|Year : 2017 | Volume
| Issue : 2 | Page : 23-31
Cardiovascular complications in patients with community-acquired pneumonia
Marta Di Pasquale, Sonia Henchi, Nicolò Vanoni, Francesco Blasi
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Department of Internal Medicine, Respiratory Unit and Regional Adult Cystic Fibrosis Center, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
|Date of Web Publication||28-Sep-2017|
Dr. Marta Di Pasquale
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan; Department of Internal Medicine, Respiratory Unit and Regional Adult Cystic Fibrosis Center, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan
Source of Support: None, Conflict of Interest: None
Community-acquired pneumonia (CAP) is the most frequent infectious disease, responsible for a great morbidity and mortality worldwide. It is known that poor outcome in CAP patients is not only directly related to pneumonia but also to comorbidities both during hospitalization and long term after discharge. Evidences show a high correlation between acute respiratory infections and increased risk of cardiovascular events (CVEs), such as acute myocardial infarction, arrhythmias, congestive heart failure, and stroke. The excessive systemic inflammatory response is responsible for hypoperfusion and activation of cytokines causing endothelial dysfunction, pro-coagulant effects, and atheroma instability. An established diagnostic tool to identify high-risk patients is not yet available, but cardiovascular biomarkers seem to be more effective than inflammatory molecules. Early identification of patients at higher risk for CVEs is mandatory to treat them effectively with prophylaxis medications, to establish adequate clinical surveillance and prevention with vaccinations. The present article reviews the epidemiology, pathophysiology, clinical presentation, risk factors, diagnosis, outcomes, and prevention of CVEs in patients hospitalized for CAP.
Keywords: Acute myocardial infarction, arrhythmia, cardiovascular events, community-acquired pneumonia, heart failure, stroke
|How to cite this article:|
Di Pasquale M, Henchi S, Vanoni N, Blasi F. Cardiovascular complications in patients with community-acquired pneumonia. Community Acquir Infect 2017;4:23-31
|How to cite this URL:|
Di Pasquale M, Henchi S, Vanoni N, Blasi F. Cardiovascular complications in patients with community-acquired pneumonia. Community Acquir Infect [serial online] 2017 [cited 2019 Jul 16];4:23-31. Available from: http://www.caijournal.com/text.asp?2017/4/2/23/215802
| Introduction|| |
Community-acquired pneumonia (CAP) is still an important cause of morbidity and mortality worldwide, especially in the elderly. In the last decades, mortality rates have not changed, despite advances in diagnostic and supportive methods.,
It is now known that poor outcome in CAP patients is not only directly related to pneumonia but also to comorbidities,, both during hospitalization and after discharge,,, with an absolute rate of events varying broadly from 10% to 30% across different cohorts.
Evidences show a high correlation between acute respiratory infections and increased risk of cardiovascular events (CVEs) [Table 1]. The occurrence of a CVE in a hospitalized patient with CAP may significantly affect clinical status and a severe CVE could be the primary cause of clinical failure.,
|Table 1: More recent studies on cardiovascular events and community-acquired pneumonia |
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The aim of this study is to evaluate epidemiology, clinical presentation, physiopathology, outcomes, risk factors, and prevention of CVEs in patients with CAP.
| Search Strategy and Selection Criteria|| |
We searched Medline for papers published from January 1, 2000 to April 30, 2017. We used the search terms "community acquired pneumonia" or "pneumonia," in combination with the terms "cardiovascular events," "acute myocardial infarction," "arrhythmia," "heart failure," "stroke," and their variations. We restricted the search strategy to adults. We also searched the reference lists of articles identified by this search strategy. Review articles and book chapters are cited to provide readers with more details and more references.
| Epidemiology|| |
Different epidemiological and primary care studies demonstrated an increased risk of CVEs in the first 3 months after an acute respiratory infection.,,, The increased risk for cardiac events in hospitalized patients may be 8 folds higher in the first 15 days from admission and reach 100 folds within the first 2-3 days. At long-term follow-up of patients with a previous episode of CAP, studies reveal that cardiovascular mortality contributes to 30% of deaths.,,,
A study by Musher et al. including 170 patients found that 19.4% of patients hospitalized with CAP developed cardiovascular complications such as acute myocardial infarction (AMI), severe arrhythmias, or acute congestive heart failure (CHF). Another study by Ramirez et al. found that 15% of patients with AMI on admission had severe CAP. During hospitalization, among patients with clinical failure, 20% of cases developed CVEs.
