a b s t r a c t

Background: The role of echocardiography in adult patients with community-acquired pneumonia has not been tested in a clinical trial. The aim of the study was to assess the cardiac changes secondary to CAP by echo- cardiography and to find out the correlation between echocardiographic findings and the severity of CAP. Methods: A total of 111 unselected consecutive adult patients hospitalized with CAP were enrolled. The control group consisted of 100 consecutive sex- and age-matched patients. The severity of CAP was evaluated with the pneumonia severity index and the CURB-65 (confusion, urea, respiratory rate, arterial blood pressure and age) score. Blood samples were taken and echocardiography was performed within the first 48 hours.

Results: White blood count, N-terminal pro-brain natriuretic peptide, and red blood cell distribution width were significantly higher in the CAP group compared with the control group. The 2 groups did not differ in terms of left and right ventricle ejection fraction, left atrial diameter, pulmonary artery systolic pressure, and left ventricular end-diastolic and end-systolic diameter. However, tricuspid annular plane systolic excursion (21.1 +- 4.3 vs 22.3 +- 4.1 mm; P = .04), aortic distensibility (2.5 +- 0.9 vs 3.5 +- 0.9 cm²:dyne:10, P b .001), and aortic strain (5.8% +- 2% vs 6.5% +- 1.9%, P = .009) were significantly reduced in CAP group than in controls. The plasma concentration of N-terminal pro-brain natriuretic peptide correlated with aortic strain, aortic distensibility, tricuspid annular plane systolic excursion, pneumonia severity index score, and CURB-65 Score.

Conclusions: Tricuspid annular plane systolic excursion and elastic properties of aorta may play a role in the diagnosis and clinical assessment of CAP severity, which could potentially guide the development of new prognostic models.

(C) 2015

Introduction

Despite the efficacy of modern treatment, Community-acquired pneumonia is the leading cause of death due to infection and also a frequent cause of medical consultation in hospital’s emergency departments (EDs) [1]. Prognostic scores, like the CURB-65 (confusion, urea, respiratory rate, arterial blood pressure and age) score and the pneumonia severity index , have been developed and validated to estimate the risk of adverse outcome and to register a patient with CAP for hospital admission [2,3]. Several serum biomarkers have been also investigated in patients with CAP. Procalcitonin and C-reactive pro- tein are commonly used biomarkers in CAP as indicators of Severity of disease and predictors of mortality [4]. Elevated N-terminal pro-brain natriuretic peptide has been shown to be associated

* Corresponding author. Mugla Sitki Kocman Universitesi Tip Fakultesi, Orhaniye Mah. Haluk Ozsoy Cad., 48000/Mugla. Tel.: +90 252 214 13 26.

E-mail address: [email protected] (B. Yildirim).

with adverse prognosis in several Cardiac conditions [5] as well as acute ischemic stroke [6] and critically ill patients [7]. N-terminal pro- brain natriuretic peptide is also shown to have a good correlation with Clinical scores and to be an important predictor of short- and long- term mortality and acute kidney injury in the ED and in hospitalized patients with CAP [8,9]. A growing number of echocardiographic markers have been evaluated as possible predictors of prognosis in patients with pulmonary and infectious diseases such as sepsis [10], septic shock [11], human immunodeficiency virus infection [12], pul- monary tuberculosis [13], and chronic obstructive pulmonary disease [14]. However, the value of right ventricular systolic functions or aortic stiffness indices has not been evaluated in Infectious conditions such as sepsis, pneomonia, or Infective endocarditis.

Although effects of pneumonia on cardiac structures are theo- retically possible because of increased systemic inflammatory activity, prothrombotic conditions, biomechanical stress on coronary arteries, variations in coronary arterial tone, and altered myocardial metabolic balance during infections, the role of transthoracic echocardiography has never been evaluated in patients with CAP. As echocardiography is a noninvasive, reliable, cost-effective, and reproducible diagnostic

http://dx.doi.org/10.1016/j.ajem.2015.06.036 0735-6757/(C) 2015

tool to evaluate cardiac function and structures, we aimed to investigate left and right ventricular functions and aortic elastic properties in CAP patients. Furthermore, we also aimed to observe relationships between echocardiographic findings and inflammatory and cardiac serum bio- markers in patients with CAP.

