Population study on the effects of pneumonia on long term ...



Long term mortality of hospitalised pneumonia in the EPIC-Norfolk cohortPhyo Kyaw Myint*1,2,4,7, Katie R Hawkins*3, Allan B Clark4, Robert N Luben5, Nicholas J Wareham6, Kay-Tee Khaw7, Andrew M Wilson3,41AGEING (Aberdeen Gerontological & Epidemiological Interdisciplinary Research Group), Epidemiology Group, Institute of Applied Health Sciences, School of Medicine & Dentistry, University of Aberdeen, AB25 2ZD, Aberdeen, Scotland, UK2Academic Centre for Applied Clinical & Translational Research into Ageing (ACTRA), Department of Medicine for the Elderly, Aberdeen Royal Infirmary, NHS Grampian, AB25 2ZN, Aberdeen, Scotland, UK3Department of Respiratory Medicine, Norfolk and Norwich University Hospital, NR4 7UY, Norwich, UK4Norwich Medical School, University of East Anglia, Norwich Research Park, NR4 7TJ, Norwich, UK5Strangeway Research Laboratory, Department of Public Health & Primary Care, CB1 8RN, Cambridge, UK6MRC-Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, UK7Clinical Gerontology Unit, Department of Public Health & Primary Care, School of Clinical Medicine, University of Cambridge, CB2 0QQ, Cambridge, UKProf. Phyo Kyaw Myint, Professor of Medicine of Old AgeDr Katie R Hawkins, General Practice TraineeDr Allan B Clark, Senior Lecturer in Medical StatisticsMr Robert N Luben, Senior Research AssociateProf. Nicholas J Wareham, MRC Epidemiology Unit DirectorProf. Kay-Tee Khaw, Professor of Clinical GerontologyDr Andrew M Wilson, Clinical Senior Lecturer in Respiratory Health *Joint first authorsCorrespondence to Phyo Kyaw Myint4:013 Polwarth BuildingSchool of Medicine & DentistryUniversity of Aberdeen, ForesterhillAberdeen, AB25 2ZDTel: +44 (0)1224 437841Fax: +44(0) 1224 437911 Mail to: phyo.myint@abdn.ac.ukConflict of interest: None for all authorsAbstractLittle is known about the cause-specific long term mortality beyond 30 days in pneumonia. We aimed to compare the mortality of patients with hospitalised pneumonia compared to age-sex matched controls beyond 30-days. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Hospitalised pneumonia cases were identified from record linkage (ICD 10 J12-J18). For this study we excluded people with hospitalised pneumonia who died within 30-days. Each case identified was matched for 4 controls and followed up till end June 2012 (total person year 15,074 years (mean 6.1 years, range 0.08– 15.2 years). Cox-regression models were constructed to examine the all-cause, respiratory and cardiovascular mortality using date of pneumonia onset as baseline with binary pneumonia status as exposure. A total of 2,465 men and women (503 cases and 1962 controls) (mean age 64.5, SD 8.3 years) were included in the study. Between a 30-day to one year period, HRs of all-cause and cardiovascular mortality were 7.3 (5.4-9.9) and 5.9 (3.5-9.7)respectively (with very few respiratory deaths within the same period) in cases compared to controls after adjusting for age, sex, asthma, smoking status, pack years, systolic and diastolic blood pressure, diabetes, physical activity, waist-to-hip ratio, prevalent cardiovascular and respiratory diseases. All outcomes assessed also showed increased risk of death in cases compared to controls after one year; respiratory cause of death being the most significant during that period (16.4;8.9-30.1). Hospitalised pneumonia was associated with increased all-cause and specific-cause mortality beyond 30 days.KeywordsPneumoniaLonger term mortalityAll cause mortalityCardiovascular mortalityRespiratory mortalityIntroductionPneumonia is common and combined with influenza is the fifth leading cause of death in the UK ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1bs6ntmdo3","properties":{"formattedCitation":"(1)","plainCitation":"(1)"},"citationItems":[{"id":229,"uris":[""],"uri":[""],"itemData":{"id":229,"type":"webpage","title":"Deaths registered in England and Wales in 2010, by cause","URL":"","note":"This bulletin presents the number of deaths registered in England and Wales in 2010 by age, sex and selected underlying cause of death.","language":"eng","author":[{"family":"Office for National Statistics","given":""}],"issued":{"date-parts":[["2011",10,28]]},"accessed":{"date-parts":[["2013",2,22]]}}}],"schema":""} (1). It is the third leading cause of death globally accounting for 7.1% of all deaths along with other lower respiratory tract infections ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1svkbof7pj","properties":{"formattedCitation":"(2)","plainCitation":"(2)"},"citationItems":[{"id":299,"uris":[""],"uri":[""],"itemData":{"id":299,"type":"book","title":"The Global Burden of Disease: 2004 Update","publisher":"World Health Organization","number-of-pages":"156","source":"Google Books","abstract":"This report provides a comprehensive assessment of the health of the world's population in 2004. Consistent and comparative description of the burden of diseases and injuries is an important input to health decision-making and planning processes. The Global Burden of Disease provides a framework for integrating the available information on mortality and health in populations to assess the comparative importance of diseases and injuries in causing premature death, loss of health and disability in all regions of the world.This report draws upon the extensive databases of the World Health Organization and information provided by Member States to provide detailed estimates of premature mortality, disability and loss of health for 135 causes by age and sex for the world as a whole, for regions of the world, and for countries grouped by average income per capita. It builds on previous assessments for the years 2000-2002 published in The World Health Reports and World Health Statistics.","ISBN":"9789241563710","shortTitle":"The Global Burden of Disease","language":"en","author":[{"family":"Mathers","given":"Colin D."},{"family":"Fat","given":"Doris Ma"},{"family":"Boerma","given":"J. T."},{"family":"Organization","given":"World Health"}],"issued":{"date-parts":[["2008"]]}}}],"schema":""} (2). Pneumonia is also one of the main causes of hospital admissions ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4jgb7ln3q","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":197,"uris":[""],"uri":[""],"itemData":{"id":197,"type":"article-journal","title":"Community-acquired pneumonia: the annual cost to the National Health Service in the UK","container-title":"The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology","page":"1530-1534","volume":"10","issue":"7","source":"NCBI PubMed","abstract":"The aim of this study was to estimate the direct annual healthcare costs to the UK National Health Service (NHS) of managing community-acquired pneumonia. Using a prevalence-based burden of illness approach, health service resource use and corresponding costs attributable to the management of community-acquired pneumonia during 1992/1993 in the UK were obtained from published sources and commercial databases, and supplemented by a telephone survey of general practitioners, finance directors, community nurses, receptionists and nurses in out-patient respiratory clinics, ambulance services, and consultant respiratory physicians. The study was appraised by a Peer Review Panel, representing a cross-section of experts from different locations. This study was a predefined subgroup analysis of a previous, larger study that estimated the annual cost to the NHS of treating all community-acquired lower respiratory tract infections. The analysis shows that there are 261,000 episodes of community-acquired pneumonia annually in the UK, costing 440.7 million pounds at 1992/1993 prices (32% of the annual cost for all community-acquired lower respiratory tract infections). Approximately 83,153 annual cases of community-acquired pneumonia are treated in hospital (32% of all episodes) and account for 96% of the annual cost. The average cost for managing pneumonia in the community is 100 pounds per episode, compared to 1,700-5,100 pounds when the patient is hospitalized, depending on the length of hospitalization. Hospitalization accounts for 87% of the total annual cost. In conclusion, community-acquired pneumonia in the UK incurs a direct healthcare cost of 440.7 million pounds annually at 1992/1993 prices. Developing and implementing strategies to prevent and minimize hospitalization will significantly reduce this annual cost and should be assessed in future studies.","ISSN":"0903-1936","note":"PMID: 9230242","shortTitle":"Community-acquired pneumonia","journalAbbreviation":"Eur. Respir. J.","author":[{"family":"Guest","given":"J F"},{"family":"Morris","given":"A"}],"issued":{"date-parts":[["1997",7]]},"PMID":"9230242"}}],"schema":""} (3) and according to US figures up to 10-20% of all hospitalisations with pneumonia require treatment in the intensive care unit ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cnsqi426s","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":297,"uris":[""],"uri":[""],"itemData":{"id":297,"type":"article-journal","title":"Burden of community-acquired pneumonia in North American adults","container-title":"Postgraduate medicine","page":"130-141","volume":"122","issue":"2","source":"NCBI PubMed","abstract":"To determine the burden of community-acquired pneumonia (CAP) affecting adults in North America, a comprehensive literature review was conducted to examine the incidence, morbidity and mortality, etiology, antibiotic resistance, and economic impact of CAP in this population. In the United States, there were approximately 4.2 million ambulatory care visits for pneumonia in 2006. Pneumonia and influenza continue to be a common cause of death in the United States (ranked eighth) and Canada (ranked seventh). In 2005, there were >60,000 deaths due to pneumonia in persons aged>or=15 years in the United States alone. The hospitalization rate for all infectious diseases increased from 1525 hospitalizations per 100 000 persons in 1998 to 1667 per 100 000 persons in 2005. Admission to an intensive care unit was required in 10% to 20% of patients hospitalized with pneumonia. The mean length of stay for pneumonia was >or=5 days and the 30-day rehospitalization rate was as high as 20%. Mortality was highest for CAP patients who were hospitalized; the 30-day mortality rate was as high as 23%. All-cause mortality for CAP patients was as high as 28% within 1 year. Streptococcus pneumoniae continues to be the most frequently identified pathogen associated with CAP, and pneumococcal resistance to antimicrobials may make treatment more difficult. The economic burden associated with CAP remains substantial at >$17 billion annually in the United States. Despite the availability and widespread adherence to recommended treatment guidelines, CAP continues to present a significant burden in adults. Furthermore, given the aging population in North America, clinicians can expect to encounter an increasing number of adult patients with CAP. Given the significance of the disease burden, the potential benefit of pneumococcal vaccination in adults is substantial.","DOI":"10.3810/pgm.2010.03.2130","ISSN":"1941-9260","note":"PMID: 20203464","journalAbbreviation":"Postgrad Med","author":[{"family":"File","given":"Thomas M, Jr"},{"family":"Marrie","given":"Thomas J"}],"issued":{"date-parts":[["2010",3]]},"PMID":"20203464"}}],"schema":""} (4). The short term mortality from pneumonia is well documented and is consistently between 10-11% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"14qr6laaia","properties":{"formattedCitation":"(5,6)","plainCitation":"(5,6)"},"citationItems":[{"id":250,"uris":[""],"uri":[""],"itemData":{"id":250,"type":"article-journal","title":"Hospitalized pneumonia. Outcomes, treatment patterns, and costs in urban and rural areas","container-title":"Journal of general internal medicine","page":"415-421","volume":"11","issue":"7","source":"NCBI PubMed","abstract":"OBJECTIVES\n\nTo describe discharge rates, geographic and patient characteristics, treatment patterns, costs, and outcomes of patients hospitalized with community-acquired pneumonia (CAP) in Pennsylvania hospitals and compare these patients from rural and urban counties.