A retrospective cohort study of 206 patients followed up to 15 days after discharge showed that 11% of CAP patients had acute coronary syndrome, with an 8-times higher risk for occurrence of CVEs in comparison to controls.
| Clinical Presentation|| |
Acute myocardial infarction
Occurrence of AMI or unstable angina is reported to be 5% among patients with pneumonia in a recent meta-analysis. Mechanisms causing myocardial ischemia (plaque rupture and in situ thrombus formation) are triggered or worsened during acute pneumonia. A multicenter, prospective observational study published in 2015 found that AMI had a prevalence of 2.3% versus 11.7% of other CVEs, but it was associated with a significantly higher severity of the disease on admission and a significantly higher in-hospital mortality (43%). In addition, this study showed that female sex, severe sepsis, and previous history of liver disease are independent risk factors for the occurrence of AMI.
Clinicians should promptly identify patients with CAP at risk for AMI, to give them adequate cardiovascular therapy, such as acetyl-salicylate acid, and to strictly monitor them for ischemic events both during and after the resolution of the acute infection.
Several explanations have been proposed to justify the association between acute respiratory infections and the risk of arrhythmias. Some studies refer to the increased levels of inflammatory cytokines in serious infections or to disturbed hemodynamic homeostasis, pro-thrombotic conditions, and increased catecholamine release. Other studies describe a direct inflammatory effect on coronary arteries, myocardium, and pericardium, as well as direct infection of cardiomyocytes, as provocative mechanisms of acute arrhythmias.,,,,,, Finally, acute disturbances, such as hypo/hyperthermia, electrolyte abnormalities, and hypoxemia, may cause arrhythmias.
A study by Soto-Gomez et al. found new-onset arrhythmias in 12% of cases among a large number of patients with pneumonia, especially in severe and elderly patients. In addition, authors found that arrhythmias were associated with an increased 30- and 90-day mortality. Older age, CHF, and septic shock were independently associated with the onset of arrhythmias. On the contrary, use of beta-blockers prior to admission seemed to prevent arrhythmias, thanks to their pharmacological effect.
Further studies in this field are needed to understand how long these patients remain at risk for arrhythmias after acute pulmonary infections, which could be the causative mechanism and what kind of therapy may be prophylactic against these CVEs.
Incidence of new or worsening CHF is the most frequent cardiac complication among patients with pneumonia. A meta-analysis by Corrales-Medina et al. reported an incidence of CHF of 14% versus 5.3% of acute coronary syndrome and 4.7% of arrhythmias. Results also show an association between CHF and female sex, older age, and preexisting coronary artery disease.
Studies with a high prevalence of chronic obstructive pulmonary disease (COPD) and pneumonia found a higher incidence of CHF.
Association between stroke and acute respiratory infections seems to be known. A case-control study published in 2009 demonstrates that patients who suffered from stroke had a significantly higher incidence of respiratory infections in the year before CVEs, especially CAP. Furthermore, in multivariable analysis adjusting for major vascular risk factors, respiratory infection was independently associated with stroke.
During an acute respiratory infection, inflammation is both local and systemic in the lungs. Thus, inflammatory processes and molecules can affect other organs, such as the heart. Locally, ventilator-perfusion mismatching and intrapulmonary shunt cause hypoxemia. On the other side, a significant systemic inflammatory response may cause severe hypoperfusion with a consequent multiorgan failure., This systemic process is mediated by the high levels of pro-inflammatory cytokines that cause endothelial dysfunction, atheroma instability, rupture of the atheromatous plaque, increased fibrinogen levels, and prothrombotic vascular conditions,, [Figure 1].
