Acute coronary syndromes (ACS), including unstable angina and myocardial infarction, are the most feared complications of coronary heart disease.43 Although the progressive reduction of the coronary arterial lumen by a growing atherosclerotic plaque can cause cardiac ischemia, ACS usually result from acute thrombosis on disrupted, hemodynamically nonsignificant lesions.6,38 ACS are preceded by a burst of inflammatory activity not only at the level of these lesions but throughout the coronary tree and systemically, which is thought to play a key role in the pathogenesis of these coronary events.3 Because acute infections induce substantial inflammatory reactions, they can potentially contribute to the development of ACS, as well.20 Several studies have suggested an association between acute infections, including those of the respiratory, gastrointestinal, and urinary tracts, and the occurrence of ACS.1,39-41 The association between acute respiratory infections and ACS, however, is the one with the most compelling evidence.1,4,5,21,26,33,37,40,41
Pneumonia is the leading cause of death from infectious diseases in the United States with an estimate of 4-5 million cases of community-acquired pneumonia occurring annually.24 Bacterial pathogens are the most common etiologic agents implicated in this condition, and despite the availability of antibiotic therapy, the mortality rate for these cases still exceeds 10%.8 In an observational study, we reported that 7% of veteran patients admitted for Streptococcus pneumoniae pneumonia have a concurrent myocardial infarction.33 In the present study, we have extended this investigation by using retrospective cohort and self-controlled case series analyses to evaluate the strength of the association between ACS and community-acquired pneumonia due to its principal bacterial causes, S. pneumoniae and Haemophilus influenzae.
PATIENTS AND METHODS
This study was approved by the Institutional Review Board of Baylor College of Medicine (Houston, TX).
We studied fully electronic medical records of all patients who were hospitalized from January 1, 2000, through December 31, 2006, and who had S. pneumoniae or H. influenzae isolated from blood or sputum. Patients were included if, within 48 hours of admission, they had clinical and radiologic evidence of pneumonia and 1) 1 blood culture yielding S. pneumoniae or H. influenzae, or 2) a sputum sample showing >10 inflammatory cells per epithelial cell with predominance of Gram-positive cocci in pairs or Gram-negative coccobacilli, and a culture of that sputum yielding pneumococci or H. influenzae as the predominant organism with no other likely bacterial pathogens.30-32
In accordance with American Heart Association guidelines,19 we considered the diagnosis of ACS if any of the following criteria were met: presence of evolving diagnostic changes in electrocardiogram or diagnostic cardiac biomarkers; or electrocardiogram findings consistent with ischemia plus cardiac symptoms or signs. Cases were then reviewed by a senior cardiologist (BB), blinded to the clinical and laboratory data concerning the reason for hospital admission, who determined the diagnosis of ACS.
Other Clinical Characteristics
We also evaluated medical records for evidence of preexisting coronary heart disease, cerebrovascular disease, peripheral vascular disease, diabetes mellitus, hypertension, dyslipidemia, tobacco use, family history of coronary heart disease, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, or alcohol abuse. The use at admission of drugs considered cardio-protective such as aspirin, clopidogrel, statins, and beta-blockers; as well as the need for intensive care unit (ICU) care, mechanical ventilation, or pressor drugs during the hospitalization were also sought.
Retrospective Cohort Analysis
We compared the incidence of ACS in the 15 days following hospital admission of patients with acute bacterial pneumonia to that of a control group of patients hospitalized for other reasons. The control group was identified by asking medical records personnel to generate a list of all patients admitted on the 1st, 7th, 13th, 19th, and 25th days of each month from January 2000 through December 2006. Patients were excluded as controls if their reason for hospital admission was an elective or therapeutic procedure, or their diagnosis of admission was either pneumonia or ACS. Two controls, matched by the closest date and time of admission, were initially selected for each case of pneumonia. Exclusion criteria common to patients and controls included human immunodeficiency virus (HIV) infection, current use of ≥16 mg/d of prednisone (or equivalent), current use of other immunosuppressive drugs, or having received chemotherapy within the previous 2 weeks.
Self-Controlled Case Series Analysis
In this type of analysis,7,47 the incidence of an outcome of interest (ACS) during an "at-risk" period following an event of interest (pneumonia) is compared to the incidence of the outcome during "control" periods, before and after the at-risk time for the same individual. If no association existed between the exposure and outcome of interest, the occurrence of the outcome should be evenly distributed throughout time and the ratio between the incidence of the outcome during the at-risk and control periods should approach 1. The main advantage of this method is that, by using each subject as his/her own control, the problem of confounding by unmeasured factors that vary from person to person is minimized. We identified all patients from the pneumonia group who had at least 1 ACS during the 365 days before the occurrence of the pneumonia or the 380 day after this event (total observation period, 745 d). We defined the at-risk period as the 15 days following the admission for pneumonia and compared the incidence of ACS during this time to that in the remaining person-time (control) periods using Poisson regression analysis. If a patient died before the end of the planned follow-up, we considered the date of death as the end of the observation period and, provided that the patient had had at least 1 at-risk and 1 control period, he or she was included for further analysis. We set the time of each period as an offset variable allowing for adjustment of the regression estimates.14 The results are given in incidence rate ratios (IRRs). We also performed sub-analyses of the IRRs for the first 3 days and for the rest of the high-risk period.
