American Journal of Emergency Medicine xxx (2015) xxx–xxx

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American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Original Contribution

The prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with community-acquired pneumonia☆,☆☆ Yalcin Golcuk, MD a,⁎, Burcu Golcuk, MD b, Adnan Bilge, MD a, Ayhan Korkmaz, MD c, Mehmet Irik, MD a, Mustafa Hayran, MD a, Alper Tunga Ozdemir, MD b, Yusuf Kurtulmus, MD d a

Department of Emergency Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkey Department of Clinical Biochemistry, Merkez Efendi State Hospital, Manisa, Turkey c Manisa State Hospital, Department of Emergency Medicine, Manisa, Turkey d Department of Clinical Biochemistry, Buca Seyfi Demirsoy State Hospital, Izmir, Turkey b

a r t i c l e

i n f o

Article history: Received 18 March 2015 Received in revised form 5 May 2015 Accepted 28 May 2015 Available online xxxx

a b s t r a c t Objective: This study aims to compare serum pregnancy-associated plasma protein A (PAPP-A) levels in surviving and nonsurviving elderly patients with community-acquired pneumonia (CAP), investigating whether PAPP-A is correlated with CAP prediction scores and whether PAPP-A can successfully predict 28-day mortality rates in elderly patients. Methods: This prospective, observational, single-center, cross-sectional study was conducted at the emergency department (ED) of Celal Bayar University Hospital in Manisa, Turkey, between January and September 2014. All patients underwent follow-up evaluations 28 days after admission. The end point was defined as all-cause mortality. Results: A total of 100 elderly patients (mean age, 77.3 ± 7.6 years [range, 65-94 years]); 60% men) with CAP were enrolled in this study. All-cause mortality at the 28-day follow-up evaluation was 22%. Admission PAPP-A levels were significantly higher in nonsurvivors compared with 28-day survivors (10.3 ± 4.5 vs 3.8 ± 2.6 ng/mL, P b .001). A significant and positive correlation between admission PAPP-A levels and pneumonia severity index; confusion, oxygen saturation, respiratory rate, blood pressure, and age 75 years or older; and confusion, urea, respiratory rate, blood pressure, and age older than 65 years scores was found (r = .440, P b .001; r = .395, P b .001; and r = .359, P b .001, respectively). Moreover, we determined that the optimal PAPP-A cutoff for predicting 28-day mortality at the time of ED admission was 5.1 ng/mL, with 77.3% sensitivity and 77.9% specificity. Conclusions: Serum PAPP-A level is valuable for predicting mortality and the severity of the disease among elderly patients with CAP at ED admission. Thus, PAPP-A might play a further role in the clinical assessment of the severity of CAP. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Community-acquired pneumonia (CAP) is one of the most common infectious diseases in emergency departments (EDs) and causes of hospitalization and mortality, even in patients receiving advanced

☆ Authors' contribution: YG, BG, MI, and MH: concept and designed; YG, AB, MI, and MH: data collection and literature research; MI and MH, collected serum samples; BG, YK, and ATO: performed the laboratory tests; YG, BG, ATO, YK, and AB: analyzed data; and YG, BG and, AK: performed the statistical analysis, wrote the manuscript, and responsibility for final content. All authors read and approved the final manuscript. ☆☆ Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript. ⁎ Corresponding author. Department of Emergency Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkey. Tel.: +90 236 4444228; fax: +90 236 2338040. E-mail address: [email protected] (Y. Golcuk).

