Introduction

William Osler’s 1885 study of malignant endocarditis patients at Montreal General Hospital set a standard for clinical-pathophysiological correlation [1]. Subsequent studies using modern microbiological techniques and echocardiography have documented dramatic shifts in the profile of this disease [2]–[7] from predominantly sub-acute streptococcal infections of younger women with rheumatic heart disease to acute staphylococcal illnesses of older men with degenerative heart diseases or intravascular devices. These data have informed recommendations regarding prophylaxis and therapy.

Endocarditis incidence estimates have come from studies at referral hospitals [5] or from a single county or metropolitan area [8]. Since virtually all patients diagnosed with endocarditis are hospitalized, we analyzed a nationally representative sample of US hospital discharges between 1998 and 2009 to document the further evolution of this disease in the 21^st century.

Methods

Results

Hospital stays for IE rose from 28,195 in 1998 to 43,419 in 2009 (Table 1); this 54.0% increase exceeded the 13.1% growth in total hospital admissions (p<.0001). After adjustment for the 9.9% of IE hospital stays that ended in a transfer to another hospital within the NIS sampling frame, the number of unique endocarditis hospitalizations was 25,511 in 1998 (9.3 per 100,000 population) rising to 38, 976 in 2009 (12.7 per 100,000 population) (p<.0001). After adjustment for population aging and growth, endocarditis hospitalizations increased by 2.4% annually. Hence, the increase was not simply due to population aging.

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Table 1. Number of Hospital Stays, and Hospitalized Cases with Diagnosed Infective Endocarditis, Mean Length of Stay and Hospital Charges, 1998–2009.

https://doi.org/10.1371/journal.pone.0060033.t001

Mean LOS was 15.3 days and varied little over the 12 years of the study (p = .55). Mean hospital charges more than doubled in real terms from $45,542 ($59,941 in 2009 dollars) to $122,204. Adjustment for transfers to other acute care hospitals would increase these figures by about 10%. Both LOS and charges were about four times higher than the average for all diagnoses, a ratio that did not change over time.

Hospital charges and LOS varied little by age among adults aged 18–69, but were lowest for those 70 and older and highest for children.

Epidemiology

Table 2 displays demographic features of patients hospitalized with endocarditis. A majority (57.7%) were male. More than a third (36.4%) were age 70 and above. Most patients resided in zip codes with below average incomes. Most hospitalizations occurred in the South, the census region with the largest population. However, the Northeast had the highest rate per 100,000 population (15.8), 53% higher than in the Midwest (10.3) or West (10.3); the South had an intermediate rate (12.1). (All-cause hospitalization rates are similar in all regions except the West, where rates were about 20% lower). Among endocarditis patients, substance use and HIV were most common in the Northeast and least common in the Midwest.

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Table 2. Demographic, Other Patient, and Hospital Characteristics of Patients Hospitalized with Endocarditis, 1998–2009.

https://doi.org/10.1371/journal.pone.0060033.t002

Table 3 displays comorbidities and predisposing factors. Between 1998 and 2009 the mean age of endocarditis patients rose from 58.6 to 60.8 years. This shift reflects stable incidence rates in younger populations, and substantial increases in all age groups older than 50 (Figure1). Cases with comorbid drug use, HIV (or both) fell both absolutely, and as a share of all endocarditis hospitalizations; the proportion with HIV fell from 4.8% to 1.5%, while the share with a diagnosis of drug use (narcotics, cocaine or amphetamines) fell from 9.7% to 4.7%. The proportion of patients with a pre-existing cardiac valve replacement, implant or indwelling device rose 42%, from 13.3% in 1998 to 18.9% in 2009. The proportion on chronic dialysis was 4.4%, peaking in 2006 before declining.