Methods

This prospective observational study was conducted at a university- affiliated hospital in Turkey from March 2015 to May 2015. All patients

>= 18 years of age and with CAP diagnosis hospitalized through the ED

were prospectively recruited. After they gave written informed consent, we enrolled 111 consecutive patients. Patients with active pulmonary tuberculosis, those with Hospital-acquired pneumonia, severely immu- nocompromised patients, patients undergoing chronic dialysis, and pa- tients sent for ambulatory treatment were excluded. Pneumonia was defined by the presence of 2 or more of the following recently acquired symptoms or signs: temperature N 38?C, dyspnea, cough, sputum pro- duction, pleuritic chest pain, or bronchial sounds or crackles on chest auscultation, plus radiographical findings of pneumonia.

Community-acquired pneumonia is defined as pneumonia acquired outside a hospital or long-term care facility that occurs within 48 hours of hospital admission or in a patient presenting with pneumonia who does not have any of the characteristics of health care-associated pneu- monia (ie, hospitalized in an acute care hospital for 2 or more days within 90 days of infection; resided in a nursing home or long-term care facility; received recent Intravenous antibiotic therapy, chemo- therapy, or wound care within the past 30 days of the current infection; or attended a hospital or hemodialysis clinic). The control group consisted of 100 consecutive sex- and age-matched patients admitted to the ED during the same period who presented with shortness of breath as their primary complaint and had no obvious traumatic or infectious cause of dyspnea. The study protocol was approved by the regional ethics committee.

Data collection

Sociodemographic characteristics and clinical data were collected on all subjects at presentation. Patients’ Demographic and clinical data were collected by the emergency medicine and infectious disease physicians by using a standard questionnaire. Patients’ informed consent was obtained by the same team. The vital signs including systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and body temperature were recorded at the triage area on arrival to the ED. Complete blood count, routine biochemical analyses, and NT-proBNP and troponin I concentrations were measured within the first 24 hours. Severity of pneumonia was quantified by the PSI, a validated prediction score for 30-day mortality in patients with CAP and CURB-65 score (confusion, blood urea nitrogen N 20 mg/dL, respiratory rate N 30 breaths per minute, blood pressure b 90/60 mm Hg, and age >=65 years) [15].

Tranthoracic echocardiography

Standard M-mode and 2-dimensional Color Doppler echocardiogra- phy was performed in all patients using Philips System (Philips Epiq 7G, Andover, MA) within 2 days of hospital admission. Transthoracic echo- cardiography was performed and interpreted by 2 experienced echo- cardiographers (OB and VD). Standard views, including the left lateral decubitus and supine positions, were obtained. The M-mode traces were recorded at a speed of 50 mm/s, and the Doppler signals were also recorded at a speed of 100 mm/s. M-mode echocardiographic mea- surements were obtained based on the standards of the American Society of Echocardiography [16]. Diameter of the Ascending aorta was measured from the same view on the M-mode tracing at 3 cm above the aortic valve. The systolic diameter was measured at the maximal anterior motion of the aorta, whereas the diastolic diameter was

measured at the peak of the QRS complex on the simultaneously recorded electrocardiogram. Five consecutive cardiac beats were mea- sured routinely and averaged. Blood pressure was measured with an external sphygmomanometer.

The aortic stiffness index, aortic distensibility, and aortic strain were determined as aortic elasticity properties. The formulae used in the calculation of these parameters were as follow [17,18]:

Aortic strain (%) = (aortic systolic diameter-diastolic diameter) x 100 /diastolic diameter, Aortic distensibility cm²/dyn = (2 x aortic strain)/(systolic pressure - diastolic pressure).

The mitral and tricuspid inflow velocity was traced and the follow- ing variables derived: peak velocity of early (E) and late (A) filling and deceleration time (DT) of the E wave velocity. The ratio of early to late peak velocities (E/A) was calculated for left and right ventricle in the Apical 4-chamber view. Left ventricular ejection fraction was measured by transthoracic echocardiography using the Modified SImpson rule.

Tricuspid annular plane systolic excursion , which is an index of right ventricular systolic function, was estimated by 2-dimensional echo-guided M-mode recordings from the apical 4-chamber view with the cursor placed at the free wall side of the tricuspid annulus [19]. The pulmonary artery systolic pressure was estimated by continuous wave Doppler evaluation of tricuspid regurgitation.

Statistical analysis

Data were analyzed using SPSS for Windows (version 15; SPSS Inc, Chicago, IL). The continuous variables were expressed as mean +- standart deviation and were compared between groups by 2-tailed Student t test. Nonparametric tests were also used when necessary (Mann-Whitney U test). Fisher exact (?²) test was used in comparison of categorical variables. Statistical differences among groups were tested by one-way analysis of variance and Kruskal-Wallis tests for parametric and nonpara- metric variables, respectively. Univariate and multivariate logistic regres- sion analyses were applied to determine crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the relationship between TAPSE, aortic distensibility, aortic strain, and CAP. Intraobserver and inter- observer variabilities were calculated as a relative error. Correlation analyses were performed using the Pearson test. For all analyses, P b . 05 was considered statistically significant.

