based cohort spanning 31 years.
The characteristics of Olmsted County are similar to those of US non-Hispanic
whites.6 This population consists largely of
middle-class whites, with a low prevalence of injection drug abuse.7 The Mayo Clinic and Olmsted Medical Center provide
the majority of medical care for the population as developed in geographic
isolation from other urban centers. Today, the closest competing medical centers
are in Minneapolis, Minn (139.2 km to the north), LaCrosse, Wis (113.6 km
to the east), Iowa City and Des Moines, Iowa (316.8 and 332.8 km to the south,
respectively), and Sioux Falls, SD (376 km to the west). Although best known
as a tertiary referral center, the Mayo Clinic has always also provided primary
and secondary care to local residents. Because Mayo Clinic and Olmsted Medical
Center offer care in every medical and surgical specialty and subspecialty,
local residents are not obliged to seek clinicians throughout a large region
but are able to obtain most of their health care within the community.6
Because virtually all clinicians in Olmsted County participate in the
Rochester Epidemiology Project, any endocarditis case that was treated in
Olmsted County would have almost certainly come to our attention. Even for
Olmsted County residents who are diagnosed and treated elsewhere, upon return
to the county the diagnosis will be noted in their medical records unless
the patient dies elsewhere. Furthermore, the population is relatively stable,
particularly among the older age groups. For example, the median length of
follow-up available for residents 50 to 59 years of age is 29 years. For these
reasons and because of the rarity and severity of IE, it would be very unusual,
albeit possible, for an IE case to be missed.
Olmsted County medical institutions use a unit medical record system
in which information is collected by health care clinicians in a single record
for each patient. These records are easily retrievable through the Rochester
Epidemiology Project, which links and indexes diagnostic and procedure information
from virtually all sources of health care in the county into a single centralized
system. Adult (≥18 years) cases of IE among Olmsted County residents were
identified using this system. Cases that were diagnosed at autopsy were also
included. In addition, we used prospectively collected records maintained
by the Division of Infectious Diseases at Mayo Clinic of all patients with
IE seen in consultation by division members. The medical records of all possible
cases were then reviewed to confirm the diagnosis of IE. All cases judged
problematic were reviewed with a more experienced investigator (J.M.S.).
New IE episodes that occurred during the study period in patients with
a previous history of endocarditis were included; 3 cases of posttreatment
IE relapse were excluded. All potential cases were screened according to specific
case definition listed below, and 107 episodes of endocarditis were identified
for study. The institutional review boards at Mayo Clinic and Olmsted Medical
Center approved the study and waived the requirement for informed consent.
Case definitions of IE have changed over time and include both the widely
used Beth Israel8 and Duke9 criteria.
Cases were identified in the current investigation by the modified Duke criteria.10 Several approaches were taken to ensure complete
ascertainment of all IE cases. First, we screened all IE cases that were defined
before the introduction of the Duke criteria in 1994. In addition, we sought
cases that were rejected because they did not fulfill the Beth Israel criteria
but were considered likely IE cases and administered empirical therapy for
One of the investigators (I.M.T.) reviewed all cases and classified
them according to the modified Duke criteria, the validity of which has been
previously demonstrated.10 To assess the reliability
of our case-classification procedure, another senior investigator (L.M.B.)
independently reviewed and classified 20 IE cases selected randomly. There
was 100% agreement on case classification.
We performed several steps to ensure reliability and inclusion of good-quality
data. First, we used a standardized data abstraction form with detailed definitions
of the variables. Demographic data as well as clinical, laboratory, and outcome
data were abstracted from the complete (inpatient and outpatient) medical
records using a precoded data collection instrument. Variables were obtained
from thorough review of the medical record, including daily physicians’
progress notes and all subspecialty consultations. Nearly all patients were
followed up daily in the hospital by infectious diseases and cardiology subspecialists,
with additional consultations when indicated. Any uncertainties in data abstraction
were discussed with an experienced investigator (J.M.S. or L.M.B.).