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Table 3. Comorbidities and Predisposing Factors Among Cases of Diagnosed Infective Endocarditis, 1998–2009.

https://doi.org/10.1371/journal.pone.0060033.t003

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Figure 1. Infective endocarditis hospitalizations: rate per thousand population according to 5 year age groups: 1998 and 2009.

https://doi.org/10.1371/journal.pone.0060033.g001

Microbiology

An organism was coded for 62.3% of IE discharges in 1998, rising to 69.4% in 2009 (Table 4). Because most case series report rates of culture-negative endocarditis of less than 10%, it seems likely that about a quarter of endocarditis patients in the NIS had known microbiology that was not coded in the discharge summary. Patients with no coded organism were similar to patients with a bacteriologic diagnosis according to age, race, predisposing factors and most complications. However, they were slightly more likely to undergo valve replacement, to live in the South or in a poor zip code, be hospitalized in a rural hospital, and be female. Multiple organisms were mentioned in 4.2% of discharge records, a number that exceeds previous estimates of polymicrobial endocarditis. Some of these probably represent a second infection (e.g. pneumonia) during an endocarditis hospitalization. The data below (and in Table 4) should be interpreted with these caveats in mind.

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Table 4. Proportion of Cases of Infective Endocarditis Due to Specific Organisms, 1998–2009.

https://doi.org/10.1371/journal.pone.0060033.t004

The most common organism was Staphylococcus aureus, mentioned in 28.7% of discharge summaries (44.2% of summaries mentioning any organism), a proportion that increased by nearly one third, from 24.4% in 1998 to 32.0% in 2009. It was particularly common among patients with substance use, mentioned in 46.9% of those cases. Methicillin resistant S. aureus (MRSA) accounted for 53.3% of S. aureus among endocarditis discharges in 2009, the only year in which NIS identified methicillin-resistance. Other staphylococci were mentioned in 6.7% of discharges. Other organisms showed no marked trends. Streptococci were mentioned in 24.7% of discharge summaries, of which more than one quarter were labeled Group D (enterococci).

There was no change in the proportion (nor in overall IE incidence) of cases attributable to non-enterococcal streptococci (i.e. cases that might be affected by antibiotic prophylaxis) coincident with the 2007 change in recommendations regarding prophylaxis (p = .53 for comparison between rate trend for non-enterococcal streptococci, 1998–2006 vs. 2008–2009).

Gram-negative bacilli were mentioned in 5.6% of endocarditis patients’ discharge summaries, and Candida species in 1.0%.

Outcomes

Table 5 summarizes endocarditis outcomes; 14.5% of patients with a diagnosis of IE died in-hospital. Changes in the death rate over the 12 years of the study were negligible. The rate of valve replacement during the hospital stay did not change (p = .92), averaging 9.6% of patients; 4.6% of mitral valves, and 6.1% of aortic valves were replaced (some patients underwent both procedures).

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Table 5. Outcomes for Patients Hospitalized with Infective Endocarditis, 1998–2009.

https://doi.org/10.1371/journal.pone.0060033.t005

Serious neurological complications (stroke or CNS infection), MI, and the composite endpoint of these plus death, all increased. The composite endpoint was met by 25.6% of discharged patients in 2009, up from 20.3% in 1998. MI rates more than doubled from 3.2% to 6.8%, while serious neurological complications rose from 9.2% to 13.3%. Overall, a stroke occurred during 9.0% of endocarditis hospitalizations, CNS infection during 2.1%, convulsions during 3.8%, and encephalopathy during 2.2% of the hospital stays. ARF was diagnosed in 18.0% of patients.

Patients with S. aureus had significantly higher mortality (17.4%) than those with other (or no) specified causative organisms (11.3%), and higher rates of CNS infection (3.9% vs. 1.4%) and ARF (22.7% vs. 16.0%). The difference in stroke rates was small (9.6% vs. 8.8%, p = .0005).

Other predictors of mortality included: any neurological complication (23.3%), especially stroke (28.5%); ARF (27.1%); and MI (31.6%). Patients over 70 had the highest mortality (16.1%), while those 18–44 had the lowest (4.8%); 8.5% of children died. Mortality was not notably affected by HIV, pre-existing valvular abnormalities, or valve replacement during hospitalization, but was lower among patients with substance use (8.3%).

