Influence of comorbid conditions on long-term mortality after pneumonia in older people. J. Aliberti et al. et al; GenIMS Investigators.

S, Alvarez In stable patients with atherosclerosis, raised inflammatory markers correlate with increased 10-yr cardiovascular risk [24, 25]. Adjusted Failure Plots to Show the Magnitude of Risk Increase for Cardiovascular Disease That Was Associated With Hospitalization for Pneumonia in CHS and ARIC, Figure 4.

We show the risk of CVD for common traditional risk factors, including hypertension, smoking, and diabetes. In ARIC, only baseline values were included. Yende L, Borhani Effects of different stenoses on thrombus growth, Platelets in defense against bacterial pathogens, Patterns of cytokine expression in community-acquired pneumonia, Systemic cytokine levels in community-acquired pneumonia and their association with disease severity, Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study, Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis, Prevalence and significance of coagulation abnormalities in community-acquired pneumonia, The effects of age on inflammatory and coagulation-fibrinolysis response in patients hospitalised for pneumonia, Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link, The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis, The role of nitric oxide in sepsis an overview, Time course of inducible nitric oxide synthase activity following endotoxin administration in dogs, Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats, Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation, Endothelial activation, dysfunction and permeability during severe infections, Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice, Differential regulation of cyclo-oxygenase-I and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment, Plasma thromboxane concentrations are raised in patients dying with septic shock, Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model, Plasma von Willebrand factor, thrombosis, and the endothelium: the first 30 years, Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides, Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines, Cardiac troponin I levels and alveolar-arterial oxygen gradient in patients with community-acquired pneumonia, Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock, Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock, Elevation of troponin I in sepsis and septic shock, Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice, Cold and the risk of cardiovascular diseases. Quartin Fried MS, Carty Sensitivity analysis of risk of cardiovascular disease after hospitalization for pneumonia in CHS including participants hospitalized for pneumonia, where pneumonia was recorded as the primary discharge diagnosis, and controls not hospitalized for pneumonia, eTable 6. Customize your JAMA Network experience by selecting one or more topics from the list below.

AA, Schein Association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia, 2003-2009. We determined whether the risk of CVD varies over a 10-year period after pneumonia and whether the association persists after adjusting for traditional and novel cardiovascular risk factors. This is also a consideration in some of the hospital-based studies described in this review. First, although we included fatal and nonfatal cardiovascular events, we did not account for competing risk of death due to noncardiovascular reasons. Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). MP,

Data from the same group also suggest that elevation of coagulation markers is greatest in elderly patients with pneumonia, the group at greatest cardiovascular risk [48]. M, Mittleman Heart disease and stroke statistics2013 update: a report from the American Heart Association. These cytokines correlate to some extent with severity and decline with treatment. Within each cohort, we used incidence density sampling to match participants hospitalized with pneumonia to 2 controls. V, Lee Similar to CHS, participants hospitalized with pneumonia had a higher risk of CVD after the infection compared with controls (P<.001). We compared distributions of categorical and continuous variables using 2 tests, 2-sample t tests, or Wilcoxon 2-sample tests, as appropriate. Thereafter, regular study visits and telephone follow ups were conducted to update cardiovascular risk factors.15,16 Participants were followed up through December 31, 2010. In addition, there may be some overlap between the less acute symptoms of coronary artery disease, left ventricular failure and acute respiratory infection. M, Musher A casecontrol study by Lamontagne et al. Recent evidence has provided new information about the profound acute inflammatory response in CAP patients. CR, Wunsch Large cohort studies utilising primary care databases have investigated a link between RTI and the incidence of acute vascular events in the weeks to months following infection. [9] followed patients for an average of 5.4 yrs after discharge. The plots in brown represent participants with pneumonia and the plots in blue represent controls with a covariate pattern in the 25th, 50th, and 75th percentiles in CHS and ARIC. CVD risk after pneumonia was highest in the first year. Our study has several implications. No other disclosures were reported. Diagnosing pneumonia by history and physical examination, Primary care summary of the British Thoracic Society Guidelines for the management of community acquired pneumonia in adults: 2009 update, Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients, Recent respiratory infection and the risk of myocardial infarction, Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients, Acute, severe noncardiac conditions in patients with acute myocardial infarction, Acute noncardiac conditions and in-hospital mortality in patients with acute myocardial infarction, Recent respiratory infection predicts atherothrombotic stroke: case-control study in a Buenos Aires healthcare system, The association between pneumococcal pneumonia and acute cardiac events, Acute myocardial infarction in hospitalized patients with community-acquired pneumonia, Incidence, etiology, timing, and risk factors for clinical failure in hospitalised patients with community-acquired pneumonia, Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes, Vaccinate your child and save its grandparents from a heart attack? The average age of patients with pneumonia was 73 years, they had a high burden of cardiovascular risk factors, and most were functional (92% had either 1 or no ADL impairments) and had normal or near-normal cognition (93% had an average modified mini-mental status examination score of 75) before pneumonia occurred (Table and eTable 3 in the Supplement). S, Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Acute respiratory infections are associated with the damaging combination of reduced myocardial contractility, increased myocardial oxygen demand and reduced myocardial oxygen delivery. Systematic review and meta-analysis, From the Centers for Disease Control and Prevention. RD. Of the 591 pneumonia cases, 211 cases (35.7%) had severe pneumonia. Hospitalization for pneumonia is associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be an important risk factor for CVD. All statistical analyses were performed using SAS (SAS Institute), version 9.2, and R statistical software, version 2.1. In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. Evidence from vaccination studies to date is summarised in table 3. et al. Funding/Support: The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Musher et al. All tests were 2-sided and a P value of less than .05 was considered statistically significant. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. In atherosclerosis, there is endothelial dysfunction with impaired vascular tone and proliferation of vascular smooth muscle. Staphylococcus aureus, S. pneumoniae, Mycoplasma pneumoniae and C. pneumoniae) was five times more likely in patients presenting with ischaemic stroke than in controls [89]. DM.