\n\n\nDESIGN\n\nA retrospective database study.\n\n\nPATIENTS\n\nAdult patients (age > or = 18) with an ICD-9-CM diagnosis of pneumonia discharged from 193 Pennsylvania hospitals (n = 36,222) in 1991 from the MediQual Systems Pennsylvania database.\n\n\nMEASUREMENTS\n\nPatient characteristics included a pneumonia-specific severity index, microbiologic etiology, and a number of comorbid conditions. Treatment indicators included the specialty of the admitting physician, length of stay, admittance to an intensive care unit, and mechanical ventilation. Cost indicators included charges and estimated costs. Outcomes measured were inpatient mortality and discharge disposition. Counties in Pennsylvania were classified into seven urban or rural groups, and patients were classified by the county of residence.\n\n\nRESULTS\n\nThe discharge rate for CAP was 4.0 per 1,000 and did not vary systematically across urban or rural counties. Most patients were treated in local hospitals. The average distance between residence and hospital was 5.4 miles and varied with urban or rural classification (range 2.5-9.3 miles). Among CAP patients, 37.8% were at low risk of mortality, with no systematic differences across rural or urban patients with respect to pneumonia severity. Rural patients were more likely to be treated by a family physician and somewhat less likely to be admitted to an intensive care unit or to be mechanically ventilated. Costs of treating rural patients were lower. In-hospital mortality rates, with controls for admission severity, were comparable or better for rural patients than for urban patients.\n\n\nCONCLUSIONS\n\nPatients with CAP are treated in hospitals located in counties similar to ones in which they reside. The cost of treatment was lower for rural patients than for urban patients, but outcomes were not different.","ISSN":"0884-8734","note":"PMID: 8842934","journalAbbreviation":"J Gen Intern Med","author":[{"family":"Lave","given":"J R"},{"family":"Fine","given":"M J"},{"family":"Sankey","given":"S S"},{"family":"Hanusa","given":"B H"},{"family":"Weissfeld","given":"L A"},{"family":"Kapoor","given":"W N"}],"issued":{"date-parts":[["1996",7]]},"PMID":"8842934"}},{"id":262,"uris":[""],"uri":[""],"itemData":{"id":262,"type":"article-journal","title":"Mortality during hospitalisation for pneumonia in Alberta, Canada, is associated with physician volume","container-title":"European Respiratory Journal","page":"148-155","volume":"22","issue":"1","source":"erj.","abstract":"The association of mortality with patient factors (severity of illness, comorbidity), physician factors (specialty training, prehospitalisation visit, in-hospital consultation, volume of patients seen per physician) and healthcare organisation factors (patient-travel distances, regional beds per capita, admitting hospital-bed occupancy, admitting hospital-bed turnover, hospital location, volume of pneumonia cases per hospital) after hospital admission with community-acquired pneumonia was investigated using administrative data from Alberta, Canada from April 1, 1994–March 31, 1999.\nDuring the 5‐yr study period there were 43,642 pneumonia hospitalisations, with an 11% in-hospital and 26% 1‐yr mortality. Patient severity of illness and comorbidity were the strongest predictors of increased mortality. Physicians with the highest in-hospital pneumonia patient volume (>27 patients·yr?1) cared for patients with greater severity/comorbidity, but with decreased odds of in-hospital mortality, compared with the lowest volume physicians (less than seven patients per year).\nThe effects of internal medicine specialist or subspecialist care were mixed, with a reduction in deaths for the first 72 h and an increase in in-hospital deaths. Pre-hospitalisation visit by a physician was associated with decreased mortality. Healthcare organisation factors were the least strong predictor of mortality, demonstrating an effect only for 1‐yr mortality in those discharged alive from hospital. Admissions to larger volume or metropolitan hospitals were associated with a decrease in mortality.\nSeverity of illness and comorbidity had the strongest association with mortality. The first association of high-volume physician and pre-hospital care with decreased in-hospital mortality for community-acquired pneumonia is reported.","DOI":"10.1183/09031936.03.00115703","ISSN":"0903-1936, 1399-3003","journalAbbreviation":"Eur Respir J","language":"en","author":[{"family":"Marrie","given":"T. J."},{"family":"Carriere","given":"K. C."},{"family":"Jin","given":"Y."},{"family":"Johnson","given":"D. H."}],"issued":{"date-parts":[["2003",7,1]]},"accessed":{"date-parts":[["2013",2,26]]}}}],"schema":""} (5,6). Mortality from pneumonia is typically assessed at 30 days or at discharge from hospital ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2g2adjic78","properties":{"formattedCitation":"(7,8)","plainCitation":"(7,8)"},"citationItems":[{"id":269,"uris":[""],"uri":[""],"itemData":{"id":269,"type":"article-journal","title":"Population-based cohort study of outpatients with pneumonia: rationale, design and baseline characteristics","container-title":"BMC infectious diseases","page":"135","volume":"12","source":"NCBI PubMed","abstract":"BACKGROUND\n\nThe vast majority of research in the area of community-acquired pneumonia (CAP) has been based on patients admitted to hospital. And yet, the majority of patients with CAP are treated on an ambulatory basis as outpatients, either by primary care physicians or in Emergency Departments. Few studies have been conducted in outpatients with pneumonia, and there is a paucity of data on short and long term morbidity or mortality and associated clinical correlates in this group of patients.\n\n\nMETHODS\n\nFrom 2000-2002, all CAP patients presenting to 7 Emergency Departments in Edmonton, Alberta, Canada were prospectively enrolled in a population-based registry. Clinical data, including pneumonia severity index (PSI) were collected at time of presentation. Patients discharged to the community were then followed for up to 5?years through linkage to the provincial administrative databases. The current report provides the rationale and design for the cohort, as well as describes baseline characteristics and 30-day morbidity and mortality.\n\n\nRESULTS\n\nThe total sample included 3874 patients. After excluding patients who were hospitalized, died or returned to the Emergency Department the same day they were initially discharged (n?=?451; 12?%), and patients who could not be linked to provincial administrative databases (n?=?237; 6?%), the final cohort included 3186 patients treated according to a validated clinical management pathway and discharged back to the community. Mean age was 51 (SD?=?20) years, 53?% male; 4?% resided in a nursing home, 95?% were independently mobile, and 88?% had mild (PSI class I-III) pneumonia. Within 30-days, return to Emergency Department was common (25?%) as was hospitalization (8?%) and 1?% of patients had died.\n\n\nCONCLUSIONS\n\nTo our knowledge, this represents the largest clinically-detailed outpatient CAP cohort assembled to date and will add to our understanding of the determinants and outcomes in this under-researched patient population. The rich clinical data along with the long term health care utilization and mortality will allow for the identification of novel prognostic indicators. Given how under studied this population is, the findings should aid clinicians in the routine care of their outpatients with pneumonia and help define the next generation of research questions.","DOI":"10.1186/1471-2334-12-135","ISSN":"1471-2334","note":"PMID: 22709357","shortTitle":"Population-based cohort study of outpatients with pneumonia","journalAbbreviation":"BMC Infect. Dis.","author":[{"family":"Eurich","given":"Dean T"},{"family":"Majumdar","given":"Sumit R"},{"family":"Marrie","given":"Thomas J"}],"issued":{"date-parts":[["2012"]]},"PMID":"22709357"}},{"id":266,"uris":[""],"uri":[""],"itemData":{"id":266,"type":"article-journal","title":"Comparison of clinical characteristics between healthcare-associated pneumonia and community-acquired pneumonia in patients admitted to secondary hospitals","container-title":"The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases","page":"321-328","volume":"16","issue":"4","source":"NCBI PubMed","abstract":"BACKGROUND\n\nSince healthcare-associated pneumonia (HCAP) is heterogeneous, clinical characteristics and outcomes are different from region to region. There can also be differences between HCAP patients hospitalized in secondary or tertiary hospitals. This study aimed to evaluate the clinical characteristics of HCAP patients admitted into secondary community hospitals.\n\n\nMETHODS\n\nThis was a retrospective study conducted in patients with HCAP or community-acquired pneumonia (CAP) hospitalized in two secondary hospitals between March 2009 and January 2011.\n\n\nRESULTS\n\nOf a total of 303 patients, 96 (31.7%) had HCAP. 42 patients (43.7%) resided in a nursing home or long-term care facility, 36 (37.5%) were hospitalized in an acute care hospital for ≥ 2 days within 90 days, ten received outpatient intravenous therapy, and eight attended a hospital clinic or dialysis center. HCAP patients were older. The rates of patients with CURB-65 scores of 3 or more (22.9% vs. 9.1%; p=0.001) and PSI class IV or more (82.2% vs. 34.7%; p<0.001) were higher in the HCAP group. Drug-resistant pathogens were more frequently detected in the HCAP group (23.9% vs. 0.4%; p<0.001). However, Streptococcus pneumoniae was the most common pathogen in both groups. The rates of antibiotic change, use of inappropriate antibiotics, and failure of initial antibiotic therapy in the HCAP group were significantly higher. Although the overall survival rate of the HCAP group was significantly lower (82.3% vs. 96.8%; p<0.001), multivariate analyses failed to show that HCAP itself was a prognostic factor for mortality (p=0.826). Only PSI class IV or more was associated with increased mortality (p=0.005).