Discussion

The incidence of hospitalization for endocarditis in the U.S. is 12.7 per 100,000 annually. Even accounting for the fact that multiple hospitalizations might occur during a single episode of IE, the incidence of this illness appears substantially higher than previously reported [5], [8]. The age adjusted 2.4% annual increase in hospitalizations between 1998 and 2009 is in keeping with reports of rising rates of sepsis and septicemia during this period [12]. However, it represents an acceleration of the trend in IE incidence observed in a review of twelve small population-based studies in Europe and Olmsted County, Minnesota [8]. That review found rates (per 100,000) of 1.4–1.8 during the 1970s and 1980s (with one outlier), rising to 2.2–4.9 during the 1990s.

The IE patients we identified resemble those in a 2000–2005 prospective cohort study of 2,781 patients in 25 countries (ICE-PC) where 25% of all cases (and 38% of US patients) had health care-associated infections [5], [13]. Several epidemiologic features of our patients – their advanced age, the male predominance, the prevalence of co-morbid illness and cardiac implants, grafts and devices, and the dominant role of S. aureus (and, in 2009, MRSA) – suggest that health care-associated infections were frequent.

Remarkably, co-morbid drug use and HIV, although probably under-reported, fell between 1998 and 2009. Perhaps harm reduction programs stressing needle hygiene, and a shift from intravenous to oral opioid use underlie this decrease [14].

The rising age of endocarditis patients explained few of our findings. Although death and MI rates were higher among the elderly, time trends for these outcomes did not vary by age. The proportion of IE hospitalizations attributed to S. aureus was slightly higher among the non-elderly (in keeping with findings from the ICE-PC cohort [15]) and rose faster. The rise in neurologic complications occurred largely among those under 70, and this group accounted for the entire decline in HIV and substance use-associated cases.

We found marked geographic variation in IE hospitalization rates, with higher rates in poorer communities and in the Northeast. This finding remains unexplained; differences in all-cause hospitalization rates and mentions of substance use and HIV were small. The ICE-PC study also documented marked geographic variation (by continent) in the epidemiology of IE [5].

The geographic variability we observed may, in part, explain the lower estimates of IE incidence in earlier studies. For instance, a widely-cited U.S. study assessed IE incidence in Olmstead County, Minnesota, a region in the Midwest with a relatively low poverty rate that may not be nationally representative.

Despite changes in recommendations that greatly reduced the use of antibiotic prophylaxis for dental and other procedures around 2007 [16], [17], we found no coincident inflection in the time trend of total IE hospitalizations or of the subset caused by non-enterococcal streptococci. These reassuring findings mirror those from England and Wales [18].

Endocarditis outcomes didn’t improve during the 12-year period we studied - perhaps due to the growing predominance of S. aureus infections. Severe complications increased. At 14.5%, mortality was lower than the 18% rate in the ICE-PC study, which oversampled referral hospitals [5]. Our analysis probably undercounts deaths; LOS was only 15 days, and some patients undoubtedly died while completing therapy in convalescent settings. In one study, 12% of IE patients died within one year and a third by four years after discharge [19].

The rate of valve replacement surgery we observed is far lower than the 48.2% who underwent surgical therapy in the ICE-PC cohort, perhaps because a larger proportion of the ICE-PC patients were cared for in referral centers [5].

Recent studies report similar neurologic complication rates to those we found [5], [20]–[22]. In our sample, 9% of IE patients suffered strokes versus 7.8% to 21% in others’ series. We found low rates of meningitis and brain abscess, only 2.1%; prior studies reported meningitis in 5% to 16.5% of patients and brain abscess in 0% to 4% [20], [23]. Our finding that CNS infections and stroke were more common with S. aureus infection confirms prior findings [20], [21], [23]. Some [21], but not all [20] previous studies have, like ours, found an association between neurologic complications and mortality.

Inflation-adjusted costs of care doubled between 1998 and 2009, rising at the same rate as costs for other diagnoses despite the absence of important therapeutic innovations for IE. The cost increase cannot be attributed to IE patients’ increasing age; costs were lowest for the oldest age group.