|Figure 1: Pathogenesis of cardiovascular events in community-acquired pneumonia|
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The majority of cardio- and cerebro-vascular events are associated with platelet activation. One of the mechanisms consists in the interaction between platelets with neutrophils and vascular endothelium. Adhesion of neutrophils to activated vascular endothelium provokes anti-inflammatory activities of endothelial cells, exacerbating microvascular coagulation., In bacterial CAP, it seems to exist an interaction between Gram-positive cell wall or Gram-negative endotoxin and receptors expressed by platelets, which activates fibrinogen cascade, production of thromboxanes, and consequent aggregation of platelets and vasoconstriction. In particular, some Staphylococcus and Streptococcus strains seem to have this property on platelets, mediated by CXC chemokine which also has antibacterial activity., In animal models of invasive pneumococcal disease, Pneumococcus cause microlesions into the myocardium that affect cardiac function.,
| Diagnosis|| |
Since an established tool to estimate long-term outcomes of CAP patients is still unavailable, several studies address the topic of biomarkers as screening tests for the presence of structural heart diseases or for short- and long-term prognosis in CAP. Actual evidences seem to show that cardiovascular biomarkers are more effective predictors of mortality than inflammatory biomarkers, both in short and long-term follow-ups. This could be explained by different reasons. Cardiovascular biomarkers are increased during sepsis, which is a known risk factor for a poorer outcome in CAP patients. In addition, they can reveal the underlying preexisting cardiac disease or septic cardiomyopathy, which may be aggravated by acute inflammatory activation caused by pneumonia.
CAPNETZ studies (the German Competence Network for Community-Acquired Pneumonia) addressed, in particular, this topic. Pro-atrial natriuretic peptide and pro-vasopressin (copeptin) levels were significantly independently associated with short- and long-term mortality among 1170 CAP patients, in comparison to inflammatory markers. Further studies showed that proadrenomedullin had the best performance and the strongest independent correlation to short- and long-term mortality and was a good prognostic factor for mortality almost 1 year after discharge from hospital, probably because of its multiple functions, such as cardiovascular activity, anti-inflammatory and antibacterial functions.
The use of these cardiovascular biomarkers could help in identifying patients at higher risk for CVEs and mortality, who may need a closer medical follow-up for complications.
Another potential diagnostic tool consists in the measurement of cardiac autonomic control (CAC), assessed by heart rate variability, as an altered sympathovagal balance, may play a role in the occurrence of CVEs during CAP and it is associated with poor outcomes.,,,, An Italian multicenter study published in 2016 hypothesized that a deregulation of CAC with a reduction of total variability and loss of sympathetic rhythmical property could be related and/or predict CVEs and mortality in CAP patients. Authors found an alteration of CAC on CAP patients, especially severe cases, consisting in a lower sympathetic modulation, and a predominant parasympathetic oscillatory rhythm, suggesting that these measurements could be useful to stratify patients by severity and cardiovascular risk.
| Outcomes|| |
Patients admitted with CAP who present or develop a CVE are at higher risk for in-hospital and long-term mortality. An observational cohort study of 500 patients with CAP found that all CVEs together were the first cause of clinical failure related to CAP. A more recent multicenter prospective study showed increased mortality in patients with CAP with CVEs compared with those without CVE (15.3% vs. 2.8%, respectively; odds ratio, 3.5; 95% confidence interval [CI], 2.3-5.2).
The study by Ramirez et al. disclosed that patients who developed AMI had a longer time to clinical stability and length of stay and a significantly higher rate of clinical failure and in-hospital mortality in comparison to patients without AMI (52% vs. 11% and 28% vs. 7%, respectively).
The same observational study cited before showed an increased mortality in patients with coronary artery occlusion and AMI also at 30 days after discharge (31% vs. 10%, respectively). Another study by Viasus et al. reported that CVEs were independently associated with 30-day mortality, with an odds ratio of 2.18 (95% CI, 1.38-3.42). Occurrence of a CVE in an early phase of pneumonia is associated with a lower rate of survival at 30 days from hospital admission also in another study in 2012.