medical care and especially the elderly [1]. Several guidelines, clinical scoring tools, and biomarkers have therefore been developed to predict mortality, safe management in the outpatient setting, and hospitalization or intensive care unit (ICU) admission of patients with CAP [2,3]. Pregnancy-associated plasma protein A (PAPP-A) is a zinc-binding matrix metalloproteinase that regulates extracellular matrix remodeling [4]. Pregnancy-associated plasma protein A degrades insulin-like growth factor binding protein 4, increasing levels of local insulin-like growth factor-1 in response to local and systemic injury [5,6]. Recently, several studies investigated the prognostic role of serum PAPP-A levels in different diseases such as acute coronary syndromes, end-stage renal disease, type 2 diabetes, and cancer [7,8]. In contrast, data on serum PAPP-A levels and their prognostic value in elderly patients with CAP have not yet been considered to our knowledge [9]. The main objective of this study was to compare serum PAPP-A levels in surviving and nonsurviving elderly patients with CAP, investigating whether PAPP-A is correlated with CAP

http://dx.doi.org/10.1016/j.ajem.2015.05.047 0735-6757/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Golcuk Y, et al, The prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with community-acquired pneumonia, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.05.047

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Y. Golcuk et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx

prediction scores and whether PAPP-A can successfully predict 28-day mortality rates in elderly patients at the time of admission to the ED [10]. 2. Methods 2.1. Study design and setting This prospective, observational, single-center, cross-sectional study was conducted at the ED of Celal Bayar University Hospital in Manisa, Turkey [11]. Data were collected from consecutive elderly patients who were admitted to the ED with a diagnosis of CAP between January and September 2014 [12]. The hospital has more than 500 beds, and the annual number of ED patient visits is approximately 40 000 per year. The study was approved by local ethical committee of the university (reference no. 20478486-241). Written informed consent was obtained from every patient or patient representative who participated in the study. 2.2. Definitions and clinical scoring tools Community-acquired pneumonia was defined in our study as occurring when patients showed evidence of new pulmonary infiltrates on chest imaging and symptoms consistent with pneumonia, including cough with or without sputum production, dyspnea, fever (N 38.0°C) or hypothermia (b36.0°C), and/or pleuritic chest pain, none of which was acquired in a hospital. Hospital-acquired pneumonia (HAP) was defined as pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission. Health care–associated pneumonia (HCAP) was defined for patients who (1) had undergone hospitalization (for ≥2 days), home infusion therapy (including antibiotics), and/or home wound care in the preceding 90 days; (2) had undergone chronic dialysis within the last 30 days; (3) were residents of nursing homes or extended care facilities; and/or (4) had family members with multidrug-resistant pathogens. The severity of CAP was evaluated using the confusion, urea, respiratory rate, blood pressure, and age older than 65 years (CURB-65) (confusion, urea N 7 mmol/L [19 mg/dL], respiratory rate ≥30 breaths/min, systolic blood pressure b 90 mm Hg and/or diastolic blood pressure ≤60 mm Hg, and age ≥65 years) [13]; confusion, oxygen saturation, respiratory rate, blood pressure, and age 75 years or older (CORB-75) (confusion, peripheral oxygen saturation ≥ 90%, respiratory rate ≥ 30 breaths/min, systolic blood pressure b 90 mm Hg and/or diastolic blood pressure ≤60 mm Hg, and age ≥75 years) [14]; and pneumonia severity index (PSI) [15] scores. 2.3. Pregnancy-associated plasma protein A assay At the time of enrollment, before the patients with CAP received treatment protocols, 2 mL of peripheral blood was collected for the measurement of serum PAPP-A in samples using direct venipuncture of the antecubital vein. Blood samples were centrifuged at 4000g for 10 minutes; serum was separated and immediately stored at −80°C in Eppendorf tubes until analysis. At the end of the study, samples were kept at room temperature and melted. The concentration of PAPP-A in plasma was analyzed using the chemiluminescent method (Unicel DxI 600; Beckman Coulter Inc, Fullerton, CA) using commercial kits (Access PAPP-A assay) in accordance with the manufacturers' instructions. The analysis was performed by laboratory specialists blinded to all patient details, treatments, and clinical outcomes. All serum samples were analyzed on the same day and in duplicate to avoid interassay variance. Other laboratory results were determined by standard methods. 2.4. Selection of participants All consecutive ED patients older than 65 years old with a diagnosis of CAP were included. We excluded patients who met any of the following