This association persisted after adjusting for demographics, the burden of cardiovascular risk factors, and crude measures of frailty, and it was observed across a range of infection severity, was validated in a cohort of younger adults, and it was robust to sensitivity analyses using different control groups and stringent case definitions for pneumonia hospitalization. ARIC indicates Atherosclerosis Risk in Communities study; CHS, Cardiovascular Health Study; CVD, cardiovascular disease. MA. D, Khalili-Tabrizi AJ.

Acute infections may stimulate platelet activation directly through pro-inflammatory cytokines or by bacterial products such as lipopolysaccharide (LPS) [40]. The estimates were adjusted for age, sex, race, hypertension, diabetes mellitus, plasma total, high-density lipoprotein and low-density lipoprotein cholesterol, smoking, alcohol abuse,26 atrial fibrillation, chronic kidney disease,27 presence of diagnostic Q waves in electrocardiogram, peripheral arterial disease (defined by ankle brachial index <0.9), carotid artery wall thickness, presence of carotid atherosclerotic plaque by ultrasound, and percentage of predicted forced expiratory volume in first second of expiration (FEV1) measured by spirometry.

Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease). VF, Musher

ES, White

Primary care research databases use computer-recorded diagnostic codes entered by general practitioners [79].

Formation of thrombus in situ leads to occlusion of the coronary (or cerebral) vessel with the subsequent clinical presentation of acute coronary syndrome or stroke [16]. Clinical diagnoses of pneumonia were present in 89% of cases and in 88% of cases for radiographic diagnoses.23 We identified severe pneumonia (pneumonia with organ dysfunction) using previously validated ICD-9-CM codes for severe sepsis.24, Our primary outcome was incident (new-onset) CVD, including myocardial infarction, stroke, and fatal coronary heart disease. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. RN, Psaty Clinical studies in both primary and secondary care settings have identified an increase in short- and long-term risk of cardiovascular events and death from vascular events following acute respiratory infections. CP. G, Kellum