Patients hospitalized with CAP are known to have a higher risk of long-term mortality., Several studies found CVEs as one of the main causes of long-term mortality among these patients. A study published by Yende et al. reported CVEs as the first cause of death over 1 year after an episode of pneumonia, along with higher levels of inflammatory markers, especially interleukin (IL)-6, suggesting that a persisting inflammatory response may have some role in the increased risk for mortality in this population. In another study conducted in Canada, CVEs were the second cause of re-hospitalization after a first episode of pneumonia in 5-year follow-up. A study by Mandal et al. underlined the association between CVEs and cerebrovascular disease and increased mortality at 90 days among 4408 patients hospitalized with CAP. An Italian study published in 2015 found that almost 50% of patients who died during the follow-up had intrahospital cardiac complications, confirming that intrahospital cardiac complications increase the risk of mortality not only after a short-term but also after a long-term follow-up.
| Risk Factors for Cardiovascular Events|| |
To prevent CVEs, it is important to promptly identify patients at risk, as these events are still underdiagnosed., Many risk factors were identified in literature. In a large prospective cohort study of patients hospitalized for CAP, the presence of age >65 years, chronic heart disease, tachycardia, septic shock, multilobar pneumonia, hypoalbuminemia, and pneumococcal pneumonia were independent predictors of acute cardiac events. Moreover, some authors have created a practical clinical score to stratify the risk of acute cardiac events in these patients. The low- and moderate-risk groups had rates of positive events of 0 and 4.4% and 9.5 and 9.9%, respectively, and the high-risk group had a rate between 18.7% and 34.6%, with a good accuracy (area under curve 0.73).
Other studies on CAP have found that the major risk factors for CVEs are older age, nursing home residence, preexisting chronic respiratory or cardiovascular conditions, severity of CAP, and smoking. Recently, Corrales-Medina et al. also reported that older age, nursing home residence, a history of heart failure, prior cardiac arrhythmias, previously diagnosed coronary artery disease, arterial hypertension, tachypnea, acidosis, elevated urea, hypernatremia, anemia, pleural effusion, and inpatient care were factors independently associated with CVEs. Similarly, in another study, risk factors for AMI were age, previous AMI, COPD, and chronic renal disease. In addition, age, diabetes mellitus, and prior AMI were predictors of atrial fibrillation. Griffin et al. demonstrated that, apart from age, also a history of hyperlipidemia, pneumonia severity, or causative pathogens such as Staphylococcus aureus or Klebsiella pneumoniae were associated with an elevated risk for CVEs.
| Adjunctive Treatments|| |
Different adjunctive therapies with anti-inflammatory and antiplatelet effects have been studied in patients with CAP at risk for CVEs [Table 2].
|Table 2: Adjunctive and preventive therapies for patients with community-acquired pneumonia at risk for cardiovascular events |
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Macrolides are now widely known as immunomodulatory medication, already used in chronic respiratory diseases such as bronchiectasis, asthma, COPD, and diffuse panbronchiolitis. Use of macrolides in CAP is not established yet, but some studies showed that they can improve clinical outcome in sepsis., Macrolides not only possess anti-inflammatory and immunomodulatory activities, but also possess an inhibitory activity on platelet-activating factor (PAF) that mediates platelet aggregation. Patients with CAP, especially with severe presentation, treated with macrolide-based antibiotic regimens, have been reported to have clinical benefit on outcomes., On the contrary, a study published in the UK in 2013 found that the use of clarithromycin in CAP patients was independently associated with higher risk of CVEs, increasing with the duration of treatment.
The evidence for corticosteroids as an adjunctive therapy in CAP (usually in severe CAP and septic shock) is still controversial.,,,,
Interestingly, prednisolone, which appears to be the most effective corticosteroid in the adjunctive therapy of CAP, has been reported to inhibit platelet activation in vitro.
| Prevention|| |
Some medications normally used in standard therapies for cardiovascular diseases seem to have a potential positive effect on systemic inflammation and incidence of CVEs in CAP patients [Table 2].