For the retrospective cohort study, descriptive statistics of demographic, clinical, and therapeutic variables were done in pneumonia patients and case controls. Proportions of ACS cases in both groups were calculated and odds ratios (ORs) of associated variables were determined by univariate analysis. Variables of biological relevance that showed a p value < 0.2 in the univariate analysis were considered in the elaboration of a multivariate logistic regression model. Data obtained in the self-controlled case series study were analyzed as described above. All statistical analyses were conducted with Intercooled Stata version 9.2 (College Station, TX).
Retrospective Cohort Analysis
A total of 206 cases of pneumonia were identified. Of those, 144 were caused by S. pneumoniae and 62 by H. influenzae. After initial selection of 412 cases for the control group, review of medical records revealed that 17 met exclusion criteria, leaving 395 for further analysis. General characteristics of patients and control subjects are shown in Table 1. Age and ethnicity were similar in both groups. As expected, patients with pneumonia were more likely to have a history of tobacco use and chronic obstructive pulmonary disease; to require ICU care, mechanical ventilation, and pressor drugs; and to have longer hospital stays and higher mortality rates at 30 days after admission.
Twenty-two of 206 pneumonia patients (10.7%) had ACS compared with 6 of 395 (1.5%) in the control group (OR, 7.8; 95% confidence interval [CI], 3.1-19.4; p < 0.001). For those with pneumonia caused by S. pneumoniae, the OR was 7.0 (95% CI, 2.6-18.5; p < 0.001), and for those with H. influenzae the OR was 9.6 (95% CI, 3.2-28.7; p < 0.001). One hundred three cases (50%) of pneumonia and 12 cases (55%) of ACS occurred during times of influenza season (November through March), but the proportion of patients with pneumonia that developed ACS did not differ during influenza season from that during the rest of the year (11.7% vs. 9.7%; p = 0.82).
Of the 22 pneumonia patients with ACS, 20 (91%) required ICU care at some point during the hospitalization, but only 10 (45%) required pressors, and only 4 (18%) were receiving them at the time the ACS was diagnosed.
In addition to pneumonia, other factors associated with the development of ACS in the univariate analysis included age; history of congestive heart failure; chronic kidney disease; use of beta blockers; and the need for ICU care, mechanical ventilation, or pressors (Table 2). A multivariate analysis model using the variables listed in Table 3 showed that pneumonia continued to be strongly associated with ACS (OR, 8.5; 95% CI, 3.4-22.2).
Self-Controlled Case Series Analysis
We identified a total of 37 patients who had an ACS during the observation period. One patient did not have available records other than those related to his admission for pneumonia and was excluded from further analysis. The timelines for the occurrence of ACS during the total observation period and the time closest to the at-risk period are presented in Figure 1. Twenty-one (58%) of the 36 cases of ACS considered for this analysis occurred during the at-risk period, which resulted in a strikingly high IRR for the occurrence of ACS following pneumonia (IRR, 47.6; 95% CI, 24.5-92.5; p < 0.001). When the analysis was made for the first 3 days after the pneumonia, the IRR was the highest (IRR, 132.0; 95% CI, 69.2-255.6; p < 0.001) and significantly fell for the rest of the at-risk period (IRR, 3.1; 95% CI, 0.7-13.0; p = 0.12 for days 4-15) (Table 4). Six patients who had an ACS during the at-risk time died within it, resulting in only pre-pneumonia control periods for them. Similarly, 11 other patients did not survive to the end of the observation period, reducing the length of the post-at-risk period. To avoid potential bias associated with this variability, we ran a new self-controlled case series analysis including only those patients who were alive by the end of the observation period. This resulted in the evaluation of 19 cases, all of whom had at least 1 documented medical evaluation in each of the control periods. Ten (53%) of these patients developed an ACS during the at-risk period. The IRRs for the at-risk period (IRR, 41.8; 95% CI, 16.9-102.9; p < 0.001) and for the first 3 days after the admission for the pneumonia (IRR, 159.1; 95% CI, 64.5-392.0; p < 0.001) were essentially unchanged.
In the present study we used 2 different approaches to examine the association between acute bacterial pneumonia and ACS. Using a retrospective cohort analysis, we found that the risk for developing an ACS in the 15 days after the admission for pneumonia was increased >8-fold. Retrospective cohort studies are subject to uncertainties in the comparability of cases and controls, the standardization of available documentation for data abstraction, and unforeseen bias inherent in the assumption that similar populations have been selected for study. The fact that all patients included in the current study had their medical care based at the same center probably enhances the validity of the results. Whereas other studies have used large numbers of cases identified by discharge diagnoses codes, we used only those that we selected for inclusion after careful review of medical records and in whom we applied stringent criteria for our definitions. The principal advantage of this approach is the preciseness of the data that we analyzed; a disadvantage is that the limited number of cases did not allow us to construct more inclusive multivariate models in our analysis.