\n\n\nCONCLUSIONS\n\nHCAP should be distinguished from CAP because of the different clinical features. However, the current definition of HCAP does not appear to be a prognostic for death. In addition, the use of broad-spectrum antibiotics for HCAP should be reassessed because S. pneumoniae was most frequently identified even in HCAP patients.","DOI":"10.1016/j.bjid.2012.06.019","ISSN":"1678-4391","note":"PMID: 22846118","journalAbbreviation":"Braz J Infect Dis","author":[{"family":"Hoo Lee","given":"Jong"},{"family":"Hyung Kim","given":"Yee"}],"issued":{"date-parts":[["2012",8]]},"PMID":"22846118"}}],"schema":""} (7,8) and patients who have clinical resolution of their symptoms at this time are classified as having survived the episode ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"314r0tfaa","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":271,"uris":[""],"uri":[""],"itemData":{"id":271,"type":"article-journal","title":"Changing needs of community-acquired pneumonia","container-title":"The Journal of antimicrobial chemotherapy","page":"iii3-9","volume":"66 Suppl 3","source":"NCBI PubMed","abstract":"Community-acquired pneumonia (CAP) is a serious condition associated with significant morbidity and potential long-term mortality. Although the majority of patients with CAP are treated as outpatients, the greatest proportion of pneumonia-related mortality and healthcare expenditure occurs among the patients who are hospitalized. There has been considerable interest in determining risk factors and severity criteria assessments to assist with site-of-care decisions. For both inpatients and outpatients, the most common pathogens associated with CAP include Streptococcus pneumoniae, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis. Atypical pathogens, Gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA) and viruses are also recognized aetiological agents of CAP. Despite the availability of antimicrobial therapies, the recent emergence of drug-resistant pneumococcal and staphylococcal isolates has limited the effectiveness of currently available agents. Because early and rapid initiation of empirical antimicrobial treatment is critical for achieving a favourable outcome in CAP, newer agents with activity against drug-resistant strains of S. pneumoniae and MRSA are needed for the management of patients with CAP.","DOI":"10.1093/jac/dkr094","ISSN":"1460-2091","note":"PMID: 21482567","journalAbbreviation":"J. Antimicrob. Chemother.","author":[{"family":"Ramirez","given":"Julio Alberto"},{"family":"Anzueto","given":"Antonio R"}],"issued":{"date-parts":[["2011",4]]},"PMID":"21482567"}}],"schema":""} (9). It is also suggested that pneumonia produces a chronic inflammatory response which may accelerate the process of cardiovascular disease in the intermediate term ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ev9hqr98e","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}}],"schema":""} (10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1po5rfafsv","properties":{"formattedCitation":"(14)","plainCitation":"(14)","dontUpdate":true},"citationItems":[{"id":211,"uris":[""],"uri":[""],"itemData":{"id":211,"type":"article-journal","title":"Influence of comorbid conditions on long-term mortality after pneumonia in older people","container-title":"Journal of the American Geriatrics Society","page":"518-525","volume":"55","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVES\n\nTo test the hypothesis that increased long-term mortality after hospitalization for community-acquired pneumonia (CAP) is independent of comorbid conditions.\n\n\nDESIGN\n\nProspective observational cohort study in metropolitan areas.\n\n\nSETTING\n\nMemphis, Tennessee, and Pittsburgh, Pennsylvania.\n\n\nPARTICIPANTS\n\nThree thousand seventy-five subjects aged 70 to 79 over 5.2 years.\n\n\nMEASUREMENTS\n\nUnadjusted and adjusted mortality from an initial hospitalization for CAP were compared with mortality from different causes of hospitalization, including cancer, fracture, congestive heart failure (CHF), cerebrovascular accident (CVA), and other causes. Demographics, smoking, nutritional markers, functional status, inflammatory markers, and chronic health conditions were adjusted for.\n\n\nRESULTS\n\nOf the 106 subjects hospitalized for CAP, 22 (20.8%) and 38 (35.8%) died at 1 and 5 years. Subjects hospitalized with CAP had higher mortality than nonhospitalized subjects (adjusted odds ratio (OR)=7.8, 95% confidence interval (CI)=4.2-14.4). One- and 5-year mortality after CAP hospitalization were higher than mortality from other causes requiring hospitalization and remained unchanged in multivariable analysis (adjusted OR=3.5, 95% CI=1.5-8.1; adjusted OR=5.6, 95% CI=2.8-11.2, respectively). One- and 5-year mortality after hospitalization for CAP were similar to or higher than mortality after an initial hospitalization for CHF, CVA, or fracture. Rehospitalization was common in subjects hospitalized for CAP and may explain greater long-term mortality.\n\n\nCONCLUSION\n\nIn this high-functioning cohort of older persons, an initial hospitalization for CAP was associated with greater long-term mortality, independent of prehospitalization comorbid conditions. Hospitalization for CAP has as serious a prognosis as hospitalization for CHF, stroke, or major fracture.","DOI":"10.1111/j.1532-5415.2007.01100.x","ISSN":"0002-8614","note":"PMID: 17397429","journalAbbreviation":"J Am Geriatr Soc","author":[{"family":"Yende","given":"Sachin"},{"family":"Angus","given":"Derek C"},{"family":"Ali","given":"Ibrahim Sultan"},{"family":"Somes","given":"Grant"},{"family":"Newman","given":"Anne B"},{"family":"Bauer","given":"Douglas"},{"family":"Garcia","given":"Melissa"},{"family":"Harris","given":"Tamara B"},{"family":"Kritchevsky","given":"Stephen B"}],"issued":{"date-parts":[["2007",4]]},"PMID":"17397429"}}],"schema":""} . Indeed, it has been shown in a study of 1,799 patients hospitalised with pneumonia, those with raised pro-inflammatory cytokines at discharge had an increased risk of cardiovascular death at one year, which was independent of the severity of the pneumonia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mknmf10mf","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}}],"schema":""} (10). More recent studies suggest that pneumonia may influence the patient’s longer term survival ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"114gfc3gq6","properties":{"formattedCitation":"{\\rtf (12\\uc0\\u8211{}14)}","plainCitation":"(12–14)"},"citationItems":[{"id":215,"uris":[""],"uri":[""],"itemData":{"id":215,"type":"article-journal","title":"Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia","container-title":"Clinical infectious diseases: an official publication of the Infectious Diseases Society of America","page":"1617-1624","volume":"37","issue":"12","source":"NCBI PubMed","abstract":"Although studies have assessed short-term mortality among patients with community-acquired pneumonia, there is limited data on prognosis and risk factors that affect long-term mortality. The mortality among patients enrolled at 4 sites of the Pneumonia Patient Outcome Research Team cohort study who survived at least 90 days after presentation to the hospital was compared with that among age-matched control subjects. Overall, 1419 of 1555 patients survived for >90 days, with a mean follow-up period of 5.9 years. There was significantly higher long-term mortality among patients with pneumonia than among age-matched controls. Factors significantly associated with long-term mortality were age (stratified by decade), do-not-resuscitate status, poor nutritional status, pleural effusion, glucocorticoid use, nursing home residence, high school graduation level or less, male sex, preexisting comorbid illnesses, and the lack of feverishness. This study demonstrates that there is significantly higher long-term mortality among patients with pneumonia than among age-matched controls and that long-term mortality largely is not affected by acute physiologic derangements.","DOI":"10.1086/379712","ISSN":"1537-6591","note":"PMID: 14689342","journalAbbreviation":"Clin. Infect. Dis.","author":[{"family":"Mortensen","given":"Eric M"},{"family":"Kapoor","given":"Wishwa N"},{"family":"Chang","given":"Chung-Chou H"},{"family":"Fine","given":"Michael J"}],"issued":{"date-parts":[["2003",12,15]]},"PMID":"14689342"}},{"id":273,"uris":[""],"uri":[""],"itemData":{"id":273,"type":"article-journal","title":"Medium-term survival after hospitalization with community-acquired pneumonia","container-title":"American journal of respiratory and critical care medicine","page":"910-914","volume":"169","issue":"8","source":"NCBI PubMed","abstract":"An episode of community-acquired pneumonia (CAP) has been suggested to predict greater than expected mortality after discharge from hospital. We ascertained the survival status as of December 2002 of a cohort of patients with CAP identified prospectively between November 1998 and June 2001. Cox regression analysis was used to examine the impact of demographic factors, comorbid illnesses, and CAP severity on subsequent mortality. Of 378 CAP survivors we ascertained the survival status of 366 (96.9%), 125 (34.1%) of whom had died. The mean length of follow-up was 1,058 days (range, 602-1,500 days). Independent predictors of mortality were increasing age (p < 0.001), comorbid cerebrovascular (p = 0.002) and cardiovascular (p = 0.023) disease, an altered mental state (p < 0.001), a hematocrit of less than 35% (p = 0.035), and increasing blood glucose level (p = 0.025). In 41- to 80-year-olds without significant comorbidities there was a trend to greater than expected mortality. In conclusion, an episode of CAP in young adults without significant comorbid illnesses does not appear to be an adverse prognostic marker of medium-term survival. The trend to greater than expected mortality in patients over 40 years of age needs further study and physicians should be particularly alert for underlying life-limiting disease processes in patients presenting with acute confusion or a hematocrit of less than 35%.","DOI":"10.1164/rccm.200310-1448OC","ISSN":"1073-449X","note":"PMID: 14693672","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Waterer","given":"Grant W"},{"family":"Kessler","given":"Lori A"},{"family":"Wunderink","given":"Richard G"}],"issued":{"date-parts":[["2004",4,15]]},"PMID":"14693672"}},{"id":206,"uris":[""],"uri":[""],"itemData":{"id":206,"type":"article-journal","title":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: a population-based cohort study","container-title":"Medicine","page":"329-334","volume":"87","issue":"6","source":"NCBI PubMed","abstract":"Little is known about the long-term sequelae of community-acquired pneumonia (CAP). Therefore, we describe the long-term morbidity and mortality of patients after pneumonia requiring hospitalization. We specifically hypothesized that the Pneumonia Severity Index (PSI), designed to predict 30-day pneumonia-related mortality, would also be associated with longer-term all-cause mortality. Between 2000 and 2002, 3415 adults with CAP admitted to 6 hospitals in Edmonton, Alberta, Canada, were prospectively enrolled in a population-based cohort. At the time of hospital admission, demographic, clinical, and laboratory data were collected and the PSI was calculated for each patient. Postdischarge outcomes through to 2006 were ascertained using multiple linked administrative databases. Outcomes included all-cause mortality, hospital admissions, and re-hospitalization for pneumonia over a maximum of 5.4 years of follow-up. Follow-up data were available for 3284 (96%) patients; 66%were > or =65 years of age, 53% were male, and according to the PSI fully 63% were predicted to have greater than 18% 30-day pneumonia-related mortality (that is, PSI class IV-V). Median follow-up was 3.8 years. The 30-day, 1-year, and end of study mortality rates were 12%, 28%, and 53%, respectively. Overall, 82(19%) patients aged <45 years died compared with 1456 (67%) patients aged > or =65 years (hazard ratio [HR], 5.07; 95% confidence interval [CI], 4.06-6.34). Male patients were more likely to die than female patients during follow-up (971 [56%] vs. 767 [49%], respectively; HR, 1.20; 95% CI, 1.13-1.37). Initial PSI classification predicted not only 30-day mortality, but also long-term postdischarge mortality, with 92 (15%) of PSI class I-II patients dying compared with 616 (82%) PSI class V patients (HR, 11.80; 95% CI, 4.70-14.70). Of 2950 patients who survived the initial CAP hospitalization, 72% were hospitalized again (median, 2 admissions over follow-up) and 16% were re-hospitalized with pneumonia. In conclusion, long-term morbidity and mortality are high following hospitalization for pneumonia and are strongly correlated with initial PSI class. This suggests that patients with pneumonia, especially those with PSI class IV and V at admission, might need better attention paid to preventive strategies and much closer follow-up due to their elevated risk of subsequent adverse events and increased health resource utilization.","DOI":"10.1097/MD.0b013e318190f444","ISSN":"1536-5964","note":"PMID: 19011504","shortTitle":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia","journalAbbreviation":"Medicine (Baltimore)","author":[{"family":"Johnstone","given":"Jennie"},{"family":"Eurich","given":"Dean T"},{"family":"Majumdar","given":"Sumit R"},{"family":"Jin","given":"Yan"},{"family":"Marrie","given":"Thomas J"}],"issued":{"date-parts":[["2008",11]]},"PMID":"19011504"}}],"schema":""} (12–14). Mortality was 10% higher at 1 year for elderly patients with pneumonia compared to other hospitalised survivors ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1nv2hhg7li","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":204,"uris":[""],"uri":[""],"itemData":{"id":204,"type":"article-journal","title":"Pneumonia: still the old man's friend?","container-title":"Archives of internal medicine","page":"317-323","volume":"163","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND\n\nHospital mortality of patients admitted with community-acquired pneumonia (CAP) has been well described. However, the long-term survival of those discharged alive is less clear. We sought to determine long-term survival of patients hospitalized with CAP and compare the outcome with controls hospitalized for reasons other than CAP.