Statins might reduce mortality in CAP patients by their immunomodulatory effect and plaque stabilization properties., They seem to have anti-inflammatory and antioxidative effects, improvement of endothelial function, and increased nitric oxide bioavailability. The anti-inflammatory effect seems to decrease the rate of incidence of severe sepsis in patients with CAP pretreated with statins, subsequently improving the survival rate., In addition, statins have been reported to suppress platelet activation by various mechanisms, which also appear to be largely attributable to inhibition of hydrated to o-methyl-8-hydroxybutyryl CoA reductase. A systematic review evaluated the immunomodulatory effects of statins in patients with CAP and found a reduction in the release of pro-inflammatory chemokines and cytokines in patients with CAP, in both the pulmonary and systemic compartments. Moreover, authors found a decreased risk of pneumonia and an improved survival of pneumonia in patients taking statins.
Angiotensin-converting enzyme (ACE) inhibitors also seem to reduce 30-day cardiovascular mortality in CAP.
A retrospective study published in 2013 suggests that the beneficial effects of statins, ACE inhibitors, and angiotensin II receptor blockers are due to other mechanisms other than preventing future CVEs. For example,, anti-inflammatory response of both statins and ACE-I, antibacterial and antiplatelet activities of statins, and protective pulmonary effect showed by ACE-I, as an increased activity of the renin-angiotensin system, are associated with a higher incidence and mortality from acute respiratory distress syndrome.,
Antiplatelet drugs may also be protective in severe sepsis and septic shock. Nevertheless, there are few studies evaluating their potential benefits on CAP outcomes. A study by Cangemi et al. found no effect of aspirin administration on the occurrence of CVEs in CAP patients. On the contrary, in a retrospective study of 886 patients in Intensive Care Unit, patients who received acetyl-salicylic acid had a significantly lower in-hospital mortality.
Influenza and pneumococcal vaccinations are the two main available prophylaxes for respiratory infections and are highly recommended for patients affected by chronic cardiovascular diseases.
Studies are available regarding the association between influenza vaccination and a reduction in AMI and stroke., A large multicenter study of 31,546 high-risk patients of at least 55 years showed an association between influenza vaccination and a lower cardiovascular risk during influenza season, when the circulating influenza matched the vaccine antigen.
Studies regarding the association between pneumococcal vaccination and CVEs are conflicting, and by now, there are no randomized controlled trials on this topic. Some observational studies failed to find a positive association between pneumococcal vaccination and decreased CVEs.,
A large prospective population-based study to evaluate the effectiveness of the polysaccharides 23 vaccine against myocardial infarction and stroke found a marginally significant reduction in the adjusted risk of ischemic stroke (35%, 95% CI: 1%-58%), suggesting a possible protective role of vaccination against some acute thrombotic events. No protective effect was found for AMI in this population.
On the contrary, a Chinese study found that patients who underwent both influenza and pneumococcal vaccinations had a significantly lower mortality for stroke and AMI.
A systematic review and meta-analysis conducted in 2015 evaluated 332,267 patients with pneumococcal vaccine, followed up for 20 months. Results showed that vaccinated patients have a significantly lower risk by 14% for total CVE events and 8% for cardiovascular mortality, especially in older patients and in patients at major cardiovascular risk. Vaccination were proved to be more effective in this cohort with a high frequency of cardiovascular comorbidities or COPD.
| Conclusions|| |
The occurrence of CVEs in patients presenting with CAP is frequent both during acute respiratory event and after its resolution, up to even 1 year after hospitalization. They carry a worse prognosis and a higher short- and long-term mortality. It is mandatory to evaluate every single patient for risk factors for CVEs, identifying the subgroup of high-risk patients in which diagnostic methods, closer monitoring, and preventive strategies may be considered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, et al.
Causes of death for patients with community-acquired pneumonia: Results from the Pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med 2002;162:1059-64.
From the Centers for Disease Control and Prevention. Pneumonia and influenza death rates - United States, 1979-1994. JAMA 1995;274:532.
Chalmers JD. ICU admission and severity assessment in community-acquired pneumonia. Crit Care 2009;13:156.
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;138:279-83.
Mortensen EM, Kapoor WN, Chang CC, Fine MJ. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia. Clin Infect Dis 2003;37:1617-24.
Johnstone J, Eurich DT, Majumdar SR, Jin Y, Marrie TJ. Long-term morbidity and mortality after hospitalization with community-acquired pneumonia: A population-based cohort study. Medicine (Baltimore) 2008;87:329-34.