criteria: younger than 65 years; pregnant; premenopausal; readmission; diagnosed with HAP, HCAP, or aspiration pneumonia; active pulmonary tuberculosis; known human immunodeficiency virus positivity; and chronic immunosuppression (defined as immunosuppression for solid organ transplantation, postsplenectomy, receiving ≥10 mg/d prednisolone or equivalent for b 30 days, treatment with other immunosuppressive agents, or neutropenia [b1.0 × 109/L neutrophils]). Patients whose PAPP-A measurements were unavailable or who were lost to follow-up were also excluded. 2.5. Data collection The following parameters were collected upon admission to the ED: age, sex, admission from home or a nursing home, comorbidities, and medication use. Hemodynamic parameters were also assessed upon admission as follows: blood pressure, pulse rate, respiratory rate, peripheral oxygen saturation in room air, body temperature, and mental confusion (defined in our study as new disorientation in time, place, or person). Additional data collected for all patients included laboratory tests at the ED, chest x-ray or chest computed tomography scan findings, and outcome variables (the requirement for ICU admission or mechanical ventilation, length of stay [LOS] in the hospital, and all-cause 28-day mortality). The severity of CAP was graded according to the CURB-65, CORB-75, and PSI scores on admission. 2.6. Study protocol and follow-up evaluation All patients included in this study were treated according to the Infectious Diseases Society of America/American Thoracic Society consensus guidelines for the management of CAP in adults and were followed up with after a 28-day period. The primary end point was 28-day allcause mortality. The secondary outcomes of interest were hospital admission, ICU admission, requirement for mechanical ventilation, and LOS in hospital. Survival status and dates of death were obtained from patients or their relatives by telephone interviews at 28 days; the data were further validated by reviewing the hospital's medical records. For deaths occurring outside the hospital, we reviewed the local civil demographics database, which reports all deaths that have occurred in the study area on a daily basis. 2.7. Statistical analysis Patients were divided into 2 groups (survival and nonsurvival) based on their survival at the 28-day mark. The normality of data distribution was checked with the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± SD or median (interquartile range) according to normal or nonnormal distributions. Categorical variables were presented as absolute values and percentages. The demographic, clinical, and laboratory variables were compared between the 2 groups. Differences between survivors and nonsurvivors were investigated using the Mann-Whitney U test for continuous variables and Fisher exact test for categorical variables. The correlations between PAPP-A and clinical scoring tools were analyzed using Spearman rank correlation. A receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value of PAPP-A for predicting 28-day mortality. The area under the ROC curve was calculated and used to evaluate diagnostic accuracy. The cumulative survival rate was calculated using the Kaplan-Meier method, and differences in survival between the groups were compared using the Mantel-Cox log-rank test. To identify variables associated with 28-day mortality, data were initially analyzed by univariate analysis. Significant variables were subsequently entered into a stepwise forward logistic regression analysis. For all tests, P b .05 was considered statistically significant. The analyses were performed using SPSS for Windows, release 21.0 (SPSS Inc, Chicago, IL).

Please cite this article as: Golcuk Y, et al, The prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with community-acquired pneumonia, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.05.047

Y. Golcuk et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx

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3. Results During the study period, a total of 125 consecutive elderly patients presenting to the ED with a diagnosis of pneumonia were enrolled in the study. Of these, 9 were excluded due to HCAP, 7 were excluded due to HAP, 5 were excluded because of immunocompromised status, and 4 were excluded because of repeated episodes. After these exclusions, the complete 28-day follow-up status was available for 100 patients with a diagnosis of CAP.