Results

Baseline characteristics of study patients

There were 111 patients (mean age, 65.8 +- 13.8; 52% male) in the CAP group and 100 patients (mean age, 66.5 +- 13.2; 49% male) in the control group. The baseline characteristics of patients with CAP and control group are presented on Table 1. The control group consisted of 100 consecutive sex- and age-matched patients admitted to the ED with shortness of breath who had no obvious traumatic or infectious cause of dyspnea. The reasons of dyspnea was asthma in 25 patients, chronic obstructive pulmonary disease in 18 patients, neuromuscular and psychiatric diseases in 13 patients, left ventricular failure in 12 pa- tients, pleural effusion in 8 patients, renal failure in 5 patients, metabolic acidosis in 3 patients, pulmonary embolism in 3 patients, pneumothorax in 1 patient, and other uncommon diseases in 12 patients.

There was no statistically difference between the groups in terms of age, sex, systolic and diastolic blood pressure, history of heart failure, atrial fibrillation, cerebrovascular disease, or chronic obstructive pulmo- nary disease. However, CAP patients had a higher prevalence of diabetes mellitus, hypertension, and coronary artery disease. The mean CURB-65 score and PSI score values were 1.7 +- 1.2 and 3.2 +- 1.2 in our CAP group, respectively.

Echocardiographic examination“>Table 1

Baseline characteristics of patients with CAP and the control group

Twelve random aortic strain, TAPSE, M-mode, and Doppler recordings were analyzed to determine the interobserver and intraobserver

Patient group (n = 111)

Control group (n = 100)

P value

variability. Intraobserver and interobserver variabilities were b 5% for all echo parameters.

Male	58 (52.3)	49 (49)	.63	However, patients with CAP had lower TAPSE (21.1 +- 4.3 vs 22.3 +-
Age (y)	65.8 +- 13.8	66.5 +- 13.2	.70	4.1 mm, P = .04), aortic distensibility (2.5 +- 0.9 vs 3.5 +- 0.9
Heart rate (beats per minute)	77.2 +- 14.2	75.2 +- 15.9	.33	cm2:dyne:10, P b .001), and aortic strain (5.8% +- 2% vs 6.5% +-

Body temperature (?C) 37.6 +- 0.6 36.9 +- 0.3 b.001

Respiratory rate (beats per minute) 24.1 +- 4.4 19.3 +- 3.6 b.001

Systolic blood pressure (mm Hg) 125.7 +- 15.2 127.1 +- 16.5 .54

Diastolic blood pressure (mm Hg) 78.2 +- 8.3 78.7 +- 7.8 .66 Medical history

Atrial fibrillation	8 (7.2)	6 (6)	.72
Smoking	23 (20.7)	15 (15)	.28
Diabetes mellitus	22 (19.8)	10 (10)	.048
Hypertension	57 (51.4)	29 (29)	.001
Hyperlipidemia	34 (30.6)	21 (21)	.11
Coronary artery disease	28 (25.2)	9 (9)	.002
Cerebrovascular disease	11 (9.9)	9 (9)	.82
Heart failure	8 (7.2)	6 (6)	.72
Chronic obstructive pulmonary disease	15 (13.5)	11 (11)	.58
Malignancy	11 (9.9)	9 (9)	.82

Values are given as mean +- standard deviation or number (percentage).

Laboratory results

Baseline laboratory parameters of the CAP and control patients are listed in Table 2. The CAP patients had significantly higher NT-proBNP (435.6 +- 730.4 vs 182.7 +- 542.4 pg/mL, P = .005), white blood count

(9.6 +- 3.6 vs 8.3 +- 2.9 x 10³ cells per milliliter, P = .008), and red

blood cell distribution width values (15.8% +- 2.6% vs 14.8% +- 2.3%,

P = .04).

Echocardiographic examination

Basal echocardiographic parameters of CAP patients and controls are presented in Table 2.

The 2 groups did not differ in terms of left ventricle ejection fraction, left atrial diameter, pulmonary artery systolic pressure, mitral and tricus- pid E/A ratio, and left ventricular end-diastolic and end-systolic diameter.

Table 2

Comparison of laboratory and echo parameters

1.9%, P = .009) compared with those with control group.

Correlation analysis

• The plasma concentration of NT-proBNP correlated with aortic strain (r = -0.363, P b .001), aortic distensibility (r = -0.298, P = .001), TAPSE (r = -0.214, P = .023), PSI score (r = 0.276, P = .003), and CURB-65 score (r = 0.330, P b .001).
• TAPSE was correlated with the presence of coronary artery disease (r = -0.231, P = .015), PSI score (r = -0.216, P = .023), and

serum troponin (r = -0.193, P = .043) and Nt-proBNP levels.