Aliberti S, Ramirez JA. Cardiac diseases complicating community-acquired pneumonia. Curr Opin Infect Dis 2014;27:295-301.
Singanayagam A, Singanayagam A, Elder DH, Chalmers JD. Is community-acquired pneumonia an independent risk factor for cardiovascular disease? Eur Respir J 2012;39:187-96.
Viasus D, Garcia-Vidal C, Manresa F, Dorca J, Gudiol F, Carratalà J. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect 2013;66:27-33.
Griffin AT, Wiemken TL, Arnold FW. Risk factors for cardiovascular events in hospitalized patients with community-acquired pneumonia. Int J Infect Dis 2013;17:e1125-9.
Cangemi R, Calvieri C, Falcone M, Bucci T, Bertazzoni G, Scarpellini MG, et al.
Relation of cardiac complications in the early phase of community-acquired pneumonia to long-term mortality and cardiovascular events. Am J Cardiol 2015;116:647-51.
Mandal P, Chalmers JD, Choudhury G, Akram AR, Hill AT. Vascular complications are associated with poor outcome in community-acquired pneumonia. QJM 2011;104:489-95.
Corrales-Medina VF, Musher DM, Wells GA, Chirinos JA, Chen L, Fine MJ. Cardiac complications in patients with community-acquired pneumonia: Incidence, timing, risk factors, and association with short-term mortality. Circulation 2012;125:773-81.
Musher DM, Rueda AM, Kaka AS, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007;45:158-65.
Aliberti S, Ramirez J, Cosentini R, Valenti V, Voza A, Rossi P, et al.
Acute myocardial infarction versus other cardiovascular events in community-acquired pneumonia. ERJ Open Res 2015;1. pii: 00020-2015.
Keatinge WR, Donaldson GC. Cardiovascular mortality in winter. Arctic Med Res 1995;54 Suppl 2:16-8.
Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory-tract infections and risk of first-time acute myocardial infarction. Lancet 1998;351:1467-71.
Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-8.
Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: Case-control study through a general practice database. Eur Heart J 2008;29:96-103.
Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010;10:83-92.
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. Am J Respir Crit Care Med 2008;177:1242-7.
Bruns AH, Oosterheert JJ, Cucciolillo MC, El Moussaoui R, Groenwold RH, Prins JM, et al.
Cause-specific long-term mortality rates in patients recovered from community-acquired pneumonia as compared with the general Dutch population. Clin Microbiol Infect 2011;17:763-8.
Ramirez J, Aliberti S, Mirsaeidi M, Peyrani P, Filardo G, Amir A, et al.
Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis 2008;47:182-7.
Corrales-Medina VF, Serpa J, Rueda AM, Giordano TP, Bozkurt B, Madjid M, et al.
Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes. Medicine (Baltimore) 2009;88:154-9.
Corrales-Medina VF, Suh KN, Rose G, Chirinos JA, Doucette S, Cameron DW, et al.
Cardiac complications in patients with community-acquired pneumonia: A systematic review and meta-analysis of observational studies. PLoS Med 2011;8:e1001048.
Wang G, Burczynski F, Hasinoff B, Zhong G. Infection of myocytes with chlamydiae. Microbiology 2002;148(Pt 12):3955-9.
Spagnoli LG, Pucci S, Bonanno E, Cassone A, Sesti F, Ciervo A, et al.
Persistent Chlamydia pneumoniae
infection of cardiomyocytes is correlated with fatal myocardial infarction. Am J Pathol 2007;170:33-42.
Antonarakis ES, Wung PK, Durand DJ, Leyngold I, Meyerson DA. An atypical complication of atypical pneumonia. Am J Med 2006;119:824-7.
Kuiken T, Taubenberger JK. Pathology of human influenza revisited. Vaccine 2008;26 Suppl 4:D59-66.
Madjid M, Aboshady I, Awan I, Litovsky S, Casscells SW. Influenza and cardiovascular disease: Is there a causal relationship? Tex Heart Inst J 2004;31:4-13.
Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection. Int J Cardiol 2008;130:304-9.