JA, Kong Study concept and design: Corrales-Medina, Angus, Chirinos, Newman, Loehr, Yende. MB. We computed these curves using the covariates described above. The institutional review boards at each CHS and ARIC study site approved the studies. We conducted a matched-cohort study nested within 2 population-based, multicenter, observational cohorts that were followed up for over 21 years: the Cardiovascular Health Study (CHS, n=5888) cohort and the Atherosclerosis Risk in Communities (ARIC, n=15792) cohort. PS, Rothberg Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. SR, Gao S, DAngelo preventing coughing chills The cumulative number of pneumonia cases that developed CVD at 30 days after pneumonia were 6 (0.9%); at 90 days, 12 (1.8%); at 1 year, 31 (4.6%); and at 5 years, 70 (10.3%). A recent study also suggested a possible benefit associated with anti-platelet agents [107]. Kuller Rosamond We used the most recent value or trajectories of longitudinal data before participants inclusion in the nested analysis cohort. Characteristics of the Nested Analysis Cohorts in the Cardiovascular Health Study and the Atherosclerosis Risk in Communities Study. Bidirectional relationship between cognitive function and pneumonia. This is particularly important in the elderly because their risk of pneumonia and subsequent CVD was high. JJ, Gilbertson CAP leads to a rapid elevation in pro-inflammatory cytokines such as CRP, IL-6, TNF- and IL-8. Elkind The risk of cardiovascular disease (CVD) after infection is poorly understood. In all three studies, the increased risk was maximal shortly after infection and decreased with time. The number of participants at risk and those who developed an event over each time interval were estimated using a complete case approach and participants with missing data for covariates were excluded. Stevens

The methodology of self-controlled case series studies. All have documented an increased risk of AMI or stroke following RTI that persists for up to 90 days after infection. et al. A review, Seasonal changes in platelets, fibrinogen and factor VII in elderly people, Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease, The UK General Practice Research Database, Validity of the general practice research database, Acute respiratory-tract infections and risk of first-time acute myocardial infarction, Risk of myocardial infarction and stroke after acute infection or vaccination, Recent respiratory infection and risk of cardiovascular disease: casecontrol study through a general practice database, Does this patient have community-acquired pneumonia? A combination of annual study visits, telephone follow ups, review of Medicare Provider Utilization files (CHS only), local hospitalization records, death certificates from state vital statistics offices, and local newspaper obituaries were used for identification of new cardiovascular events, hospital admissions, and mortality.15,16, Hospital discharge abstracts were obtained for all hospitalizations. Current evidence suggests that CAP is associated with significant increase in short- and long-term risk of cardiovascular events and death from vascular events.

A number of studies have sought to study the long-term sequelae of CAP by following patients after discharge from hospital. P, The cumulative number of pneumonia cases that experienced CVD events by 30 days after pneumonia were 68 (11.5%); at 90 days, 79 (13.4%); at 1 year, 106 (17.9%); and at 5 years, 177 (30.0%). Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial 2 years experience. S, Angus OMeara The average age of participants with pneumonia was 55 years. b) Ruptured atherosclerotic plaque. LE, Controls were not hospitalized with pneumonia when matched or prior to matching but could develop pneumonia at a later time during follow-up; thus, 54 controls in CHS and 22 controls in ARIC developed pneumonia after matching. Studies assessing cardiovascular risk in patients admitted to hospital with CAP are summarised in table 2. EA, Fine These patients are unlikely to have had sepsis and less is known about how relatively mild infections affect the heart, vasculature and inflammatory pathways. Hospitalization for pneumonia in the Cardiovascular Health Study: incidence, mortality, and influence on longer-term survival.

Conclusions and Relevance A population-based study from Finland [12] followed elderly patients for a mean of 9.2 yrs and identified a significantly increased risk of long-term mortality among CAP patients and an independent association with cardiovascular mortality (relative risk (RR) 2.4, 95% CI 1.73.4; p<0.001).