\n\n\nMETHODS\n\nWe performed a matched case-control analysis using the Medicare hospital discharge database from the first quarter of 1997. We compared all Medicare recipients 65 years or older hospitalized with CAP and controls matched for age, sex, and race hospitalized for reasons other than CAP. We measured 1-year mortality determined from the Medicare Beneficiary Entitlement file and the Social Security Administration.\n\n\nRESULTS\n\nWe identified 158 960 CAP patients and 794 333 hospitalized controls. Hospital mortality rates for the CAP cohort and hospitalized controls were 11.0% and 5.5%, respectively (P<.001). One-year mortality rates for the CAP cohort and hospitalized controls were 40.9% and 29.1%, respectively (P<.001). One-year mortality rates in hospital survivors of the CAP and control cohorts were 33.6% and 24.9%, respectively (P<.001). The difference in mortality between the CAP and control cohorts was not explained by underlying disease. Standardized against the general population, the risk of death for both cohorts decreased monthly but was still elevated 1 year after hospital discharge. The standardized mortality ratio was 2.69 (95% confidence interval, 2.47-2.93) for CAP patients and 1.93 (95% confidence interval, 1.79-2.08) for hospital controls.\n\n\nCONCLUSIONS\n\nAlmost half of all elderly patients admitted for CAP die in the subsequent year, with most deaths occurring after hospital discharge. The mortality is considerably higher than that of either the general population or a control population hospitalized for reasons other than CAP.","ISSN":"0003-9926","note":"PMID: 12578512","shortTitle":"Pneumonia","journalAbbreviation":"Arch. Intern. Med.","author":[{"family":"Kaplan","given":"Vladimir"},{"family":"Clermont","given":"Gilles"},{"family":"Griffin","given":"Martin F"},{"family":"Kasal","given":"Jan"},{"family":"Watson","given":"R Scott"},{"family":"Linde-Zwirble","given":"Walter T"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2003",2,10]]},"PMID":"12578512"}}],"schema":""} (15) and though few studies have analysed specific cause of death post pneumonia diagnosis, cardiovascular disease caused a third of all deaths from 300 patients at one year follow up in a hospital-based study ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ndad62loq","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}}],"schema":""} (10). It is not known whether pneumonia has impact on longer term mortality in an unselected general population and whether it is linked to cardiovascular cause of death post one year follow up. While there appears to be a greater incidence of cardiovascular disease at 1 year following pneumonia, the risk of cardiovascular disease at different time points post pneumonia diagnosis has not been assessed. The goals of this study were to examine the association of hospitalised pneumonia on both short (beyond 30 days up to a year) and long term all cause and cause-specific mortality focusing on respiratory and cardiovascular causes of death in a general population of middle and older age participants after taking into account potential confounders. Material and MethodsStudy PopulationAll study participants were selected from the participants of European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population based cohort study. This cohort forms part of a Europe-wide multicentre prospective population study, primarily designed to investigate the relationship between diet and cancer. The study was approved by the Norwich Research Ethics Committee (R&D Reference No. 98CN01). The methods of the EPIC-Norfolk study have been described in depth elsewhere ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2i0m2mmig2","properties":{"formattedCitation":"(16)","plainCitation":"(16)"},"citationItems":[{"id":154,"uris":[""],"uri":[""],"itemData":{"id":154,"type":"article-journal","title":"Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study","container-title":"PLoS Med","page":"e12","volume":"5","issue":"1","source":"PLoS Med","abstract":"From a large prospective population study, Kay-Tee Khaw and colleagues estimate the \n combined impact of four behaviors--not smoking, not being physically inactive, moderate \n alcohol intake, and at least five vegetable servings a day--amounts to 14 additional years \n of life.","DOI":"10.1371/journal.pmed.0050012","shortTitle":"Combined Impact of Health Behaviours and Mortality in Men and Women","journalAbbreviation":"PLoS Med","author":[{"family":"Khaw","given":"Kay-Tee"},{"family":"Wareham","given":"Nicholas"},{"family":"Bingham","given":"Sheila"},{"family":"Welch","given":"Ailsa"},{"family":"Luben","given":"Robert"},{"family":"Day","given":"Nicholas"}],"issued":{"date-parts":[["2008",1,8]]},"accessed":{"date-parts":[["2013",2,5]]}}}],"schema":""} (16). The Norfolk population is a mix of urban and rural populations and has high coverage of primary care physicians (General Practitioners). It is for the most part representative of the UK population, however, there is lower ethnic diversity in this area than the general UK population and the EPIC-Norfolk cohort is 99.6% white. Briefly, participants were men and women aged 40 -79 years recruited between 1993 and 1998. Participants underwent a detailed baseline health examination in which demographic, physiological and behavioural factors were ascertained. This included prevalent illness, smoking status, body mass index (BMI) measured using standard protocols (16). They were followed up for health events using record linkage.Hospitalised cases of pneumonia were identified through linkage with hospital records using ICD 10 J12-J18. 1064 cases and 4120 controls (1:4) matched for age, sex and year of recruitment in the EPIC-Norfolk. All participants who reported cancer, myocardial infarction and stroke at the EPIC-Norfolk study baseline were excluded. To reduce the bias of excess mortality within 30-days from respiratory cause of death of cases which are identified through death certification from the Office of National Statistics, we excluded any cases who died within 30-days of hospitalisation and their matched controls leaving 503 cases and 1962 controls for the analyses. The start date for analysis for the current study was the date of diagnosis of pneumonia for cases and the same date for case matched controls. The study follow up period was from the start date to date of death or end of follow up (end June 2012). Prevalent cardiovascular disease (CVD) for the current report was defined as new diagnosis of CVD after EPIC-Norfolk enrolment but made before the pneumonia date for cases and respective corresponding date for controls. Outcome MeasurementsThe primary outcome of interest was all-cause mortality. Secondary outcomes were respiratory mortality and cardiovascular mortality. Mortality data were obtained from linkage with Office of National Statistics in UK. Mortality was assessed between 30 days and 1 year for short term and greater than 1 year for long term ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2bdafcss9k","properties":{"formattedCitation":"(11,14,17)","plainCitation":"(11,14,17)"},"citationItems":[{"id":211,"uris":[""],"uri":[""],"itemData":{"id":211,"type":"article-journal","title":"Influence of comorbid conditions on long-term mortality after pneumonia in older people","container-title":"Journal of the American Geriatrics Society","page":"518-525","volume":"55","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVES\n\nTo test the hypothesis that increased long-term mortality after hospitalization for community-acquired pneumonia (CAP) is independent of comorbid conditions.\n\n\nDESIGN\n\nProspective observational cohort study in metropolitan areas.\n\n\nSETTING\n\nMemphis, Tennessee, and Pittsburgh, Pennsylvania.\n\n\nPARTICIPANTS\n\nThree thousand seventy-five subjects aged 70 to 79 over 5.2 years.\n\n\nMEASUREMENTS\n\nUnadjusted and adjusted mortality from an initial hospitalization for CAP were compared with mortality from different causes of hospitalization, including cancer, fracture, congestive heart failure (CHF), cerebrovascular accident (CVA), and other causes. Demographics, smoking, nutritional markers, functional status, inflammatory markers, and chronic health conditions were adjusted for.\n\n\nRESULTS\n\nOf the 106 subjects hospitalized for CAP, 22 (20.8%) and 38 (35.8%) died at 1 and 5 years. Subjects hospitalized with CAP had higher mortality than nonhospitalized subjects (adjusted odds ratio (OR)=7.8, 95% confidence interval (CI)=4.2-14.4). One- and 5-year mortality after CAP hospitalization were higher than mortality from other causes requiring hospitalization and remained unchanged in multivariable analysis (adjusted OR=3.5, 95% CI=1.5-8.1; adjusted OR=5.6, 95% CI=2.8-11.2, respectively). One- and 5-year mortality after hospitalization for CAP were similar to or higher than mortality after an initial hospitalization for CHF, CVA, or fracture. Rehospitalization was common in subjects hospitalized for CAP and may explain greater long-term mortality.\n\n\nCONCLUSION\n\nIn this high-functioning cohort of older persons, an initial hospitalization for CAP was associated with greater long-term mortality, independent of prehospitalization comorbid conditions. Hospitalization for CAP has as serious a prognosis as hospitalization for CHF, stroke, or major fracture.","DOI":"10.1111/j.1532-5415.2007.01100.x","ISSN":"0002-8614","note":"PMID: 17397429","journalAbbreviation":"J Am Geriatr Soc","author":[{"family":"Yende","given":"Sachin"},{"family":"Angus","given":"Derek C"},{"family":"Ali","given":"Ibrahim Sultan"},{"family":"Somes","given":"Grant"},{"family":"Newman","given":"Anne B"},{"family":"Bauer","given":"Douglas"},{"family":"Garcia","given":"Melissa"},{"family":"Harris","given":"Tamara B"},{"family":"Kritchevsky","given":"Stephen B"}],"issued":{"date-parts":[["2007",4]]},"PMID":"17397429"}},{"id":5,"uris":[""],"uri":[""],"itemData":{"id":5,"type":"article-journal","title":"Pneumonia mortality in a UK general practice population cohort","container-title":"The European Journal of Public Health","page":"521-526","volume":"19","issue":"5","source":"eurpub.","abstract":"Background: Pneumonia is a common diagnosis in general practice in the United Kingdom and yet there is little known about the short- and long-term prognosis of people with a diagnosis of pneumonia in general practice. We investigated the short- and long-term survival of people with pneumonia diagnosed in general practice as compared to the general population for all ages. Methods: This was a general population-based cohort study. Data was obtained from a comprehensive general practice database called The Health Improvement Network (THIN) database which has computerized medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses. Results: For pneumonia cases the 30-day mortality was 18.5% and the 3-year mortality was 30.8%. The equivalent figures for the general population controls were 0.4% and 10.3% respectively. The adjusted hazard ratio (HR) for all-cause mortality (for total follow-up time) in pneumonia cases vs. general population was 4.64 (95% CI 4.35–4.95). For the first 30 days the risk of mortality in cases was 46 times more (adj. HR 45.90, 95% CI 36.80–55.20). Even in the period of follow-up 91 days after diagnosis cases were almost 20% more likely to die compared to general population (adj. HR 1.19, 95% CI 1.08–1.31). Conclusion: People in general practice who have a diagnosis of pneumonia have a markedly increased mortality in the short-term but some increase in mortality persists during longer-term follow-up.","DOI":"10.1093/eurpub/ckp081","ISSN":"1101-1262, 1464-360X","journalAbbreviation":"Eur J Public Health","language":"en","author":[{"family":"Myles","given":"Puja R."