Wasi F, Shuter J. Primary bacterial infection of the myocardium. Front Biosci 2003;8:s228-31.
Soto-Gomez N, Anzueto A, Waterer GW, Restrepo MI, Mortensen EM. Pneumonia: An arrhythmogenic disease? Am J Med 2013;126:43-8.
Zurrú MC, Alonzo C, Brescacín L, Romano M, Cámera LA, Waisman G, et al.
Recent respiratory infection predicts atherothrombotic stroke: Case-control study in a Buenos Aires healthcare system. Stroke 2009;40:1986-90.
Schuetz P, Christ-Crain M, Zimmerli W, Mueller B. Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia. Intensive Care Med 2011;37:970-80.
Mirsaeidi M, Peyrani P, Aliberti S, Filardo G, Bordon J, Blasi F, et al.
Thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia. Chest 2010;137:416-20.
Peyrani P, Ramirez J. What is the association of cardiovascular events with clinical failure in patients with community-acquired pneumonia? Infect Dis Clin North Am 2013;27:205-10.
Crawford VL, McNerlan SE, Stout RW. Seasonal changes in platelets, fibrinogen and factor VII in elderly people. Age Ageing 2003;32:661-5.
Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: Winter infections and death from cardiovascular disease. Lancet 1994;343:435-9.
Feldman C, Anderson R. Community-acquired pneumonia: Pathogenesis of acute cardiac events and potential adjunctive therapies. Chest 2015;148:523-32.
Maugeri N, Campana L, Gavina M, Covino C, De Metrio M, Panciroli C, et al.
Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 2014;12:2074-88.
Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al.
Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 2014;34:1977-84.
Arman M, Krauel K, Tilley DO, Weber C, Cox D, Greinacher A, et al.
Amplification of bacteria-induced platelet activation is triggered by Fc?RIIA, integrin aIIbß3, and platelet factor 4. Blood 2014;123:3166-74.
Naik UP. Bacteria exploit platelets. Blood 2014;123:3067-8.
Brown AO, Mann B, Gao G, Hankins JS, Humann J, Giardina J, et al. Streptococcus pneumoniae
translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 2014;10:e1004383.
Krüger S, Ewig S, Kunde J, Hartmann O, Suttorp N, Welte T; CAPNETZ Study Group. Pro-atrial natriuretic peptide and pro-vasopressin for predicting short-term and long-term survival in community-acquired pneumonia: Results from the German Competence Network CAPNETZ. Thorax 2010;65:208-14.
Krüger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T; German Competence Network for the Study of Community Acquired Pneumonia (CAPNETZ) Study Group. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: Results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med 2010;182:1426-34.
Bello S, Lasierra AB, Mincholé E, Fandos S, Ruiz MA, Vera E, et al.
Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J 2012;39:1144-55.
Corrales-Medina VF, Musher DM, Shachkina S, Chirinos JA. Acute pneumonia and the cardiovascular system. Lancet 2013;381:496-505.
La Rovere MT, Bigger JT Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998;351:478-84.
Huikuri HV, Stein PK. Clinical application of heart rate variability after acute myocardial infarction. Front Physiol 2012;3:41.
La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, et al.
Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 2003;107:565-70.
Aliberti S, Tobaldini E, Giuliani F, Nunziata V, Casazza G, Suigo G, et al.
Cardiovascular autonomic alterations in hospitalized patients with community-acquired pneumonia. Respir Res 2016;17:98.
Aliberti S, Amir A, Peyrani P, Mirsaeidi M, Allen M, Moffett BK, et al.
Incidence, etiology, timing, and risk factors for clinical failure in hospitalized patients with community-acquired pneumonia. Chest 2008;134:955-62.
Mortensen EM. Potential causes of increased long-term mortality after pneumonia. Eur Respir J 2011;37:1306-7.
Tsoupras AB, Chini M, Tsogas N, Lioni A, Tsekes G, Demopoulos CA, et al. In vitro
anti-inflammatory and anti-coagulant effects of antibiotics towards Platelet Activating Factor and thrombin. J Inflamm (Lond) 2011;8:17.
Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al.
Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-8.
Garcia-Vidal C, Calbo E, Pascual V, Ferrer C, Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J 2007;30:951-6.
Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, et al.
Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. JAMA 2015;313:677-86.
Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, et al.
Adjunct prednisone therapy for patients with community-acquired pneumonia: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015;385:1511-8.
Wan YD, Sun TW, Liu ZQ, Zhang SG, Wang LX, Kan QC. Efficacy and safety of corticosteroids for community-acquired pneumonia: A systematic review and meta-analysis. Chest 2016;149:209-19.
Liverani E, Banerjee S, Roberts W, Naseem KM, Perretti M. Prednisolone exerts exquisite inhibitory properties on platelet functions. Biochem Pharmacol 2012;83:1364-73.
Merx MW, Weber C. Sepsis and the heart. Circulation 2007;116:793-802.
Chalmers JD, Short PM, Mandal P, Akram AR, Hill AT. Statins in community acquired pneumonia: Evidence from experimental and clinical studies. Respir Med 2010;104:1081-91.
Owens AP 3 rd
, Mackman N. The antithrombotic effects of statins. Annu Rev Med 2014;65:433-45.
Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax 2006;61:729-34.
Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, et al.
Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;166:646-50.
Jerng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC. Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome. Crit Care Med 2006;34:1001-6.
Otto GP, Sossdorf M, Boettel J, Kabisch B, Breuel H, Winning J, et al.
Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets 2013;24:480-5.
Johnstone J, Loeb M, Teo KK, Gao P, Dyal L, Liu L, et al.
Influenza vaccination and major adverse vascular events in high-risk patients. Circulation 2012;126:278-86.
Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, Gutierrez-Perez A, Vila-Rovira A, Gomez F, et al.
Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: The CAPAMIS study, one-year follow-up. BMC Public Health 2012;12:222.
Schultz MJ. Macrolide activities beyond their antimicrobial effects: Macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother 2004;54:21-8.
Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis 2005;18:125-31.
Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J 2009;33:153-9.
Asadi L, Sligl WI, Eurich DT, Colmers IN, Tjosvold L, Marrie TJ, et al.
Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia: A systematic review and meta-analysis. Clin Infect Dis 2012;55:371-80.
Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: A systematic review and meta-analysis. Crit Care Med 2014;42:420-32.
Schembri S, Williamson PA, Short PM, Singanayagam A, Akram A, Taylor J, et al.
Cardiovascular events after clarithromycin use in lower respiratory tract infections: Analysis of two prospective cohort studies. BMJ 2013;346:f1235.
Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, et al.
Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004;110:880-5.
Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: A population-based cohort analysis. Lancet 2006;367:413-8.
Troeman DP, Postma DF, van Werkhoven CH, Oosterheert JJ. The immunomodulatory effects of statins in community-acquired pneumonia: A systematic review. J Infect 2013;67:93-101.
Mortensen EM, Pugh MJ, Copeland LA, Restrepo MI, Cornell JE, Anzueto A, et al.
Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur Respir J 2008;31:611-7.
Wu A, Good C, Downs JR, Fine MJ, Pugh MJ, Anzueto A, et al.
The association of cardioprotective medications with pneumonia-related outcomes. PLoS One 2014;9:e85797.
Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther 2000;294:1043-6.
Dagenais NJ, Jamali F. Protective effects of angiotensin II interruption: Evidence for antiinflammatory actions. Pharmacotherapy 2005;25:1213-29.
Tseng HF, Slezak JM, Quinn VP, Sy LS, Van den Eeden SK, Jacobsen SJ. Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men. JAMA 2010;303:1699-706.
Siriwardena AN, Gwini SM, Coupland CA. Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: Matched case-control study. CMAJ 2010;182:1617-23.
Hung IF, Leung AY, Chu DW, Leung D, Cheung T, Chan CK, et al.
Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: A prospective cohort study. Clin Infect Dis 2010;51:1007-16.
Vlachopoulos CV, Terentes-Printzios DG, Aznaouridis KA, Pietri PG, Stefanadis CI Association between pneumococcal vaccination and cardiovascular outcomes: A systematic review and meta-analysis of cohort studies. Eur J Prev Cardiol 2015;22:1185-99.
[Table 1], [Table 2]