Table 1 Baseline characteristics of the 100 study subjects, categorized with respect to the center of origin Variables

Demographic data Age (y) Women/men (n) Previous medical history Diabetes mellitus Chronic heart disease Chronic pulmonary disease Chronic renal failure Chronic liver failure Cerebrovascular disease Dementia Neoplasm Hemodynamic parameters at presentation Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Respiratory rate (breaths/min) Oxygen saturation (SaO2%) Forehead temperature (°C) Labaratory results PAPP-A (ng/mL) White blood cell count (× 103/μL) Platelet count (K/μL) Hemoglobin level (g/dL) Hct (%) MPV (fL) PCT (%) PDW (%) RDW (%) Glucose (g/dL) Blood urea nitrogene (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Sodium (mmol/L) Potassium (mmol/L) Chlorine (mmol/L) Calcium (mmol/L) Blood gas analysis (arterial) pH (pH units) PaO2 (mm Hg) PaCO2 (mm Hg) HCO3− (mmol/L) BEecf (mmol/L) Radiographic findings Bilateral lung involvement N2 zones involvement Pleural effusion Clinical scoring tools Median CURB-65 score (range) Median CORB-75 score (range) Median PSI score (range) Secondary outcomes ICU admission Mechanical ventilation Hospital LOS (d)

Survivors

Nonsurvivors

(n = 78)

(n = 22)

P

76.8 ± 7.7 30/96

79.0 ± 7.5 48/12

.340 .554

13 (16.6) 47 (60.2) 53 (67.9) 2 (2.5) 1 (1.2) 7 (8.9) 4 (5.1) 16 (20.5)

4 (18.1) 14 (63.6) 8 (36.3) 3 (13.6) 0 (0) 2 (9.0) 5 (22.7) 2 (9.0)

.867 .774 .007 .035 .594 .987 .011 .218

143.4 ± 27.5 76.8 ± 17.2 96.4 ± 18.9 21.7 ± 6.9 89.7 ± 7.3 38.1 ± 6.7

117.5 ± 35.1 68.1 ± 21.1 103.3 ± 22.5 27.5 ± 8.7 83.4 ± 11.4 37.0 ± 1.0

.001 .022 .052 .002 .001 .268

3.8 ± 2.6 14.9 ± 8.1 245.7 ± 104.5 12.5 ± 2.2 38.0 ± 6.2 9.5 ± 1.3 0.22 ± 0.09 16.4 ± 0.6 15.9 ± 3.7 141.5 ± 52.5 24.9 ± 16.5 56.2 ± 36.7 1.1 ± 0.7 136.9 ± 5.0 4.3 ± 0.7 101.1 ± 7.8 8.9 ± 0.6

10.3 ± 4.5 13.2 ± 6.4 235.4 ± 89.8 13.2 ± 2.6 40.2 ± 7.0 8.1 ± 0.6 0.23 ± 0.08 16.2 ± 0.6 15.4 ± 2.6 155.0 ± 64.4 41.3 ± 36.4 84.0 ± 75.7 1.8 ± 1.3 138.3 ± 5.0 4.3 ± 0.7 101.1 ± 4.8 8.9 ± 0.6

b.001 .459 .796 .277 .139 b.001 .456 .349 .878 .156 .017 .096 .031 .103 .767 .851 .812

7.42 ± 0.08 66.0 ± 17.3 39.3 ± 11.4 25.7 ± 3.6 2.17 ± 4.37

7.38 ± 0.10 63.4 ± 16.9 46.6 ± 21.7 25.0 ± 3.7 1.29 ± 6.17

.076 .469 .727 .276 .272

21 (26.9) 31 (39.7) 19 (24.3)

11 (50.0) 15 (68.1) 12 (54.5)

.040 .018 .007

2 (0-5) 1 (0-5) 104 (40-254)

3 (0-5) b.001 2.5 (0-5) b.001 153 (40-254) b.001

10 (12.8) 4 (5.1) 6.6 ± 8.4

17 (77.2) 16 (72.7) 11.9 ± 9.3

Fig. 1. Box plots showing admission serum PAPP-A levels in elderly patients with CAP according to the survival status at the 28-day follow-up. Lines denote median values, boxes represent 25 to 75th percentiles, and whiskers indicate the range. There are several outliers at the upper range of the data.