},{"family":"Hubbard","given":"Richard B."},{"family":"Gibson","given":"Jack E."},{"family":"Pogson","given":"Zara"},{"family":"Smith","given":"Christopher J. P."},{"family":"McKeever","given":"Tricia M."}],"issued":{"date-parts":[["2009",10,1]]},"accessed":{"date-parts":[["2013",2,15]]}}},{"id":206,"uris":[""],"uri":[""],"itemData":{"id":206,"type":"article-journal","title":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: a population-based cohort study","container-title":"Medicine","page":"329-334","volume":"87","issue":"6","source":"NCBI PubMed","abstract":"Little is known about the long-term sequelae of community-acquired pneumonia (CAP). Therefore, we describe the long-term morbidity and mortality of patients after pneumonia requiring hospitalization. We specifically hypothesized that the Pneumonia Severity Index (PSI), designed to predict 30-day pneumonia-related mortality, would also be associated with longer-term all-cause mortality. Between 2000 and 2002, 3415 adults with CAP admitted to 6 hospitals in Edmonton, Alberta, Canada, were prospectively enrolled in a population-based cohort. At the time of hospital admission, demographic, clinical, and laboratory data were collected and the PSI was calculated for each patient. Postdischarge outcomes through to 2006 were ascertained using multiple linked administrative databases. Outcomes included all-cause mortality, hospital admissions, and re-hospitalization for pneumonia over a maximum of 5.4 years of follow-up. Follow-up data were available for 3284 (96%) patients; 66%were > or =65 years of age, 53% were male, and according to the PSI fully 63% were predicted to have greater than 18% 30-day pneumonia-related mortality (that is, PSI class IV-V). Median follow-up was 3.8 years. The 30-day, 1-year, and end of study mortality rates were 12%, 28%, and 53%, respectively. Overall, 82(19%) patients aged <45 years died compared with 1456 (67%) patients aged > or =65 years (hazard ratio [HR], 5.07; 95% confidence interval [CI], 4.06-6.34). Male patients were more likely to die than female patients during follow-up (971 [56%] vs. 767 [49%], respectively; HR, 1.20; 95% CI, 1.13-1.37). Initial PSI classification predicted not only 30-day mortality, but also long-term postdischarge mortality, with 92 (15%) of PSI class I-II patients dying compared with 616 (82%) PSI class V patients (HR, 11.80; 95% CI, 4.70-14.70). Of 2950 patients who survived the initial CAP hospitalization, 72% were hospitalized again (median, 2 admissions over follow-up) and 16% were re-hospitalized with pneumonia. In conclusion, long-term morbidity and mortality are high following hospitalization for pneumonia and are strongly correlated with initial PSI class. This suggests that patients with pneumonia, especially those with PSI class IV and V at admission, might need better attention paid to preventive strategies and much closer follow-up due to their elevated risk of subsequent adverse events and increased health resource utilization.","DOI":"10.1097/MD.0b013e318190f444","ISSN":"1536-5964","note":"PMID: 19011504","shortTitle":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia","journalAbbreviation":"Medicine (Baltimore)","author":[{"family":"Johnstone","given":"Jennie"},{"family":"Eurich","given":"Dean T"},{"family":"Majumdar","given":"Sumit R"},{"family":"Jin","given":"Yan"},{"family":"Marrie","given":"Thomas J"}],"issued":{"date-parts":[["2008",11]]},"PMID":"19011504"}}],"schema":""} (11,14,17). Specific causes of death were coded by a nosologist with ICD 10 codes J00-J99 (ICD 9 460-496) for respiratory and ICD 10 codes L10-179 (ICD 9 401-448) for cardiovascular causes, respectively. Statistical analysisStatistical analyses were conducted using Stata 11.2/SE (StatCorp, USA). The baseline characteristics were given as means and standard deviations for normally distributed continuous data and by number and percentages for categorical data. Comparisons between groups at baseline were based on univariable conditional logistic regression models in order to take into account the non-independence due to the matching of cases and controls. Respiratory and cardiovascular mortality in pneumonia cases compared to controls were analysed at different time frames. The cut off between short term and long term mortality were 1 year and until the end of the follow up, respectively. The difference in mortality in pneumonia cases compared to controls was examined using Cox regression ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1lkgkftas2","properties":{"formattedCitation":"(18)","plainCitation":"(18)"},"citationItems":[{"id":223,"uris":[""],"uri":[""],"itemData":{"id":223,"type":"article-journal","title":"Regression models and life tables. J R Stat Soc B 1972;34:187–220","container-title":"Journal of Royal Statistical Society.","collection-title":"Methodological","page":"187-220","volume":"34","issue":"2","author":[{"family":"Cox","given":"DR"}],"issued":{"date-parts":[["1972"]]}}}],"schema":""} (18) with a frailty term to account for the non-independence due to the matching of cases and controls. Covariates in the multiple variable models were chosen for the characteristics that differ significantly between group means for at least one cause of mortality using Cox regression on all of the available risk factors (Table 1) at univariate analysis. Multivariate analysis was thus adjusted for history of asthma, smoking status, pack years, forced expiratory volume 1 (FEV1), forced vital capacity (FVC), and physical activity levels (as outlined previously ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"25k062bt60","properties":{"formattedCitation":"(16)","plainCitation":"(16)"},"citationItems":[{"id":154,"uris":[""],"uri":[""],"itemData":{"id":154,"type":"article-journal","title":"Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study","container-title":"PLoS Med","page":"e12","volume":"5","issue":"1","source":"PLoS Med","abstract":"From a large prospective population study, Kay-Tee Khaw and colleagues estimate the \n combined impact of four behaviors--not smoking, not being physically inactive, moderate \n alcohol intake, and at least five vegetable servings a day--amounts to 14 additional years \n of life.","DOI":"10.1371/journal.pmed.0050012","shortTitle":"Combined Impact of Health Behaviours and Mortality in Men and Women","journalAbbreviation":"PLoS Med","author":[{"family":"Khaw","given":"Kay-Tee"},{"family":"Wareham","given":"Nicholas"},{"family":"Bingham","given":"Sheila"},{"family":"Welch","given":"Ailsa"},{"family":"Luben","given":"Robert"},{"family":"Day","given":"Nicholas"}],"issued":{"date-parts":[["2008",1,8]]},"accessed":{"date-parts":[["2013",2,5]]}}}],"schema":""} (16)), waist-to-hip ratio, diabetes mellitus, pre-existing cardiovascular disease and pre-existing respiratory disease. A final model was constructed after additionally adjusting for aspirin use (statin use was not included as there were too few participants who were on statin to provide any meaningful results). No adjustment for age and sex was required due to the matching criteria. Results A total of 503 participants were identified as hospitalised pneumonia cases and these cases were matched by age, gender and year of entry into the EPIC-Norfolk study with 1962 controls (1:3.9) after exclusion of cases who died within 30 days of pneumonia and their respective controls. Participants were followed from the date of diagnosis of pneumonia in cases or the same date for matched controls for a total of 15,074 person-years (mean 6.1 years, range 0.08– 15.2 years). The mean time from entry into EPIC-Norfolk (which began in 1993) and the diagnosis of pneumonia was 9.0 years. As controls were age and sex matched, these baseline characteristics were comparable between cases and controls (Table 1). However, the cases had a significantly higher proportion of current smokers and a higher mean number of pack years than the control group. The prevalence of diabetes mellitus, cardiovascular and respiratory diseases including asthma were significantly higher within the case population. Mean FEV1 and FVC were lower within the case group compared to the controls. Although the difference in body mass index between the two groups was non-significant, the case group had a significantly higher waist to hip ratio than controls.There was a higher incidence of mortality in the case group which was maintained throughout both time frames and this difference was greatest in terms of respiratory mortality (Table 2). There was an increased risk of mortality for the case group compared to the control group after adjusting for significant risk factors identified (Table 3). There was an increased risk of all-cause mortality and specific-cause mortality between 30 days and 1 year, and greater than longer than 1 year. The all-cause mortality rate was highest initially following pneumonia then reduced over time whereas the initial higher respiratory and cardiovascular mortality rates for cases compared to controls was maintained throughout the study period. The risk of cardiovascular mortality was increased in the case groups for both time periods, and the highest risk period was between 30 days and 1 year. Interestingly risk of death due to respiratory cause was excessively high one year post pneumonia and the overall risk was driven mainly by this.Additionally adjusting for aspirin use did not alter the results (data not shown). Discussion Our findings indicate that hospitalised pneumonia is associated with increased risk of mortality not only in the short term beyond 30 days up to one year, but also in longer term (beyond 1 year) compared to age, sex matched controls within the general population of middle and older age. This increase in mortality persisted throughout the entire length of follow up for all-cause respiratory, and cardiovascular mortality. Risk of death due to cardiovascular cause appeared to be particularly high within 1 yr of pneumonia and increased risk of mortality from respiratory causes appeared to be very high after one year in cases (who did not die within one month) compared to the control normal population who did not have hospitalised pneumonia during the study period. Our findings support previous studies. Recently, it was reported that hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD (19). Furthermore, Kaplan found that mortality in elderly patients hospitalised with community acquired pneumonia was 10% higher at one year than those hospitalised for other reasons ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1q1fgh6fp6","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":204,"uris":[""],"uri":[""],"itemData":{"id":204,"type":"article-journal","title":"Pneumonia: still the old man's friend?","container-title":"Archives of internal medicine","page":"317-323","volume":"163","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND\n\nHospital mortality of patients admitted with community-acquired pneumonia (CAP) has been well described. However, the long-term survival of those discharged alive is less clear. We sought to determine long-term survival of patients hospitalized with CAP and compare the outcome with controls hospitalized for reasons other than CAP.