• • • A significant negative correlation was found between aortic strain and serum levels of NT-proBNP (r = - 0.204, P = .015) and tropo- nin (r = -0.298, P = .002).

Discussion

We investigated the role of echocardiography and laboratory parameters in this prospective study of 111 patients presenting with CAP to the ED. Our pilot study showed for the first time that CAP is associated with reduced levels of TAPSE and impaired elasticity of the ascending aorta. Moreover, these markers are correlated with the severity of the disease as evaluated by PSI score and NT-proBNP levels. Although the interactions between the pulmonary and cardiovascular systems are increasingly appreciated and the value of echocardiography has been extensively studied in various lung diseases [20,21], its role in pneumonia has not been evaluated yet. Diseases of the respiratory sys- tem affect primarily the right side of the heart, and echocardiography provides a rapid and noninvasive method to evaluate the right ventricle functions. However, assessing right ventricular function by echocardiog- raphy is challenging because of complex geometry and the retrosternal position of the right ventricle, which can limit echocardiographic imaging windows [22]. Recently, systolic displacement of the tricuspid annulus toward the right ventricle referred to as TAPSE emerged as a simple, rapid, quantitative tool for noninvasively assessing right ventricular

Laboratory results

NT-proBNP (pg/mL)	435.6 +- 730.4	182.7 +- 542.4	.005
Troponin I (ng/mL)	12.2 +- 11.4	9.4 +- 11.5	.078
White blood count (x103cells per milliliter)	9.6 +- 3.6	8.3 +- 2.9	.008
Hemoglobin (g/dL)	12.5 +- 1.9	12.2 +- 2	.30
Albumin (g/dL)	3.8 +- 0.5	3.9 +- 0.4	.32
Creatinine (mg/dL)	0.90 +- 0.32	0.85 +- 0.28	.21
Sedimentation
Mean platelet volume (fL)	8.5 +- 1.1	8.5 +- 1.1	.95
Red blood cell distribution width (%)	15.8 +- 2.6	14.8 +- 2.3	.04
Blood urea nitrogen (mg/dL)	20.2 +- 11.3	20.5 +- 10.1	.85
Glucose (mg/dL)	107.1 +- 41.2	103.2 +- 33.9	.46
Echo parameters
Aortic systolic diameter (cm)	3.5 +- 0.4	3.4 +- 0.3	.60
Aortic diastolic diameter (cm)	3.3 +- 0.4	3.2 +- 0.3	.19
Aortic strain (%)	5.8 +- 2	6.5 +- 1.9	.009
Aortic distensibility (cm2:dyne:10)	2.5 +- 0.9	3.5 +- 0.9	b .001
Left ventricle ejection fraction (%)	59.4 +- 7.4	58.6 +- 6.3	.41
Left ventricle end-diastolic diameter (cm)	4.6 (3.7-5.8)	4.7 (3.8-5.9)	.39
Left ventricle end-systolic diameter (cm)	3.1 (2.4-3.7)	3.2 (2.6-3.6)	.42
interventricular septum (cm)	0.8 (0.5-1.3)	0.8 (0.6-1.4)	.76
Left atrial dimension (cm)	3.3 (2.4-4.6)	3.4 (2.6-4.7)	.65
Mitral E/A ratio	1.3 (0.8-3)	1.34 (1-2.3)	.57
Tricuspid E/A ratio	1.3 (0.6-2.4)	1.36 (0.7-2.6)	.67
Pulmonary artery systolic pressure (mm Hg)	19.4 (15-46)	18.5 (16-44)	.53
TAPSE (mm)	21.1 +- 4.3	22.3 +- 4.1	.04

Patient group (n = 111)

Control group (n = 100)

P value

systolic function [23]. Depressed TAPSE portends a poor prognosis and is associated with longer hospital length of stay in patients with pulmo- nary hypertension [24] and heart failure [25] and in critically ill patients [26]. right ventricular dysfunction due to pulmonary hypertension is also shown to be a predictor of exercise intolerance, morbidity, and mor- tality in patients with chronic obstructive pulmonary disease [27]. Our study showed that TAPSE was significantly lower in the adult patient group with CAP than in the control group. Our results suggest that CAP may influence the right ventricular function. Similar findings of abnormal TAPSE values have also recently been reported in other Acute conditions, which raise the question of the effect of acute illness and possible inflam- mation on the right ventricle [28,29].