Ascertainment of death at 6 months was obtained from medical records
in the majority of cases and was supplemented by the recording of all obituaries
and notices of deaths by the Mayo Clinic registration office and the National
For calculating incidence rates, the adult population (≥18 years)
of Olmsted County was considered to be at risk; the denominator age- and sex-specific
person-years were derived from decennial census figures. Intercensus figures
were estimated using high-degree polynomial interpolation. Ninety-five percent
confidence intervals (CIs) for IE rates were estimated assuming that the incidence
cases follow a Poisson distribution. Rates were age- and sex-adjusted to the
population of whites in the United States in 2000. A Poisson regression model
(GENMOD procedure, SAS version 8; SAS Institute Inc, Cary, NC) was used to
examine the temporal trends in the incidence of IE, with categorical year
variables. Exact Wilcoxon tests for the ordered contingency table, in the
case of categorical characteristics, were used to study time trends. The Spearman
rank correlation coefficient was used to assess whether there was a significant
temporal trend in age at diagnosis.
Definite and possible IE cases as defined by the modified Duke criteria
were used in the analysis. A sensitivity analysis excluded all possible cases
and included only definite cases in order to examine the effect of disease
misclassification. We also performed a second sensitivity analysis that included
only native valve IE cases. All analyses were conducted in SAS version 8.
The level of significance for all statistical tests was 2-sided, with P<.05.
One hundred seven IE episodes occurred in 102 patients during the study
period. The characteristics of the cohort are summarized in Table 1.
Table 2 summarizes the distribution
of underlying heart disease, risk factors, and causative microorganisms. Mitral
valve prolapse was the most frequent underlying valvular heart disease. Eighty-six
percent of IE cases were caused by either streptococcal or staphylococcal
species. Viridans group streptococci were the most common causative organisms
and were isolated in 47 cases (44%); S aureus was
identified in 28 cases (26%).
The Olmsted County adult population ranged from approximately 51 000
in 1970 to 90 000 in 2000. The overall average crude IE incidence for
the period 1970-2000 was 4.95 per 100 000 person-years. The age- and
sex-adjusted annual incidence was 6.06 per 100 000 (95% CI, 4.89-7.22).
Incidence. The overall adjusted incidence of
IE ranged from 5.0 to 7.0 cases per 100 000 person-years during the study
period and did not change significantly over time (P = .42
for trend) (Figure 1). Infective endocarditis
continues to be a disease of older individuals, with a mean age ranging from
54.1 years in 1980-1984 to 67.4 years in 1995-2000 (P = .24
for trend). There was a male predominance (67%-83%), which did not significantly
change over time (Table 3).
Causative Organisms. Viridans group streptococcal
IE was the most common organism-specific IE subgroup, with an annual adjusted
incidence of 1.7 to 3.5 cases per 100 000 person-years. Staphylococcus aureus IE had an annual adjusted incidence of 1.0 to
2.2 cases per 100 000. No time trend was detected for either pathogen
group (P = .63 and P = .66, respectively) (Figure
Underlying Heart Disease and Infected Valves.Table 3 summarizes the time trend of different
IE characteristics. There was a nonsignificant declining trend over time in
the proportion of cases with underlying rheumatic heart disease (P = .08). The proportions of cases with MVP and congenital
heart disease did not change significantly over time (P = .19 and P = .82, respectively,
for trend). In the subgroup of IE cases with identified underlying heart disease,
there was a significant increasing trend in MVP over time (P = .04) and a decreasing trend in rheumatic heart disease
(P = .08). However, the absolute numbers
were small. The proportions of IE cases with aortic valve involvement (19%-54%)
decreased over time (P = .02). An increasing
trend was detected in the proportions of IE cases with prosthetic valve involvement
(P = .09).
Outcome. There was no significant time trend
in rates of valve surgery or in 6-month mortality over the 31-year study period
(P = .97 and P = .59,
respectively). Six-month mortality rates ranged from 14% to 33% (Table 3).
Limiting the analysis to Duke criteria definite IE cases did not substantially
change incidence compared with when both definite and possible cases were
included. The adjusted IE incidence ranged from 3.2 to 6.6 cases per 100 000
person-years, with the lowest incidence in the period 1970-1974. During the
period 1970-1974 and before the introduction of echocardiography, one half
of the cases (n = 6) were excluded because they were designated
Duke criteria possible (Table 4). Viridans
group streptococci remained the most common cause of IE, followed by S aureus. There were no trends over time in IE incidence
caused by either organism. Similar findings were observed when the analysis
was restricted to native valve IE cases (Table
We postulated that transesophageal echocardiography, which was introduced
in the mid 1980s, might affect any observed trend over time because of detection
bias. Therefore, we compared the different incidences between the 1970-1984
and 1985-2000 periods. There was no significant difference in overall or organism-specific
IE incidence (Table 5).