\n\n\nMETHODS\n\nWe performed a matched case-control analysis using the Medicare hospital discharge database from the first quarter of 1997. We compared all Medicare recipients 65 years or older hospitalized with CAP and controls matched for age, sex, and race hospitalized for reasons other than CAP. We measured 1-year mortality determined from the Medicare Beneficiary Entitlement file and the Social Security Administration.\n\n\nRESULTS\n\nWe identified 158 960 CAP patients and 794 333 hospitalized controls. Hospital mortality rates for the CAP cohort and hospitalized controls were 11.0% and 5.5%, respectively (P<.001). One-year mortality rates for the CAP cohort and hospitalized controls were 40.9% and 29.1%, respectively (P<.001). One-year mortality rates in hospital survivors of the CAP and control cohorts were 33.6% and 24.9%, respectively (P<.001). The difference in mortality between the CAP and control cohorts was not explained by underlying disease. Standardized against the general population, the risk of death for both cohorts decreased monthly but was still elevated 1 year after hospital discharge. The standardized mortality ratio was 2.69 (95% confidence interval, 2.47-2.93) for CAP patients and 1.93 (95% confidence interval, 1.79-2.08) for hospital controls.\n\n\nCONCLUSIONS\n\nAlmost half of all elderly patients admitted for CAP die in the subsequent year, with most deaths occurring after hospital discharge. The mortality is considerably higher than that of either the general population or a control population hospitalized for reasons other than CAP.","ISSN":"0003-9926","note":"PMID: 12578512","shortTitle":"Pneumonia","journalAbbreviation":"Arch. Intern. Med.","author":[{"family":"Kaplan","given":"Vladimir"},{"family":"Clermont","given":"Gilles"},{"family":"Griffin","given":"Martin F"},{"family":"Kasal","given":"Jan"},{"family":"Watson","given":"R Scott"},{"family":"Linde-Zwirble","given":"Walter T"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2003",2,10]]},"PMID":"12578512"}}],"schema":""} (15). Boden et al, based on their study on hospitalised population, also found an increased 7 year all-cause mortality amongst patients hospitalised with CAP compared to hospitalised controls ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1jofco10a4","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":231,"uris":[""],"uri":[""],"itemData":{"id":231,"type":"article-journal","title":"Decrease in Long-term Survival for Hospitalized Patients With Community-Acquired Pneumonia","container-title":"CHEST Journal","page":"279-283","volume":"138","issue":"2","source":"Silverchair","abstract":"Background:? \n\t\t\tThe association of hospitalization because of community-acquired pneumonia (CAP) and long-term survival has not been fully examined. We measured the long-term survival of hospitalized patients with CAP adjusted for the effects of comorbidities.Methods:? \n\t\t\tA cohort of adult patients admitted to the medical services of the Veterans Affairs Medical Center, Louisville, Kentucky, was retrospectively examined. A Kaplan-Meier survival curve was constructed to assess the effect of CAP admission status on patient survival. A Cox proportional hazards regression model included comorbidities as predictors and time to death as the outcome in the construction of a modified Charlson Comorbidity Index (mCCI). The mCCI was internally validated to evaluate the predictability of patient survival. The mCCI and age > 65 years were included as potential confounders in a final Cox proportional hazards regression model with CAP admission status as the main predictor and time to death as the outcome.Results:? \n\t\t\tCAP was identified in 624 (9%) out of 6,971 patients. The Kaplan-Meier survival curve showed a significantly shorter survival among patients with CAP than those without CAP (P < .0001). The internal validation of the mCCI showed that patients were more likely to die as the mCCI increased (P < .0001). The Cox proportional hazards regression modeling the association between time to death and CAP admission after adjusting for elderly age and the mCCI showed that hospitalization due to CAP was a statistically significant predictor of decreased survival (hazard ratio, 1.4; 95% CI, 1.2-1.5; P < .0001).Conclusion:? \n\t\t\tThere is a decreased long-term survival among hospitalized patients with CAP after adjusting for comorbidities and aging. Future research to understand the pathophysiology of the long-term CAP outcomes is necessary to develop treatment strategies.","DOI":"10.1378/chest.09-2702","ISSN":"0012-3692","journalAbbreviation":"CHEST","author":[{"family":"Bordon","given":"Jose"},{"family":"Wiemken","given":"Timothy"},{"family":"Peyrani","given":"Paula"},{"family":"Paz","given":"Maria Luz"},{"family":"Gnoni","given":"Martin"},{"family":"Cabral","given":"Patricio"},{"family":"Venero","given":"Maria del Carmen"},{"family":"Ramirez","given":"Julio"}],"issued":{"date-parts":[["2010",8,1]]},"accessed":{"date-parts":[["2013",2,22]]}}}],"schema":""} (20). A cohort study, also using the general population as controls, found that the patients with pneumonia were almost 46 times as likely to die in the first 30 days as the participants without pneumonia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2c0q0jjc34","properties":{"formattedCitation":"(17)","plainCitation":"(17)"},"citationItems":[{"id":5,"uris":[""],"uri":[""],"itemData":{"id":5,"type":"article-journal","title":"Pneumonia mortality in a UK general practice population cohort","container-title":"The European Journal of Public Health","page":"521-526","volume":"19","issue":"5","source":"eurpub.","abstract":"Background: Pneumonia is a common diagnosis in general practice in the United Kingdom and yet there is little known about the short- and long-term prognosis of people with a diagnosis of pneumonia in general practice. We investigated the short- and long-term survival of people with pneumonia diagnosed in general practice as compared to the general population for all ages. Methods: This was a general population-based cohort study. Data was obtained from a comprehensive general practice database called The Health Improvement Network (THIN) database which has computerized medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses. Results: For pneumonia cases the 30-day mortality was 18.5% and the 3-year mortality was 30.8%. The equivalent figures for the general population controls were 0.4% and 10.3% respectively. The adjusted hazard ratio (HR) for all-cause mortality (for total follow-up time) in pneumonia cases vs. general population was 4.64 (95% CI 4.35–4.95). For the first 30 days the risk of mortality in cases was 46 times more (adj. HR 45.90, 95% CI 36.80–55.20). Even in the period of follow-up 91 days after diagnosis cases were almost 20% more likely to die compared to general population (adj. HR 1.19, 95% CI 1.08–1.31). Conclusion: People in general practice who have a diagnosis of pneumonia have a markedly increased mortality in the short-term but some increase in mortality persists during longer-term follow-up.","DOI":"10.1093/eurpub/ckp081","ISSN":"1101-1262, 1464-360X","journalAbbreviation":"Eur J Public Health","language":"en","author":[{"family":"Myles","given":"Puja R."},{"family":"Hubbard","given":"Richard B."},{"family":"Gibson","given":"Jack E."},{"family":"Pogson","given":"Zara"},{"family":"Smith","given":"Christopher J. P."},{"family":"McKeever","given":"Tricia M."}],"issued":{"date-parts":[["2009",10,1]]},"accessed":{"date-parts":[["2013",2,15]]}}}],"schema":""} (17). They found that for pneumonia cases the adjusted risk of all-cause mortality over total follow up period was 4.6, which is in line with our findings. This study further supports the evidence that the increase in cardiovascular risk persists past one year. In light of this finding, patients admitted to hospital with pneumonia should have a cardiac risk assessment including medication review, to consider interventions for cardiovascular disease prevention if appropriate. The reason why people with pneumonia had increased CV mortality risk is unclear. However, there are plausible mechanisms which could lead to this observed link between pneumonia and subsequent CV mortality. Pneumonia increases the levels of inflammatory cytokines promoting thrombogenesis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oqj9meq2k","properties":{"formattedCitation":"(20)","plainCitation":"(20)"},"citationItems":[{"id":281,"uris":[""],"uri":[""],"itemData":{"id":281,"type":"article-journal","title":"Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease.","container-title":"Heart","page":"273-277","volume":"78","issue":"3","source":"heart.","abstract":"OBJECTIVE: To determine whether serum concentrations of the cytokines tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which regulate C reactive protein, are associated with cardiovascular risk factors and prevalent coronary heart disease. DESIGN: A population based cross sectional study. SUBJECTS AND METHODS: 198 men aged 50 to 69 years were part of a random population sample drawn from south London. Serum cytokine and C reactive protein concentrations were determined by enzyme linked immunosorbent assay. The presence of coronary heart disease was determined by Rose angina questionnaire and Minnesota coded electrocardiogram. RESULTS: Serum TNF alpha concentrations were positively related to body mass index and Helicobacter pylori infection, but inversely related to alcohol consumption. IL-6 concentrations were positively associated with smoking, symptoms of chronic bronchitis, age, and father having a manual occupation. TNF alpha was associated with increased IL-6 and triglycerides, and reduced high density lipoprotein cholesterol. IL-6 was associated with raised fibrinogen, sialic acid, and triglycerides. ECG abnormalities were independently associated with increases in IL-6 and TNF alpha, each by approximately 50% (P < 0.05 for TNF alpha, P < 0.1 for IL-6). The corresponding increases in men with an abnormal ECG or symptomatic coronary heart disease were 28% for TNF alpha and 36% for IL-6 (P = 0.14 for TNF alpha and P < 0.05 for IL-6). CONCLUSIONS: This study confirms that many of the phenomena with which C reactive protein is associated, are also associated with serum levels of cytokine, which may be the mechanism.","DOI":"10.1136/hrt.78.3.273","ISSN":", 1468-201X","journalAbbreviation":"Heart","language":"en","author":[{"family":"Mendall","given":"M. A."},{"family":"Patel","given":"P."},{"family":"Asante","given":"M."},{"family":"Ballam","given":"L."},{"family":"Morris","given":"J."},{"family":"Strachan","given":"D. P."},{"family":"Camm","given":"A. J."},{"family":"Northfield","given":"T. C."}],"issued":{"date-parts":[["1997",9,1]]},"accessed":{"date-parts":[["2013",2,28]]}}}],"schema":""} (21) and reduces ventricular function ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"261a1lj3kk","properties":{"formattedCitation":"(21,22)","plainCitation":"(21,22)"},"citationItems":[{"id":284,"uris":[""],"uri":[""],"itemData":{"id":284,"type":"article-journal","title":"Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum.","container-title":"The Journal of Experimental Medicine","page":"949-958","volume":"183","issue":"3","source":"jem.","abstract":"Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-alpha and IL-1beta each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL-1beta (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamma failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-alpha and IL-1beta cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans.","DOI":"10.1084/jem.183.3.949","ISSN":"0022-1007, 1540-9538","journalAbbreviation":"J Exp Med","language":"en","author":[{"family":"Kumar","given":"A."