Terzano and colleagues [28] evaluated 75 patients hospitalized for chronic obstructive pulmonary disease exacerbation and demonstrated a relationship between TAPSE and hypoxemia. Park et al [29] showed significant correlations between TAPSE natriuretic peptide levels in patients with acute pulmonary embolism. Although multiple echo- cardiographic parameters were analyzed in our study, only TAPSE and aortic stiffness indices were markedly different between the patient and control groups. Aortic elasticity can also be assessed by various parameters measured by echocardiography. Increased arterial stiffness is a marker of cardiovascular aging and an independent predictor of coronary artery disease and stroke in the general population, and previous studies have shown that hypertension and diabetes mellitus

decrease aortic strain and distensibility [30]. Although associations between increased aortic stiffness and several infections such Hepatitis C virus [31] and human immunodeficiency virus-1 infections [32] are previously reported, the diagnostic or predictive value of increased aortic stiffness in patients with pneumonia has not yet been investi- gated. Although the mechanism underlying the association between increased aortic stiffness and CAP is unknown, our data suggest that increased aortic stiffness might be regarded as a valuable marker for a high level of inflammatory activity in adult patients with CAP. A mechanism that could be involved in such a process is the release of cytokines in response to inflammatory stress. Recent studies have revealed the importance of inflammation on the pathogenesis of ar- terial stiffness [33]. Arterial stiffness is associated with the increased activity of Angiotensin II and nicotinamide adenine dinucleotide phosphate hydride oxidase, reduced Nitric oxide bioavailability, and increased production of Reactive oxygen species [34]. Angioten- sin II signaling also activates cytokines, including monocyte chemoattractant protein-1, tumor necrosis factor-?, interleukin-1, interleukin-17, and interleukin-6 [35]. Recent studies have also demonstrated a significant association of high-sensitivity C- reactive protein that is a surrogate marker of Vascular inflammation and arterial stiffness [36]. We found that CAP patients had stiffer aor- tas than did Control subjects. Moreover, a significant negative corre- lation was found between aortic stiffness indexes and serum levels of NT-proBNP and troponin. These results indicate that aortic stiffness may be used as a relevant tool to assess the influence of cardiovascu- lar risk factors on respiratory system in patients with CAP.

Biomarkers are also useful tools in the diagnosis, prognostics, and follow-up treatment of CAP. Because CAP is an infectious disease, commonly-used laboratory parameters include the C-reactive protein, white blood cell count, and procalcitonin. However, recent studies showed that cardiac complications are common in patients with CAP, are associated with more severe disease, and may predict prognosis [8]. As a result, new cardiovascular biomarkers are found to be superior compared with inflammatory markers, especially for the determination of long-term prognosis in CAP [8]. Elevated levels of Natriuretic peptides and troponins are reported to be common and are associated with a higher risk of adverse outcome in CAP. Chang et al [8] found that a raised level of NT-proBNP is a strong predictor of early mortality independent of existing clinical risk prediction scores following admission to hospital for CAP.

Elevated troponin T was also associated with increased risk of early mortality but was not a significant predictor once clinical risk scores or NT-proBNP levels were taken into account [8]. Mean platelet volume

[37] and red blood cell distribution width levels [38] have also been shown to be valuable markers for predicting mortality and the severity of disease among patients with CAP at ED admission. In our study, CAP patients had significantly higher NT-proBNP, white blood count, and red blood cell distribution width values compared with those in the control group. Plasma concentration of NT-proBNP correlated with aortic stiffness indices, TAPSE, and PSI and CURB-65 scores. Our data are in agreement with those reported by Christ-Crain et al [39], who demonstrated that B-type natriuretic peptide levels increased with rising disease severity as classified by the PSI in patients with CAP.

Study limitations

This study was performed at a single center, and only adult patients who were hospitalized with a diagnosis of CAP were included. Therefore, our results cannot be directly applied to all patients with CAP. Carotid- femoral pulse wave velocity, which is accepted as the current criterion- standard Noninvasive measure of arterial stiffness, was not used. The CAP and control groups were significantly different with regard to coro- nary artery disease and hypertension, which may be a confounder with regard to the measured echocardiographic parameters.

Echocardiographic parameters and NT-proBNP measurements were not systematically repeated during the follow-up period; and therefore,

the prognostic value of serial changes could not be assessed. Further prospective studies in a larger population with longer follow-up are needed to confirm our results.

Conclusions

In CAP patients, abnormalities in the structure and function of the right ventricle and reduced elasticity of aorta may be present at early stages of the disease. Further research with more patients is needed to determine the prognostic significance of TAPSE and aortic stiffness indices in patients with CAP.

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