The mean age of the patients included in the study was 77.3 ± 7.6 years (range, 65-94 years); 60% were men. Twenty-two patients (22%) died during the first 28 days. The median survival period of the patients who died during follow-up was 7 days (range, 1-28 days). Seventy-four cases were hospitalized, and 26 were discharged from the ED and were followed up in outpatient clinics. For secondary outcomes, the study cohort had an ICU admission rate of 27%, mechanical ventilation rate of 20%, and a mean LOS in hospital of 7.7 ± 8.9 days. Table 1 shows the baseline characteristics of patients according to their survival status at the end of the 28-day follow-up. The most prevalent comorbidities were chronic pulmonary disease (61%), chronic heart disease (61%), and neoplasm (18%). In addition, a history of chronic pulmonary disease, chronic renal failure, and dementia was associated with high mortality (P = .007, P = .035, and P = .011, respectively). The median PAPP-A level for all 100 patients was 3.6 ng/mL (interquartile range, 1.0-18.3 ng/mL). Admission PAPP-A levels were significantly higher in nonsurvivors compared with 28-day survivors (10.3 ± 4.5 vs 3.8 ± 2.6 ng/mL, P b .001) (Fig. 1). In terms of the laboratory results, there were significant differences in blood urea nitrogen, creatinine, and mean platelet volume (MPV) between survivors and nonsurvivors (P = .017, P = .031, and P b .001, respectively). There were significant

b.001 b.001 .002

Data are expressed as mean ± SD or count (percentage of the 100 subjects) for categorical variables unless otherwise indicated. Abbreviations: Hct, hematocrit; PCT, plateletcrit; PDW, platelet distribution width; RDW, red cell distribution width; BEecf, base excess of extracellular fluid.

Fig. 2. Areas under the ROC curve in prediction of 28-day mortality.

Please cite this article as: Golcuk Y, et al, The prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with community-acquired pneumonia, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.05.047

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Y. Golcuk et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx

Table 2 Areas under the ROC curve in prediction of 28-day mortality Variables

PAPP-A PSI CORB-75 CURB-65

P

b.001 b.001 b.001 b.001

SE

.45 .40 .46 .49

Areas

.886 .885 .825 .814

Table 3 Multivariate logistic regression analysis for the prediction of death

95% CI Lower bound

Upper bound

.797 .808 .735 .719

.975 .963 .915 .910

positive correlations between admission PAPP-A levels and PSI (r = .440, P b .001), CORB-75 (r = .395, P b .001), and CURB-65 (r = .359, P b .001) scores. Among patients with CAP, ROC analysis demonstrated that the optimal PAPP-A cutoff point for predicting 28-day mortality was 5.1 ng/mL, which had 77.3% sensitivity and 77.9% specificity (95% confidence interval [CI], area under the curve, 0.886; P b .001) (Fig. 2 and Table 2). Twentytwo patients died during the first 28-day period. Of those 22 patients, 17 (68.1%) had a PAPP-A level higher than 5.1 ng/mL (Fisher exact test, P = .002). Fig. 3 shows the Kaplan-Meier survival curve for PAPP-A level according to these cutoff values. Patients with PAPP-A levels above the cutoff value had significantly higher mortality rates at 28 days than those with PAPP-A levels below the cutoff (log-rank test = 22.43, P b .001). Independent predictors for 28-day mortality rates were determined to be PAPP-A (N5.1 ng/mL), mechanical ventilation, and MPV (P = .008, P b .001, and P = .001, respectively, Table 3).

