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Introduction
The
epidemiology, clinical, and microbiologic spectrum of
infective endocarditis (IE) is significantly different
in the developing countries compared to the western
world. These differences can be attributable to multiple
factors present in poorer countries including
significantly higher incidences of rheumatic heart
disease and uncorrected congenital heart disease,
excessive and improper use of antibiotics, late clinical
presentation, and worse outcomes.1,2 In
addition, developing countries may have a higher
incidence of ‘culture negative endocarditis’ than in the
west, largely secondary to prior doctor-prescribed or
self-administered antibiotic use3,4, and
life-threatening complications from IE are still common
despite echocardiographic diagnosis and use of effective
antibiotics.5
There is a
paucity of published reports about IE from developing
regions of the world5,6, and there are no
large case series from centers involved in cardiac
intervention and surgery. In light of the changing
global trends in endocarditis over the last four
decades, further insight into the clinical expression of
the disease in developing countries and a comparison
with western data is warranted. The authors have
previously conducted the first case series of
endocarditis from Pakistan. The study showed that
life-threatening complications from endocarditis are
still common despite the use of effective antibiotics
and echocardiographic diagnosis.5 Herein, we
present one of the largest case series on IE from the
Indian subcontinent.
Patients and
Methods
We reviewed the
medical records of all patients admitted to the Aga Khan
University Hospital in Karachi, Pakistan with a
diagnosis of IE during the period, January 1988 through
December 2001. The Aga Khan University Hospital is a
tertiary care hospital serving more than 10 million
people of the city, the surrounding province of Sindh,
and elsewhere throughout Pakistan. The patient
population includes a large number of immigrants from
around the country and referrals from underserved rural
areas where rheumatic heart disease and undetected
congenital heart disease are very common. The mean
number of medical adult medicine and pediatric
admissions during the study period was more than 13,000
patients annually.
The search was
made through electronically-coded medical records and
the echocardiography logbook maintained by the Cardiac
Diagnostic Laboratory. One hundred and eighty-eight
patients were identified with suspected endocarditis. Of
these, 159 patients fulfilled the modified Duke criteria7,
and were included in the final analysis. We used the
modified Duke criteria in order to validate our
results. Cases were defined clinically as “definite” if
they fulfilled two of the Duke major criteria, one major
plus three minor criteria, or five minor criteria; they
were defined as “possible” if they fulfilled one major
plus one minor criteria, or three minor criteria.
“Acute” endocarditis was defined as beginning suddenly
with a high fever (102° to 104°F [38.9° to 40°C]), fast
heart rate, fatigue, and rapid and extensive heart valve
damage. “Subacute”endocarditis was defined as symptoms
of fatigue, mild fever (99° to 101° F [37.2° to
38.3°C]), moderately fast heart rate, weight loss,
sweating, a low red blood cell count, all generally
occurring for months before diagnosis.
The laboratory
workup of the study group included: complete blood
count, erythrocyte sedimentation rate, serum creatinine,
serum electrolytes, urinalysis and urine culture, chest
x-ray, blood cultures (3-5 sets of aerobic and anaerobic
bottles) drawn before the initiation of antibiotics,
transthoracic echocardiography (TTE) and, if needed,
transesophageal echocardiography (TEE). In cases with
negative blood cultures, abdominal ultrasonography, and
where appropriate, Mantoux skin testing and sputum for
acid-fast bacilli smear and culture were performed. In
patients with fever and headache or with neurologic
signs, cerebrospinal fluid examination and neuroimaging
(computed tomography or magnetic resonance imaging) were
conducted. In selected cases, an autoimmune profile was
obtained. A peripheral blood smear looking for malarial
parasites was performed in all subjects with unexplained
fever. Fungal blood cultures were sent in selected
cases.
Statistical
analysis
Statistical
analysis of data was performed using the computerized
software program SPSS version 13.0. Descriptive
statistics were presented as percentages and as mean +/-
standard deviation (SD). Univariate analysis was
performed for prognostic factors of mortality using
Pearson’s chi square test, Fischer’s exact test, or
student’s t test, where appropriate. A p value of < 0.05
was considered statistically significant.