},{"family":"Thota","given":"V."},{"family":"Dee","given":"L."},{"family":"Olson","given":"J."},{"family":"Uretz","given":"E."},{"family":"Parrillo","given":"J. E."}],"issued":{"date-parts":[["1996",3,1]]},"accessed":{"date-parts":[["2013",2,28]]}}},{"id":287,"uris":[""],"uri":[""],"itemData":{"id":287,"type":"article-journal","title":"Inflammatory Mediators and the Failing Heart Past, Present, and the Foreseeable Future","container-title":"Circulation Research","page":"988-998","volume":"91","issue":"11","source":"circres.","abstract":"Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.","DOI":"10.1161/01.RES.0000043825.01705.1B","ISSN":"0009-7330, 1524-4571","journalAbbreviation":"Circulation Research","language":"en","author":[{"family":"Mann","given":"Douglas L."}],"issued":{"date-parts":[["2002",11,29]]},"accessed":{"date-parts":[["2013",2,28]]}}}],"schema":""} (22,23), both of which could lead to an increase in cardiac events in the short term. It is also thought that pneumonia produces a chronic inflammatory response which would accelerate the process of cardiovascular disease in the intermediate term ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iAMN3prl","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}}],"schema":""} (10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nFCTncl6","properties":{"formattedCitation":"(14)","plainCitation":"(14)","dontUpdate":true},"citationItems":[{"id":211,"uris":[""],"uri":[""],"itemData":{"id":211,"type":"article-journal","title":"Influence of comorbid conditions on long-term mortality after pneumonia in older people","container-title":"Journal of the American Geriatrics Society","page":"518-525","volume":"55","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVES\n\nTo test the hypothesis that increased long-term mortality after hospitalization for community-acquired pneumonia (CAP) is independent of comorbid conditions.\n\n\nDESIGN\n\nProspective observational cohort study in metropolitan areas.\n\n\nSETTING\n\nMemphis, Tennessee, and Pittsburgh, Pennsylvania.\n\n\nPARTICIPANTS\n\nThree thousand seventy-five subjects aged 70 to 79 over 5.2 years.\n\n\nMEASUREMENTS\n\nUnadjusted and adjusted mortality from an initial hospitalization for CAP were compared with mortality from different causes of hospitalization, including cancer, fracture, congestive heart failure (CHF), cerebrovascular accident (CVA), and other causes. Demographics, smoking, nutritional markers, functional status, inflammatory markers, and chronic health conditions were adjusted for.\n\n\nRESULTS\n\nOf the 106 subjects hospitalized for CAP, 22 (20.8%) and 38 (35.8%) died at 1 and 5 years. Subjects hospitalized with CAP had higher mortality than nonhospitalized subjects (adjusted odds ratio (OR)=7.8, 95% confidence interval (CI)=4.2-14.4). One- and 5-year mortality after CAP hospitalization were higher than mortality from other causes requiring hospitalization and remained unchanged in multivariable analysis (adjusted OR=3.5, 95% CI=1.5-8.1; adjusted OR=5.6, 95% CI=2.8-11.2, respectively). One- and 5-year mortality after hospitalization for CAP were similar to or higher than mortality after an initial hospitalization for CHF, CVA, or fracture. Rehospitalization was common in subjects hospitalized for CAP and may explain greater long-term mortality.\n\n\nCONCLUSION\n\nIn this high-functioning cohort of older persons, an initial hospitalization for CAP was associated with greater long-term mortality, independent of prehospitalization comorbid conditions. Hospitalization for CAP has as serious a prognosis as hospitalization for CHF, stroke, or major fracture.","DOI":"10.1111/j.1532-5415.2007.01100.x","ISSN":"0002-8614","note":"PMID: 17397429","journalAbbreviation":"J Am Geriatr Soc","author":[{"family":"Yende","given":"Sachin"},{"family":"Angus","given":"Derek C"},{"family":"Ali","given":"Ibrahim Sultan"},{"family":"Somes","given":"Grant"},{"family":"Newman","given":"Anne B"},{"family":"Bauer","given":"Douglas"},{"family":"Garcia","given":"Melissa"},{"family":"Harris","given":"Tamara B"},{"family":"Kritchevsky","given":"Stephen B"}],"issued":{"date-parts":[["2007",4]]},"PMID":"17397429"}}],"schema":""} . It was shown that patients hospitalised with pneumonia who experience persistently raised pro-inflammatory cytokines at discharge had an increased risk of cardiovascular death at one year, independent of the severity of illness ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FwuoW09E","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}}],"schema":""} (10). This study has limitations. Firstly, neither the clinical severity of pneumonia nor the virulence of the disease causing organisms was accounted for. Neither were the different levels of inflammatory markers which indicate an extent of host immune response, both of which have had a demonstrated effect on mortality ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1a17m1bbib","properties":{"formattedCitation":"(10,14)","plainCitation":"(10,14)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis","container-title":"American journal of respiratory and critical care medicine","page":"1242-1247","volume":"177","issue":"11","source":"NCBI PubMed","abstract":"RATIONALE\n\nSurvivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown.\n\n\nOBJECTIVES\n\nTo investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes.\n\n\nMETHODS\n\nProspective cohort study at 28 sites.\n\n\nMEASUREMENTS AND MAIN RESULTS\n\nWe used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008).\n\n\nCONCLUSIONS\n\nDespite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1535-4970","note":"PMID: 18369199","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A"},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D"},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C"}],"issued":{"date-parts":[["2008",6,1]]},"PMID":"18369199"}},{"id":206,"uris":[""],"uri":[""],"itemData":{"id":206,"type":"article-journal","title":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: a population-based cohort study","container-title":"Medicine","page":"329-334","volume":"87","issue":"6","source":"NCBI PubMed","abstract":"Little is known about the long-term sequelae of community-acquired pneumonia (CAP). Therefore, we describe the long-term morbidity and mortality of patients after pneumonia requiring hospitalization. We specifically hypothesized that the Pneumonia Severity Index (PSI), designed to predict 30-day pneumonia-related mortality, would also be associated with longer-term all-cause mortality. Between 2000 and 2002, 3415 adults with CAP admitted to 6 hospitals in Edmonton, Alberta, Canada, were prospectively enrolled in a population-based cohort. At the time of hospital admission, demographic, clinical, and laboratory data were collected and the PSI was calculated for each patient. Postdischarge outcomes through to 2006 were ascertained using multiple linked administrative databases. Outcomes included all-cause mortality, hospital admissions, and re-hospitalization for pneumonia over a maximum of 5.4 years of follow-up. Follow-up data were available for 3284 (96%) patients; 66%were > or =65 years of age, 53% were male, and according to the PSI fully 63% were predicted to have greater than 18% 30-day pneumonia-related mortality (that is, PSI class IV-V). Median follow-up was 3.8 years. The 30-day, 1-year, and end of study mortality rates were 12%, 28%, and 53%, respectively. Overall, 82(19%) patients aged <45 years died compared with 1456 (67%) patients aged > or =65 years (hazard ratio [HR], 5.07; 95% confidence interval [CI], 4.06-6.34). Male patients were more likely to die than female patients during follow-up (971 [56%] vs. 767 [49%], respectively; HR, 1.20; 95% CI, 1.13-1.37). Initial PSI classification predicted not only 30-day mortality, but also long-term postdischarge mortality, with 92 (15%) of PSI class I-II patients dying compared with 616 (82%) PSI class V patients (HR, 11.80; 95% CI, 4.70-14.70). Of 2950 patients who survived the initial CAP hospitalization, 72% were hospitalized again (median, 2 admissions over follow-up) and 16% were re-hospitalized with pneumonia. In conclusion, long-term morbidity and mortality are high following hospitalization for pneumonia and are strongly correlated with initial PSI class. This suggests that patients with pneumonia, especially those with PSI class IV and V at admission, might need better attention paid to preventive strategies and much closer follow-up due to their elevated risk of subsequent adverse events and increased health resource utilization.","DOI":"10.1097/MD.0b013e318190f444","ISSN":"1536-5964","note":"PMID: 19011504","shortTitle":"Long-term morbidity and mortality after hospitalization with community-acquired pneumonia","journalAbbreviation":"Medicine (Baltimore)","author":[{"family":"Johnstone","given":"Jennie"},{"family":"Eurich","given":"Dean T"},{"family":"Majumdar","given":"Sumit R"},{"family":"Jin","given":"Yan"},{"family":"Marrie","given":"Thomas J"}],"issued":{"date-parts":[["2008",11]]},"PMID":"19011504"}}],"schema":""} (10,14). A possible weakness is the misclassification of pneumonia diagnosis due to variable coding practices and lack of confirmatory radiological evidence as a requirement for inclusion. Evidence is unclear as to how accurate the pneumonia diagnosis is in hospital ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1s93jki2df","properties":{"formattedCitation":"(23)","plainCitation":"(23)"},"citationItems":[{"id":224,"uris":[""],"uri":[""],"itemData":{"id":224,"type":"article-journal","title":"P17 The Accuracy of a Diagnosis of Pneumonia in a UK Teaching Hospital","container-title":"Thorax","page":"A71-A71","volume":"67","issue":"Suppl 2","source":"thorax.","abstract":"Background Obtaining an accurate diagnosis of pneumonia is an essential part of optimal patient care. Analysis of patients’ hospital records allows clinical coding (ICD-10) of admission events which assist development of clinical decision algorithms, assessment of quality of care and public health evaluation. We sought to evaluate the reliability of applied clinical codes and the accuracy of a diagnosis of pneumonia in our institution.\nMethods A retrospective case note review of all patients admitted to University Hospital Llandough in 2011 with a final clinical code diagnosis of pneumonia. Pneumonia was defined as the presence of new radiographic infiltrate in patients with symptoms consistent with an acute lower respiratory tract infection.1 The chest radiographs of each patient were reviewed by a respiratory physician (KP, HED) and the formal radiology report was independently scrutinised (IM).\nResults 710 patient episodes of ICD-10 coded pneumonia were identified in a 1 year period at our hospital. Ten patients had no chest x-ray performed and one x-ray had no report. Radiological confirmation of pneumonia (by radiology reporting) occurred in 69.8% (488/699); a radiological diagnosis of pneumonia was made by a respiratory physician (KP, HED) in 71.8% (502/699) of patients. There was 85% agreement between the Respiratory and Radiology reports (592/699 cases) with a kappa of 0.66 (95% CI 0.57 to 0.69). The accuracy of a pneumonia diagnosis differed little between patients cared for by a respiratory physician (72.3% agreement with radiology report) and those admitted to a non-respiratory ward (68.1%). In 27.0% and 31.9% of patients respectively there was no radiological evidence of pneumonia.\nConclusions A clinical coding diagnosis of pneumonia is unreliable with 30.2% of patients not having compatible radiograph change. This has implications for the validity of any research performed on data selected on the basis of clinically coded information. Misdiagnosis by clinicians is the most likely reason for this discrepancy.