4. Discussion This study was conducted to determine whether admission serum PAPP-A levels are elevated in nonsurviving elderly patients with CAP and whether this enhancement correlates with the severity of clinical scoring tools in these patients. Our results demonstrated, for the first time, that the admission PAPP-A levels were significantly higher in elderly CAP patients dying within 28 days compared with survivors. Furthermore, the admission PAPP-A level was identified as a reliable and independent marker to predict patients at risk for 28-day mortality. Importantly, the serum level of PAPP-A was strongly correlated with the severity of CAP based on the CURB-65, CORB-75, and PSI scores. This finding suggests that admission PAPP-A may have potential as a new candidate prognostic marker in elderly CAP patients. Many previous studies have revealed that PAPP-A is not only a sensitive, specific, and early biomarker for diagnosis but also predicts

Variables for 28 d

Odds ratio

95% CI

P

Mechanical ventilation PAPP-A (N5.1 ng/mL) MPV

49.333 28.216 .127

12.464-195.258 2.405-331.093 .039-.410

b.001 .008 .001

outcomes such as all-cause mortality and other cardiovascular events in patients with acute coronary syndromes [16]. However, only a few studies have been performed to investigate the relationship between PAPP-A and lung diseases such as asthma [17], lung cancer [18], and pulmonary embolism [19]. Until now, the value of admission PAPP-A levels and the relationship between PAPP-A levels and the clinical outcomes in elderly patients with CAP have remained unknown. Patients with CAP, the most common cause of sepsis, exhibit various elevated proinflammatory cytokines, including tumor necrosis factor α, interleukin 1 (IL-1), and IL-6. The most plausible explanation might be that the elevation of PAPP-A in septic patients represents not only continuous tissue damage, including alveolar injury due to metalloproteolytic activity but also indicates a systemic inflammatory burden. Pregnancy-associated plasma protein A can serve as a target of inflammatory cytokines such as tumor necrosis factor α, IL-1, and IL-6, which are abundantly expressed during sepsis through the nuclear factor κB pathway. These cytokines can in turn stimulate the overexpression of PAPP-A [20,21]. In this context, we can only speculate about the putative role of the PAPP-A in the setting of alveolar injury, which may lead to CAP as a clinical manifestation. The results of this study showed a positive correlation between PAPP-A levels and clinical scoring tools in elderly patients with CAP in the ED setting. Still, this research has some potential limitations. First, the small sample size and single-center setting of our study may result in reduced applicability to patients with CAP. Second, because no patients with CAP younger than 65 years old were included, the results cannot be extrapolated to a younger population. Third, no blood, bronchoalveolar lavage, or sputum cultures were performed routinely in our ED for patients with CAP, and so we cannot comment on the effect of different causative pathogens on the clinical outcomes. Finally, the effects of unmeasured confounding variables—including body mass index; the period between the onset of symptoms and confirming diagnosis; timing of PAPP-A collection; and/or complex interactions between covariates such as smoking status, causative microorganisms of CAP, race/ethnicity, nutritional status, prior pneumococcal and influenza vaccination status, and effects of socioeconomic factors—cannot be excluded. 5. Conclusions In conclusion, elevated admission serum PAPP-A levels were identified in elderly nonsurviving patients with CAP, and the significant correlation between PAPP-A and the severity of disease suggests that it may be an independent prognostic marker. However, further studies are needed to corroborate these observations. Acknowledgments The authors thank the ED staff for their great assistance. Beckman Coulter Biyomedikal Urun. San. ve Tic. Ltdi. Sti. is acknowledged for providing the PAPP-A immunoassay kits. The company had no role in the conduct of the study, analysis of the data, interpretation of results, writing of the manuscript, or the decision to submit this manuscript for publication. References

Fig. 3. Kaplan-Meier survival curve according to PAPP-A level above and below optimal cutoff value (5.1 ng/mL) for 28 days.

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Please cite this article as: Golcuk Y, et al, The prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with community-acquired pneumonia, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.05.047

Prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with CAP.

This study aims to compare serum pregnancy-associated plasma protein A (PAPP-A) levels in surviving and nonsurviving elderly patients with community-a...
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