Results
General
characteristics
One hundred and
fifty-nine patients with IE were identified according to
the modified Duke criteria, and their general
characteristics are shown in Table 1. The annual number
of IE episodes during the study period was 0.87 per
1,000-hospital medical admissions. Mean patient age was
34 years + 21.2 SD (range, < 1 month to 87 years), and
34 (27%) patients were < 16 years of age. The mean age
for patients > 16 years was 42 +/- 16.7 (SD). The male:
female ratio was 1.8:1. Nosocomial endocarditis was seen
in five patients (3%). One-third of subjects had acute
endocarditis and the remainder had subacute IE. Of the
159 subjects, 86 (54%) were classified as having
culture-negative endocarditis and 73 (46%) as having
culture-positive endocarditis. Sixty percent of patients
had definitive endocarditis according to the Duke
criteria while the rest had possible endocarditis.
Underlying
predisposing factors
Overall, 94
patients (59%) had an underlying predisposing factor
(Table 2). Most commonly encountered risk factors
included congenital heart disease (25%), most commonly a
ventricular septal defect and rheumatic heart disease
(21%). Other important conditions were mitral valve
prolapse with regurgitation (6%), prosthetic valve
endocarditis (5%), and stenotic aortic valve disease
(2%). Only one patient had documented history of
intravenous drug use. Two patients were on dialysis with
indwelling central catheters.
Microbiology
Causative
microorganisms included streptococci (23%),
staphylococci (13%; equally split between Staphylococcus
aureus and Staphylococcus epidermidis), Gram-negative
bacilli (5%), and Enterococcus faecalis (4%) (Table 3).
Eighty-six subjects (54%) had no growth on multiple
blood cultures and were thus classified as
culture-negative IE.
Echocardiography
Echocardiography was performed in 155 of 159 (97%)
patients: TTE in 152 (96%) and TEE in 20 (13%) patients.
TTE was positive in 110 of 152 (72%) subjects and TEE in
15 of 20 subjects (75%). Fourteen (8%) patients had
right-sided cardiac involvement. The distribution of
valves and other significant findings on
echocardiography can be seen in Table 3.
Treatment
The
antibiotic therapy used in our patients conformed in
most cases to the guidelines of the American Heart
Association for the treatment of IE. Sixty-eight percent
of patients with streptococcal infections were treated
with a combination of penicillin plus an aminoglycoside
(gentamicin). The remainder received monotherapy with a
beta-lactam or a glycopeptide (vancomycin or
teicoplanin). Methicillin-sensitive staphylococci (62%
of all staphylococci isolated) were treated with
cloxacillin; subjects with methicillin-resistant
Staphylococcus aureus (MRSA) or Staphylococcus
epidermidis (MRSE) received vancomycin. Aminoglycosides
were added for synergy in one-third of MRSA subjects,
while rifampin was added in only one patient.
Sixty-eight percent of patients with culture-negative
endocarditis received a combination containing at least
one beta-lactam drug (penicillin G with or without
cloxacillin) and an aminoglycoside; 12% patients also
received vancomycin and 21% also received a
3rd-generation cephalosporin. All patients received 4-6
weeks of antimicrobial therapy. Surgical intervention
was required in 18 (11%) of the study group, with the
most common indications being heart failure refractory
to medical treatment, valve or myocardial abscess,
prosthetic valve endocarditis, very large vegetations,
systemic embolization, or IE refractory to medical
treatment.
Complications
and outcome
Complications occurred in about half of the study group
and included neurologic (26%), cardiac (25%), renal
(13%), hematologic (13%), embolic (10%), pneumonic (8%),
and septic (4%) complications (Table 4). Thirty-seven
(23%) patients died of IE or its complications. Mean
patient follow-up was 3.5 months. Twenty-one patients
were lost to follow-up.
Risk factors for
mortality
Table 5
demonstrates the risk factors for mortality using
univariate analysis. In general, patients with
neurological, cardiac, or renal complications or sepsis
were at increased risk of dying. Nosocomial endocarditis
was also associated with an increased mortality. No
individual microorganism, or specific site, size, or
morphology of vegetation seen on echocardiogram were
significantly associated with death. Patients with
previous cardiac surgery, especially those with
prosthetic valve endocarditis, were also at increased
risk of death.