Several caveats apply to our analysis. While the NIS data offers advantages of sample size, wide geographic coverage, the ability to assess time trends, and lack of referral bias, ascertainment of diagnoses depends upon both diagnostic and coding rigor. The discharge summaries from which the NIS data are compiled serve, in part, as the basis for hospital payment, and are hence subject to regulation and audit. Hospitals are supposed to code all diagnoses treated during the stay. Major diagnoses and procedures (e.g. endocarditis or valve replacement) are unlikely to go uncoded, or to be affected by changes in coding practices during our study period. Conversely, regulations proscribe coding for inactive problems and those not treated during the hospital stay (e.g. a history of IE); hospitals that billed for IE in the absence of active infection would be subject to sanctions.

To explore whether over-diagnosis might explain the high incidence of endocarditis we found, we examined hospitalizations in which the IE diagnosis was not listed first. In such cases the most common first diagnoses were conditions closely associated with IE such as sepsis or “complication of an implanted device”. Similarities in patient demographics, organisms, outcomes and cost between patients whose IE was coded as a first vs. subsequent diagnosis suggests that our case ascertainment strategy accurately reflects physicians’ diagnoses of IE.

However, predisposing factors or complications are probably under-coded, since clinicians and coders might not consider them important to patients’ care or to reimbursement. Hence, the NIS likely under-reports conditions such as intermittent drug use, anatomically abnormal but functionally adequate heart valves, the presence of a pacemaker, or the occurrence of a single seizure or brief bout of ARF.

The NIS does not specify the sequence of events during a hospitalization. Hence, we cannot ascertain whether a valve surgery that occurred during an IE hospitalization represented a cause or a treatment of the infection. However, few cases of early prosthetic valve IE acquired during surgery would come to light prior to discharge.

Our hospital-based analysis may underestimate population IE incidence. Some IE patients may die prior to a hospital admission or (rarely) be diagnosed and treated without being admitted. Similarly, we could not identify hospitalized cases whose IE was never identified and who either died or were cured by treatment for another condition such as osteomyelitis. Our downward adjustment to account for transfers to another hospital probably causes underestimation of the number of unique cases; it assumes that all cases were coded as having IE at the receiving hospital.

On the other hand, as emphasized above, some patients are probably double-counted in our analysis because they underwent more than one hospital admission in the course of a single episode of IE. We would expect such readmissions to be more frequent at hospitals which often complete treatment in the outpatient setting. However, recent IE case series from such institutions indicate that such readmission are uncommon −3% to 5% of all admitted IE patients [24], [25]. In any event, it seems unlikely that readmissions of outpatient-treated cases accounts for the sharp upswing in IE admissions we observed. While we’re unaware of any national data on trends in the frequency of outpatient IE treatment, the stable length of IE inpatient stay during the course of our study argues against a large increase in outpatient therapy.

The major caveat is that, unlike case series that include only verified and adjudicated diagnoses, we examined clinically diagnosed IE. Hence, our findings reflect the over-diagnosis (and perhaps under-diagnosis) of IE in actual clinical practice, where physicians must sometimes presumptively treat IE despite inconclusive blood culture and echocardiographic data. In von Reyn’s sentinel study [25], the first to apply the now standard [26], strict definitions of endocarditis, and in the recent prospective ICE-PS study [5], only 85% of clinically diagnosed cases met strict criteria for IE. A 15% downward adjustment would reduce our incidence estimate to 10.8 IE hospitalizations annually per 100,000, a figure that is still about twice previous U.S. estimates. Unless diagnosis accuracy is deteriorating, over-diagnosis could not explain the temporal increase we observed.

IE is much more common than previously believed and continues to increase due to the increasing incidence among individuals 50 and older. Rising numbers of cases of IE are due to S. aureus or associated with cardiac devices and implants, and a falling number is linked to drug use. These trends point to the growing importance of patient safety measures to minimize health care-acquired infection. The marked geographic variation we observed remains unexplained, suggesting the salience of future research on Staphylococcal virulence factors as well as environmental and social factors associated with IE.