We used previously validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 480 through 487 in the first 5 discharge diagnoses fields to identify pneumonia hospitalizations.21,22 We reviewed the medical charts of 158 pneumonia admissions identified by this approach in CHS. In addition, patients with respiratory infections are frequently hypoxic. ARIC indicates Atherosclerosis Risk in Communities study; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CHS, Cardiovascular Health Study; CVD, cardiovascular disease; LDL, low-density lipoprotein. Objective We considered, but did not include, statin usage before pneumonia hospitalization because its prevalence at baseline was very low and similar (2.3% in CHS) in participants with and without pneumonia and it remained similar between the 2 groups over the first 10 years. BJ, Plouffe The risk was highest during the first year and persisted through the second year. JA, Surveillance and ascertainment of cardiovascular events: the Cardiovascular Health Study. Thank you for your interest in spreading the word on European Respiratory Society . MF, Kuller Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. G, J, Rueda JF, File MS, Pekow Release of cytokines promotes further infiltration by macrophages and promotes smooth muscle proliferation. et al. Smeeth A detailed discussion of the potential role of these drugs is beyond the scope of this review. First, we explored whether the association between pneumonia and CVD in our primary analysis was specific to this infection or whether it was also present with other acute illnesses that lead to hospitalization. Results After matching, the analysis cohort nested within ARIC consisted of 2040 participants (680 pneumonia cases and 1360 controls, Figure 1B). We therefore repeated our primary analysis but matched each participant hospitalized with pneumonia to a participant hospitalized for other reasons (excluding hospitalizations for CVD and infections). Pathological studies have identified C. pneumoniae in atherosclerotic plaques using numerous methods (PCR, electron microscopy and immunocytochemistry), whereas C. pneumoniae antigens were not detectable in normal or non-atherosclerotic segments of arterial wall [71, 72]. Town R, Karajala-Subramanyam We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n=5888; enrollment age, 65 years; enrollment period, 19891994) and the Atherosclerosis Risk in Communities study (ARIC, n=15792; enrollment age, 45-64 years; enrollment period, 19871989). Patients with acute coronary syndromes have evidence of systemic inflammation, with elevated pro-inflammatory cytokines and coagulation markers [22, 23]. Both identified that one third of deaths following a CAP episode were due to cardiovascular causes. Hall Experiments on apolipoprotein-deficient mice (a well-established mouse model of atherosclerosis) have shown that infection with influenza virus promotes inflammatory cell infiltration, smooth muscle cell proliferation and fibrin deposition in atherosclerotic plaques [70]. Corrales-Medina SR, Platz CVD indicates cardiovascular disease. 2015;313(3):264274. Assessment of cerebrovascular disease in the Cardiovascular Health Study. This activation is an essential part of innate immunity, as activated platelets participate in host defence through reactive oxygen species generation, phagocytosis, cytokine release and interaction with neutrophils and monocytes [42].

We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status. [2] investigated causes of mortality within 90 days of presentation with CAP. Risk of Cardiovascular Disease (CVD) Events After Hospitalization for All Pneumonia in the Atherosclerosis Risk in Communities Study, Table. In general, the adjusted HRs for severe pneumonia were higher and remained above 1 for longer duration compared with the cases of nonsevere pneumonia, but the 95% CIs of these estimates overlapped between the 2 groups. Atherosclerosis. Moreover, in our analyses, the magnitude of risk for CVD associated with pneumonia was similar or higher compared with the risk of CVD associated with traditional risk factors, such as smoking, diabetes, and hypertension. P, Litovsky H, Snyder G, Mayr PN; Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. These primary care-based studies are large and uniformly give similar conclusions, but there are a number of inherent limitations related to the study design. Septicemia in the United States dialysis population, 1991 to 1999. RP, Lemaitre Milbrandt et al. In sepsis, activation of the endothelium occurs early and may be beneficial, facilitating the passage of leukocytes to infected areas [50]. Crawford et al.

While great progress has been made in understanding the link between respiratory infections and cardiovascular events, many areas require further study. TR, Psaty National Hospital Discharge Survey: 2007 summary. C-reactive protein (CRP) in particular has been identified as an independent predictor of a risk of cardiovascular events [2631] and has been shown to correlate with the extent of coronary atherosclerosis seen on angiography [3234]. Should we use a case-crossover design? M, physiotherapy respiratory cardiopulmonary nursing Z, Clermont Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. The risk was highest (4-fold) in the first 30 days after pneumonia and although it progressively declined during the first year, it remained approximately 1.5-fold higher in subsequent years. Similar to CHS, pneumonia was associated with a large increase in the risk of CVD in younger adults across different risk groups (Figure 3).

The elderly population, who are those most frequently affected by CAP, are also at high risk of mortality from cardiovascular disease [14]. Decreased systolic and diastolic ventricular contractility in septic patients has been evidenced by numerous scientific and clinical studies, and results in reduced coronary perfusion pressure [54, 63, 64]. CAP also induces a marked pro-thrombotic state associated with elevation of thrombotic markers such as fibrinogen, factor IX, thrombinanti-thrombin complex and D-dimer [4345]. However, this limitation would bias our estimates toward the null. [92] on patients admitted with atherothrombotic ischaemic stroke noted respiratory infections in the past year to be more common, with radiologically confirmed CAP being the most prevalent type of infection (19% in cases versus 6% in controls; OR 3.9, 95% CI 1.98; p<0.0001). TJ, Cooke However, they analyzed only patients on dialysis, and their results cannot be generalized to the broader population. Role of acute infection in triggering acute coronary syndromes.

Magnitude and duration of the effect of sepsis on survival.