Discussion
This study
represents one of the largest case series of IE reported
from the Indian subcontinent, and our data confirm that
IE continues to be an important cause of morbidity and
mortality in Pakistan. The spectrum of IE in our
country differs from the west with respect to
epidemiology, predisposing factors, microbiology, and
outcome but is similar to that reported from neighboring
India.8-12
The young age of
our study group (mean age, 34 years) is consistent with
other studies from the region,9,10,13, but
contrasts an older group (mean age 45-60 years) for
patients with IE in the west.14-17 The
reasons for this discrepancy are likely multifactorial
and include a higher incidence of rheumatic heart
disease and uncorrected congenital heart disease in
poorer countries like Pakistan, and a more aged
population with a higher incidence of degenerative heart
disease in the west.13,14,16
We have
previously reported on the impact of prior antibiotic
use in culture-negative endocarditis.18 Prior
antibiotic therapy before clinical presentation (seen in
52% of our study group) was the primary contributor to
the high incidence (54%) of negative blood cultures in
our series. This incidence is consistent with the low
yield from blood cultures, ranging from 21 to 67%,
reported from elsewhere on the subcontinent.5,6,10,13,14
In contrast, studies from industrialized counties report
a diagnostic yield from blood cultures as high as 90% or
more.13-16 Excessive antibiotic dispensing is
common in developing countries; at least one antibiotic
may be prescribed for 54%-62% of patients presenting to
general practitioners in Pakistan.3,4 In
addition, self-administration of antibiotics is
commonplace in many developing countries where drugs are
freely available and accessible without a prescription.
As in the west, we assume that inadequate microbiologic
techniques and infections with highly fastidious
bacterial or non-bacterial microorganisms are other less
likely reasons for negative blood cultures in our
patients.
The Duke and
modified Duke criteria both depend on echocardiographic,
microbiologic, and pathologic criteria and patients with
clinically-suspected IE are classified as “definite”,
“probable”, and “rejected” cases based upon these
criteria.7 The degree of certainty of the
diagnosis of IE often depends on the presence or absence
of only one criterion. The modified Duke diagnostic
criteria are heavily based upon positive blood cultures,
and a low microbiologic yield from blood culture raises
questions as to the validity of these criteria in
diagnosing culture-negative endocarditis in developing
countries.17 More than 60% of our subjects
with blood culture-negative endocarditis had ‘possible
endocarditis’ according to the Duke criteria compared to
< 15% of patients with positive blood cultures (p <
0.001, 95% CI 0.07-0.3). Furthermore, 29 patients
diagnosed and treated for clinically presumptive IE were
rejected from study entry according to the Duke criteria
and negative blood cultures. In a study of the
individual value of each of the Duke criteria for the
diagnosis of IE, Rognon and colleagues found that the
major microbiologic criteria had the highest relative
importance.19 Similarly, Tissieres and
coworkers demonstrated the importance of positive blood
cultures as a major IE criterion, with echocardiographic
findings playing a less important role in diagnosis.20
A positive blood culture was the only criterion that
differentiated “definite” from “possible” IE. Thus, for
patients with clinically-suspected IE, but with
persistently negative blood cultures (54% of our entire
study cohort), the negative predictive value of the
modified Duke criteria could be significantly
compromised.
During the
1990s, a significant change occurred in the microbiology
of IE in the west. By the end of the decade, S aureus
had overtaken viridans streptococci as the most
frequently isolated pathogen, accounting for nearly
30-40% of cases.15,16,21 This microbiologic
trend may be attributable to an aging population, more
frequent intravenous drug use in the community, and an
increased frequency of nosocomial, prosthetic valve, and
iatrogenic endocarditis. In contrast, rheumatic and
congenital heart diseases account for the majority of
our IE cases, prosthetic valve insertion is infrequently
performed, and thus, streptococci still dominate our
patient population, as in other studies from poorer
countries.5,8,22 Previous studies have shown
S aureus to be an independent predictor of mortality.15,16,21
We did not encounter an increased mortality in patients
with S aureus IE, and this may be because staphylococcal
infection in the west is seen in different, high-risk
patient populations, occurring in individuals with
nosocomial, iatrogenic, hemodialysis-related or
prosthetic valve infection.