There were 4 IE cases in 2001 (2 due to viridans group streptococci,
1 due to Cardiobacterium hominis from the HACEK group, and 1 culture-negative),
with an annual adjusted incidence of 4.65 (95% CI, 2.34-9.23). A complete
enumeration of all IE cases in the county after 2001 was not possible because
capture of all diagnoses through the medical records linkage system was not
completed at the time of study.
The Rochester Epidemiology Project provides a unique opportunity to
investigate trends in IE epidemiology among residents of Olmsted County, Minnesota.
In this geographically defined community, the incidence of IE has remained
stable during the past 3 decades. The adjusted incidence of IE ranged from
5.0 to 7.0 cases per 100 000 person-years. The broader diagnostic criteria
that include Duke definite and possible classifications identified slightly
more IE cases than did the stricter Duke definite classification alone, but
the incidence remained stable, irrespective of the diagnostic criteria used.
The adjusted annual incidence was 5.4 per 100 000 (95% CI, 3.7-7.2) for
the period 1970-1984 and 6.5 per 100 000 (95% CI, 5.0-8.1) for the period
1985-2000 (P = .29). A recent study from
France with a larger sample size observed a small decrease in the annual incidence
of definite IE, from 3.1 cases per 100 000 in 1991 to 2.6 per 100 000
in 1999.11 However, it was not designed to
study temporal trends in IE.
Our results support the recent conclusion that despite improvements
in health care over the past 30 years, the incidence of IE has not decreased.1 At least 2 potential factors may contribute to this
finding. First, there may have been a true overall decline in IE incidence,
which was concealed by a detection bias with better blood culture techniques
and more frequent use of echocardiography. Second, an increase in incidence
caused by a more frequent use of echocardiography may have been offset, in
part, by a declining number of autopsy-diagnosed cases.12
We observed that IE continues to be a disease predominately affecting
older men, a finding consistent with other studies.11,13,14 In
the last 5 years of our study, the majority of IE cases occurred in patients
with no known underlying heart disease. This finding is consistent with a
recent study.11 There was a declining trend
in proportion of rheumatic heart disease and an increasing trend in prosthetic
valve and MVP proportions over time, although these trends did not reach statistical
significance. However, absolute numbers were small, which made the proportions
unstable and could have led to a spurious observation of apparent temporal
trends as well as inadequate power to detect true ones.
We also observed that the incidence rates of viridans group streptococcal
and S aureus IE have not changed significantly over
time. Other groups have described an increasing frequency of S aureus IE15,16 or a decrease
in viridans group streptococcal IE,11,14,17 leading
to a general consensus that S aureus has surpassed
viridans group streptococci as the leading cause of IE.1 In
contrast, we found that viridans group streptococci continue to be the most
common cause of IE in the study population and that its incidence rate is
approximately twice that of S aureus. There are several
possible explanations for these discrepant findings. First, differences in
underlying at-risk populations may modify the organism-specific incidence
rates. For example, communities with a high prevalence of intravenous drug
use may observe an increased incidence of S aureus endocarditis.
The rate of intravenous drug use is low in our population compared with that
in other US populations, in which the rate of intravenous drug use among some
IE series is as high as 18%.15,18
A second possible explanation is underdiagnosis of IE among Olmsted
County patients with S aureus bacteremia. A high
proportion of S aureus IE cases can be missed clinically
and are only diagnosed at autopsy or with routine use of transesophageal echocardiography
in all patients with S aureus bacteremia. In a national
study of all S aureus IE cases in Denmark between
1982 and 1991, IE was not suspected clinically and was only diagnosed at postmortem
evaluation in 32% of the cases.19 Nevertheless,
because medical care is largely self-contained within the Olmsted County community,
patients with undiagnosed S aureus IE would ultimately
seek medical care at one of the Olmsted County hospitals.