Recognition of these limitations led us to undertake a self-controlled case series analysis. This kind of analysis uses each patient as his/her own control, thereby removing possible influence by unrecognized variations within the population. The null hypothesis for this analysis is that, within a 745-day period, rates of ACS are relatively constant. Application of this analysis showed that acute bacterial pneumonia in an individual patient results in a remarkable temporary increase (almost 50-fold) in the risk for developing an ACS during the 15 days following admission for this infection; and that increase is most significant (>100-fold) in the first three days following the recognition of the infection. Although the self-controlled case series method has proved to be valid for risk analyses, it is still subject to bias such as the inability to adjust for confounders that vary over time. In addition, the possibility of overestimation of its risk ratios has been noted.10 Nonetheless, the strength of our results is highly suggestive of a causal role for the acute infection in triggering the cardiovascular events.
The development of ACS is preceded by a burst of inflammatory activity in the atherosclerotic lesions of the coronary arteries and systemically.18,25,28,46,50 In pneumonia, a generalized inflammatory response is usually fully activated by the time patients present to the hospital.12,49 Accumulating evidence suggests that this systemic inflammatory response may also cause inflammation in coronary arteries and their pre-existing atherosclerotic lesions. For instance, influenza infection in apolipoprotein E-deficient mice (a well-validated model of atherosclerosis) produces significant acute inflammatory changes in their atherosclerotic lesions.36 Coronary arteries of humans who die of acute infections have significantly more inflammatory cells infiltrating their walls than do those of patients dying from other causes.23 The potential for acute infections to trigger ACS through these mechanisms has been recognized.23,36
Alterations in the thrombogenic state of the blood also contribute to the development of ACS by promoting the development of a thrombus in the disrupted coronary lesion.35 Acute infections are known to produce changes in coagulation that include increases in platelet activation, circulating levels of tissue factor, and thrombin production9,15,27 and a decrease in fibrinolytic activity.11 Acute infections can also cause acute dysfunction and/or physical disruption of the endothelium34,44 with further contribution to thrombus formation. The hemoconcentration and increased blood viscosity seen in infectious states also promote procoagulant conditions.2,16
Other mechanisms by which acute infections might contribute to the development of ACS include the following: 1) changes in hemodynamic forces acting on coronary lesions;2,16 2) hypoxemia and demand ischemia;22,33 3) increased expression of matrix metalloproteinases;48 4) release of endogenous catecholamines;22 and 5) changes in lipoprotein levels and function including loss of the anti-inflammatory properties of high-density lipoprotein particles.13
Clinical studies by us and others have shown a 6%-7% rate of ACS in pneumonia due to S. pneumoniae33 or in all-cause community-acquired pneumonia.37 The even greater incidence (10.7%) in the present study could be related to differences in the inclusion criteria, since our study excluded patients with known immunosuppressive conditions. We also included only those who had an established bacterial cause, which might have selected for more severe degrees of inflammation than, for example, pneumonia due to viruses or Mycoplasma.
Influenza virus infection increases the risk for a superimposed bacterial pneumonia29 and has been associated with the development of ACS.21 Most patients in the current series were not studied for the presence of influenza virus. Nonetheless, the proportion of patients with pneumonia that developed ACS during periods of influenza season was not significantly different from that during the rest of the year, suggesting that in our population, influenza infection did not further impact the occurrence of ACS.
Patients with severe sepsis and shock are at increased risk for developing ACS17,42 due to, at least in part, perfusion and metabolic mismatches in cardiac tissue and the use of pressors.42 Some patients developed severe sepsis with shock as a result of the pneumonia; however, in most instances, the ACS was already recognized before the onset of shock and the administration of pressors, suggesting that the occurrence of coronary events could not be attributed to the circulatory collapse associated with a septic state or to the use of these drugs. Nevertheless, measurements of severity of the pneumonia such as higher need for ICU, mechanical ventilation, or use of pressors, were strongly associated with the occurrence of ACS in the univariate analysis, suggesting that this is an important factor in this association. Ramirez et al37 already showed that the incidence of acute myocardial infarction in patients with community-acquired pneumonia significantly increased with the severity of the infection.
The fact that the association with ACS was equally strong for pneumonia due to S. pneumoniae and H. influenzae suggests that this phenomenon is common to all bacterial pneumonias as well as to bacterial infections in other organs. An association with ACS has been demonstrated with urinary tract infections, gastrointestinal infections, and bacteremia.1,39,40,45 A described association between ACS and influenza21 implicates viral infections, as well.
We conclude that bacterial pneumonia is significantly associated with the occurrence of ACS in older adults who, by virtue of their age and coexisting diseases, are at substantial risk for coronary heart disease. The association is so striking in the few days after pneumonia is recognized that an actual causal link is suggested. Further studies are warranted to elucidate the underlying mechanisms of this association, to identify patients at the highest risk for these acute myocardial events, and to develop strategies to prevent their occurrence.
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