\nReference BTS Guidelines for the Management of Community Acquired Pneumonia in Adults Update 2009.","DOI":"10.1136/thoraxjnl-2012-202678.158","ISSN":", 1468-3296","journalAbbreviation":"Thorax","language":"en","author":[{"family":"Pink","given":"K. L."},{"family":"Mitchell","given":"I."},{"family":"Davies","given":"H. E."}],"issued":{"date-parts":[["2012",12,1]]},"accessed":{"date-parts":[["2013",2,22]]}}}],"schema":""} (24). However, the main misclassified diagnosis is likely to be other causes of lower respiratory tract infection and this inclusion bias would result in a lower mortality within the case group as lobar pneumonia is the LRTI with the highest mortality rate ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"11icaqm3n4","properties":{"formattedCitation":"(24)","plainCitation":"(24)"},"citationItems":[{"id":227,"uris":[""],"uri":[""],"itemData":{"id":227,"type":"article-journal","title":"The Continuing Challenge of Lower Respiratory Tract Infections","container-title":"Clinical Infectious Diseases","page":"S1-S3","volume":"34","issue":"Supplement 1","source":"CrossRef","DOI":"10.1086/324524","ISSN":"1058-4838, 1537-6591","author":[{"family":"Moellering","given":"R. C."}],"issued":{"date-parts":[["2002",3,1]]},"accessed":{"date-parts":[["2013",2,22]]}}}],"schema":""} (25) thus the observed associations if any would be attenuation of the actual impact of pneumonia. We identified only individuals with hospitalised pneumonia so those with episodes of pneumonia treated only the community were not included. Hospitalised pneumonia cases are likely to be more severe so the generalizability of findings to all pneumonias occurring in the community is limited. To reduce such bias associated with high mortality due to pneumonia related death (i.e. respiratory cause) we deliberately excluded cases within EPIC-Norfolk who died within 30 days of pneumonia diagnosis. We were also unable to examine the specific cause of CVD mortality. People who are admitted to hospital for pneumonia are also more likely to have co-morbidities which may predispose to increased mortality risk. Although we adjusted for many covariates including lung function as well as history of asthma and chronic respiratory illnesses, there may be unknown confounders or there may be residual confounding effect of known confounders. Whilst any hospitalisation may increase the risk of mortality, more relevant issue perhaps is whether people who had pneumonia were associated with increased CV risk in longer term. We acknowledge that we were not able to examine this issue in people with pneumonia who were not hospitalised. Indeed, it is possible that a proportion of controls might have had pneumonia which did not result in hospitalisation during follow up of the study. This misclassification as well as any hospitalisation with increased risk of death however would only attenuate the results. Finally in clinical practice especially in older people where conditions such as pneumonia and heart failure co-exist and there may be possibility of mis-diagnosis. Nevertheless, such error is likely to contribute mostly to within 30 day mortality and unlikely to influence the beyond 30-day relationships between pneumonia and mortality outcome.The EPIC-Norfolk cohort comprised community dwelling middle and older aged participants who agreed to participate at baseline recruitment therefore there may be healthy responder bias. However, truncation of sample distribution would be likely to attenuate the findings. The participant’s baseline characteristics (e.g. FEV1/FEV) were taken from entry into the EPIC-Norfolk cohort which predated the current study entry date by a mean of 9.0 years. There could be significant differences between characteristics at entry into EPIC-Norfolk study and at the point of pneumonia diagnosis, resulting in measurement error in the co-variables. However we were able to control for wide ranging demographic, lifestyle and medical factors including prevalent cardiovascular and chronic lower respiratory tract illnesses. In summary, hospitalised pneumonia is associated with subsequent increased risk of mortality and this persists beyond 1 year after diagnosis in middle and older ages. Clinicians should be aware of the increased mortality from not only respiratory causes but also cardiovascular causes. FundingThe EPIC-Norfolk study is supported by programme grants from the Medical Research Council G1000143 and the Cancer Research UK 8257. Funders have no roles in study design, analysis, and interpretation of the findings.Conflict of interestsNone AcknowledgementsWe gratefully acknowledge the participants of the study and participating General Practitioners. We also like to thank our funders. ContributorsKTK and NJW are PIs of EPIC-Norfolk study. RNL performed record linkage. PKM and AMW conceived the idea. KRH and ABC conducted statistical analyses and drafted the manuscript with critical input from AMW and PKM. All authors contributed in writing of the paper. PKM is the guarantor.References ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY 1. Office for National Statistics. Deaths registered in England and Wales in 2010, by cause [Internet]. 2011 [cited 2013 Feb 22]. Available from: . Mathers CD, Fat DM, Boerma JT, Organization WH. The Global Burden of Disease: 2004 Update. World Health Organization; 2008. 3. Guest JF, Morris A. Community-acquired pneumonia: the annual cost to the National Health Service in the UK. European Respiratory Journal. 1997 Jul;10(7):1530–4. 4. File TM Jr, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgraduate Medicine. 2010 Mar;122(2):130–41. 5. Lave JR, Fine MJ, Sankey SS, Hanusa BH, Weissfeld LA, Kapoor WN. Hospitalized pneumonia. Outcomes, treatment patterns, and costs in urban and rural areas. Journal of General Internal Medicine. 1996 Jul;11(7):415–21. 6. Marrie TJ, Carriere KC, Jin Y, Johnson DH. Mortality during hospitalisation for pneumonia in Alberta, Canada, is associated with physician volume. European Respiratory Journal. 2003 Jul 1;22(1):148–55. 7. Eurich DT, Majumdar SR, Marrie TJ. Population-based cohort study of outpatients with pneumonia: rationale, design and baseline characteristics. BMC Infectious Diseases. 2012;12:135. 8. Hoo Lee J, Hyung Kim Y. Comparison of clinical characteristics between healthcare-associated pneumonia and community-acquired pneumonia in patients admitted to secondary hospitals. Brazilian Journal of Infectious Diseases. 2012 Aug;16(4):321–8. 9. Ramirez JA, Anzueto AR. Changing needs of community-acquired pneumonia. J Antimicrobial Chemotheraphy. 2011 Apr;66 Suppl 3:iii3–9. 10. Yende S, D’Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. American Journal of Respiratory and Critical Care Medicine. 2008 Jun 1;177(11):1242–7. 11. 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Archives of Internal Medicine. 2003 Feb 10;163(3):317–23. 16. Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A, Wareham N.EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. British Journal of Cancer. 1999 Jul;80 Suppl 1:95-103.17. Myles PR, Hubbard RB, Gibson JE, Pogson Z, Smith CJP, McKeever TM. Pneumonia mortality in a UK general practice population cohort. European Journal of Public Health. 2009 Oct 1;19(5):521–6. 18. Cox D. Regression models and life tables. J R Stat Soc B 1972;34:187–220. Journal of Royal Statistical Society. 1972;34(2):187–220. 19. Corrales-Medina VF, Alvarez KN, Weissfeld LA, Angus DC, Chirinos JA, Chang CC, Newman A, Loehr L, Folsom AR, Elkind MS, Lyles MF, Kronmal RA, Yende S. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. Journal of the American Medical Association. 2015;313(3):264-74.20. Bordon J, Wiemken T, Peyrani P, Paz ML, Gnoni M, Cabral P, et al. Decrease in Long-term Survival for Hospitalized Patients With Community-Acquired Pneumonia. CHEST. 2010 Aug 1;138(2):279–83. 21. Mendall MA, Patel P, Asante M, Ballam L, Morris J, Strachan DP, et al. Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart. 1997 Sep 1;78(3):273–7. 22. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE. Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. Journal of Experimental Medicine. 1996 Mar 1;183(3):949–58. 23. Mann DL. Inflammatory Mediators and the Failing Heart Past, Present, and the Foreseeable Future. Circulation Research. 2002 Nov 29;91(11):988–98. 24. Pink KL, Mitchell I, Davies HE. P17 The Accuracy of a Diagnosis of Pneumonia in a UK Teaching Hospital. Thorax. 2012 Dec 1;67(Suppl 2):A71–A71. 25. Moellering RC. The Continuing Challenge of Lower Respiratory Tract Infections. Clinical Infectious Diseases. 2002 Mar 1;34(Supplement 1):S1–S3. Table 1: Comparison of characteristics of pneumonia cases and controls without pneumonia CharacteristicsCases Controls P Value *Total503 1962 Males 269 (53.5%)1030 (52.5%)N/AAge Mean (sd) (Range) <50yrs 50-65yrs >65yrs 64.7 (8.4)41-77 35 (7.0%)189 (37.6%)279 (55.5%) 64.4 (8.3)41-77 132 (6.7%)752 (38.3%)1078 (54.9%)N/ASmoking status Current Previous Never Pack Years Mean (sd) 93 (18.7%) 225 (45.3%) 179 (36.0%) 14.8 (17.9) 162 (8.4%) 944 (48.7%) 834 (43.0) 10.4 (15.2)<0.001<0.001BMI Mean (sd) (Range) <18.5 18.5 ≥ 25 25 ≥ 30 ≥ 30 26.7 (3.7)16.9 - 46.45 (1.0)174 (34.6)226 (44.9)98 (19.5)26.64 (3.7)16.0-43.5 9(0.5) 681 (34.7)949 (48.4)321 (16.4)0.580.12Asthma 73 (14.5)151 (7.7)<0.001Diabetes Mellitus26 (5.2)52 (2.7)0.005FEV1 Mean (sd)N=5037210.51 (75.0)235.66 (70.93)<0.001FVC Mean (sd)N=5037268.4 (93.93)291.2 (90.6)<0.001Systolic Mean(sd)N = 5170141.1 (19.5)140.5 (18.9)0.60Alcohol Intake Mean(sd)N = 50178.5 (13.0)7.9 (11.7)0.30InactiveActive351 (69.8)152 (30.2)1243 (63.4)719 (36.7)0.004Social class I II-IV V26 (5.3)440 (90.2)22 (4.5)132 (7.0)1703 (89.9)59 (3.1)0.162Cholesterol Mean (sd)6.2 (1.2)6.3 (1.2)0.19Waist:hip Ratio Mean (sd)0.88 (0.09)0.87 (0.09)0.001Statin use6 (1.2)15 (0.8)0.076Aspirin use 43 (8.6)124 (6.3)0.319Respiratory Disease prior to censored pneumonia73 (14.5) 300 (15.3)Respiratory disease within 1 year prior to pneumonia date46 (9.2)36 (1.8)Cardiovascular Disease prior to pneumonia date#168 (33.4)449 (22.9)Cardiovascular disease within 1 year prior to censored pneumonia date57 (11.3)72 (3.7)Data presented are mean (sd) for continuous data and number (%) for categorical data.* indicates that overall P values are provided for categorical comparisons where there are more than 2 categories#prevalent MI and stroke at the time of baseline of the EPIC-Norfolk study were excluded from the outset and these numbers indicate the number (%) of participants with incident cardiovascular disease diagnosed between EPIC-Norfolk study enrolment and pneumonia date (baseline of the current report). Table 2: Short, intermediate and long term crude mortality rates for both pneumonia cases and controls by causes of deathCasesControlsP ValueTime and cause of mortalityN at riskDeaths N (%)N at riskDeaths N (%)All-Cause Mortality Total50330460.4196248824.9<0.001≥30 days <1 year50312224.31962723.7<0.001≥ 1year38118247.8189041622.0<0.001Respiratory MortalityTotal5036312.51962211.1<0.001≥30 days <1 year503193.8196240.2<0.001≥ 1year3814411.51890170.9<0.001CVS Mortality Total5038316.519621779.0<0.001≥30 days <1 year503397.81962281.4<0.001≥ 1year3814411.518901497.90.013Table 3: Hazard Ratios (HR) and corresponding 95% Confidence Intervals (95%CI) of incident mortality for cases using the control group as a reference categoryAll-Cause MortalityRespiratory MortalityCardiovascular MortalityTime HR95% CIP ValueHR95% CIP ValueHR95% CIP ValueTotal 4.03.4-4.7<0.00120.411.7-35.8<0.0012.62.0-3.5<0.001≥30 days <1 year7.35.4-9.9<0.0015.93.5-9.7<0.001≥ 1year2.82.3-3.4<0.00116.48.9-30.1<0.0011.61.1-2.30.02Covariates adjusted are smoking status, pack years, physical activity levels, waist to hip ratio, diabetes mellitus, prevalent cardiovascular disease and prevalent respiratory disease for all modes of mortality and all time frames. Matching is account for by a shared frailty term of each matched-set. ................
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