Third, and most likely, differences may arise due to different study
design. The apparent increase in the proportion of IE cases due to S aureus in passively reported series from referral centers may be
artifactual due to changes in medical practice that affect likelihood and
patterns of referral.7
Our study has several important strengths. To our knowledge, it is the
first population-based study that examined trend changes of IE characteristics
in the US population over the past 2 decades. We used several approaches to
overcome different biases, including case ascertainment bias and disease misclassification,
that may have impacted the calculation of IE incidence in other work.
The essentially complete ascertainment of all IE cases in our study
by active search in a well-established medical record linkage system for a
population of known size and age distribution allows an unbiased and accurate
estimation of the IE incidence rate. Case ascertainment is a major problem
in studies of IE. Reported population-based studies have used 3 major types
of study design to identify all IE cases and include survey design11,15,18,20,21 and
national discharge registries,13,22 which
are affected by the voluntary nature of notification or a lack of standardized
diagnostic criteria and therefore incomplete case ascertainment.
We used 2 different sets of screening criteria to overcome disease misclassification,
which is another type of bias in population-based studies of IE. Disease misclassification
can be related either to case definition or to level of diagnostic certainty.
First, we applied a unique case definition (ie, the modified Duke criteria)
retrospectively to all identified cases to study trends in IE. Second, a sensitivity
analysis was conducted that excluded all possible cases and included only
definite cases to examine the effect of disease misclassification.
There are potential limitations to our study. First, the diagnosis of
underlying heart disease was obtained from medical records and was based primarily
on echocardiography and physician assessment without consistent pathological
confirmation. However, pathological ascertainment is impossible in all cases
because not all patients undergo valve surgery, die, or undergo a postmortem
evaluation. Second, the relative uniformity of the racial and ethnic composition
of Olmsted County and the low prevalence of intravenous drug use potentially
limits the ability to generalize the study’s findings to groups underrepresented
in the population. Finally, the sample size was small but provided 80% power
to detect a change in the incidence of IE of 3.1% or more per year, or a 2.56-fold
change during the 31 years of the study. However, this limitation was insurmountable
because a 3-decade study of secular trends in endocarditis would be difficult
in another population without the unique records-linkage system serving Olmsted
In conclusion, our community-based survey revealed no substantial change
in the incidence of IE over the past 3 decades. At least in the Olmsted County
population, viridans group streptococci continue to outnumber S aureus as the major causative organisms of IE.
Corresponding Author: Imad M. Tleyjeh, MD,
200 First St SW, Rochester, MN 55905 (firstname.lastname@example.org).
Author Contributions: Dr Tleyjeh had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Tleyjeh, Steckelberg,
Acquisition of data: Tleyjeh, Steckelberg,
Murad, Anavekar, Ghomrawi, Mirzoyev, Moustafa.
Analysis and interpretation of data: Tleyjeh,
Steckelberg, Ghomrawi, Hoskin, Mandrekar, Wilson, Baddour.
Drafting of the manuscript: Tleyjeh, Steckelberg,
Mirzoyev, Hoskin, Mandrekar, Baddour.
Critical revision of the manuscript for important
intellectual content: Tleyjeh, Steckelberg, Murad, Anavekar, Ghomrawi,
Moustafa, Mandrekar, Wilson, Baddour.
Statistical analysis: Tleyjeh, Hoskin, Mandrekar.
Obtained funding: Baddour.
Administrative, technical, or material support:
Steckelberg, Ghomrawi, Mirzoyev, Baddour.
Study supervision: Tleyjeh, Steckelberg, Wilson,
Financial Disclosures: None reported.
Funding/Support: This study was supported in
part by grants AR30582 from the Public Health Service and HL59205 from the
National Institutes of Health.
Role of the Sponsor: The funding organizations
had no role in the design and conduct of the study; the collection, management,
analysis, and interpretation of the data; or the preparation, review, or approval
of the manuscript.
Previous Presentation: Presented in part as
an abstract at the American College of Cardiology Scientific Meeting; March
6-9, 2005; Orlando, Fla.
Acknowledgment: We thank Jennifer L. St. Sauver,
PhD, for her generous advice and review of the manuscript and Barbara Yawn,
MD, for her help with study coordination.