Like elsewhere
on the Indian subcontinent, rheumatic heart disease and
congenital heart disease continue to be the most
important causes of IE in Pakistan. This is consistent
with other studies from this part of the world.8-10
Right-sided endocarditis has a prevalence of 5-10% in
the west, and most of these cases are attributed to
parenteral drug abuse.23,24 Fourteen (9%) of
our patients had right-sided endocarditis but only one
subject had a history of iv drug use. More than half of
these patients had congenital heart disease and
one-quarter had prior corrective cardiac surgery.
Right-sided endocarditis in non-iv drug users has been
previously reported from the Indian subcontinent and
attributed to anatomic cardiac defects largely from
congenital heart disease.25-27 These defects
are generally corrected in early life in developed
countries; usually in pre-school years and thus do not
manifest as IE in later years. We found no particular
microorganisms associated with right-sided endocarditis,
in contrast to the west where S aureus and P. aureginosa
are the major causes of tricuspid valve infection.23-24
Unlike in the
west where addict-associated IE generally has a better
prognosis, subjects in our study cohort with right-sided
endocarditis had no difference in mortality compared to
patients with left-sided IE. They did, however, have
fewer neurologic complications and peripheral emboli,
and more pneumonia and larger vegetations.
Studies from
industrialized countries have shown a consistent
improvement in survival of patients with IE over the
past four decades, with mortality recently reported
between 15%–33%.11,14,28,29 A
similar decrease in mortality is also seen in patients
from the Indian subcontinent: 42% in 197012,
20.3% in 198110, 21%–25% in 19929,30,
13.9% in 199831, and 13% in 20016.
The higher in-hospital mortality in our study (23%) may
be explained by the fact that the Aga Khan University is
a tertiary care referral center representing a skewed
population of complicated cases. We did not find valve
site or vegetation size or morphology to significantly
correlate with mortality, stroke, or peripheral
embolism. As expected, prosthetic valve endocarditis,
and neurologic, renal, cardiac, and peripheral
complications were all associated with an increased risk
of death.32-34 Other authors have observed
similar associations with kidney and heart complications
and prosthetic valve infection9,32,34,35, and
in 1992 Choudhry and colleagues reported from India that
patients with neurologic complications had a higher
incidence of death from IE.9 Others have
also reported prosthetic valve endocarditis and systemic
embolism as independent risk factors of mortality.33,35
Death in five patients who developed IE >72 hrs in the
hospital was very high (60%). This is consistent with a
recent series from Madrid, where nosocomial infection
accounted for 22% of IE patients, and resulted in a very
high mortality (>50%).36 These infections
are often related to intravenous catheters or surgical
procedures, and fewer than 50% of patients have
underlying structural heart disease.16
Our study has
several limitations. First, the ‘true’ microbiology of
our cases could not be determined because many of the
patients received prior antibiotic therapy prior to
diagnosis, and because serology and polymerase chain
reaction testing for fastidious organisms such as
Brucella, Bartonella, Coxiella, and other rare causes of
endocarditis were not performed. Second, only 20
patients (13%) underwent transesophageal
echocardiography; the prevalence of culture-negative
endocarditis may have increased if TEE had been
performed on all patients. Finally, being a tertiary
care referral center our data may not truly represent
endocarditis in the general community and may be skewed
towards a sicker patient population, although they may
be comparable to results from other academic centers.
Conclusion
In conclusion,
endocarditis continues to be an important contributor to
morbidity and mortality in Pakistan, especially among
young adults. Our patients differ from those seen in the
west in terms of epidemiology, predisposing factors,
microbiology, complications, and outcome.
Culture-negative endocarditis continues to have a high
prevalence in developing countries like Pakistan,
largely due to prior antibiotic use before clinical
presentation. We believe that this practice may lead to
a decreased sensitivity of the Duke criteria in
diagnosing endocarditis. Further studies are needed to
validate the negative predictive value of the Duke
criteria in developing countries. Clinicians in
countries like Pakistan should be advised to maintain a
high index of suspicion of endocarditis and send blood
cultures or refer appropriately before prescribing
antibiotics.
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