1. Department of Pulmonology 백승숙

2. Community-acquired pneumonia (CAP) –The most common cause of severe sepsis and the leading cause of death from infection in United States –Despite many advances in medical science, the mortality rate from CAP has changed little in the past four decades

3. OBJECTIVES Discuss a number of significant advances in our understanding of the pathophysiology of severe CAP and its optimal management Outline the current deficiencies in our understanding and the key priorities for future research

4. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Clinical Scoring Tools A number of clinical scoring systems have been developed to help physicians identify patients with CAP at risk of adverse outcomes –Pneumonia Severity Index –CURB-65 (CRB-65) –American Thoracic Society major and minor criteria –CURXO –SMART-COP –CAP-PIRO Younger patients Cannot replace thorough clinical assessment

5. CURB-65

6. Pneumonia Severity Index

7. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Clinical Scoring Tools Some patients present to hospital already severely ill Patients initially triaged as having non-severe pneumonia but who subsequently deteriorate and require ICU admission –Up to 50% of ICU admissions for CAP –High mortality rate None of the criteria have been prospectively demonstrated to avoid late transfers or lower mortality

8. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Biomarkers The deficiencies of the existing clinical scoring systems directly correlate with the interest in biomarkers to stratify patients on the basis of risk The use of biological markers of infection to help guide physicians in making clinical decisions –The need for hospital admission –Switching from intravenous to oral antibiotics

9. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Biomarkers Peripheral white cell count or platelet counts –Adverse prognostic factors in sepsis –Predict a worse outcome in severe pneumonia Serum lactate levels –Detect occult hypoperfusion in sepsis and thus respond more aggressively Procalcitonin (PCT) –A calcitonin precursor –Elevated in infection as well as in trauma, burns, and neuroendocrine tumors –A relatively specific marker of bacterial infection (as distinct from viral)

10. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Biomarkers

11. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Quantitative Bacterial Load in Blood Pneumococcal DNA in whole blood –Twice as sensitive as blood cultures Bacterial load (measured as copy number/ml) –Strong predictor of the risk of shock and the risk of death PCR-based pneumococcal assay –Deliver results to clinicians within 3 hours –Relatively inexpensive (under U.S. $20) –Determination of penicillin susceptibility

12. DETERMINING PATIENTS AT RISK OF ADVERSE ACUTE OUTCOMES - Quantitative Bacterial Load in Blood Correlation between bacterial load in blood and clinical outcome Use of whole blood genomic load and other molecular techniques –Increase the etiologic diagnosis –Decrease use of inappropriately broad antibiotic therapy

13. OPTIMAL ANTIBIOTIC THERAPY IN SEVERE COMMUNITY-ACQUIRED PNEUMONIA The increased mortality in patients with severe CAP who do not receive empiric antibiotics that cover the infecting pathogen is well documented Pathogen identification and pathogen-directed therapy –Better outcome in patients with severe disease

14. OPTIMAL ANTIBIOTIC THERAPY IN SEVERE COMMUNITY-ACQUIRED PNEUMONIA

15. The benefit of combination therapy in severe CAP is seen only when a macrolide antibiotic is part of the regimen –Atypical bacterial pathogens frequently coinfect patients with CAP, possibly in as much as 1/3 of cases of pneumococcal pneumonia –Viral coinfection may be affected by macrolides –The immunomodulating properties of macrolides likely play a major role in their beneficial effects –Nonbactericidal/static effects on the microorganism itself –Reduce the production of key virulence factors, including quorum sensing, toxin production, and biofilms

16. OPTIMAL PROCESS OF CARE OR CLINICAL PATHWAY IN PATIENTS WITH CAP The management of CAP has been subject to intense scrutiny by health care payors –Significant health care costs –CAP is much easier to define than generic lower respiratory tract infections A large proportion of patients receive therapies different from recommended guidelines and agreement of clinical practice with guidelines remains a great challenge

17. OPTIMAL PROCESS OF CARE OR CLINICAL PATHWAY IN PATIENTS WITH CAP Key quality-of-care markers –Performance of blood cultures –Delivery of the first dose of antibiotics within a set period –Adherence to antibiotic guidelines Delay in delivering antibiotic therapy –Comorbidities that reduce clinical suspicion of pneumonia –Cardiac failure, cardiac ischemia, thrombosis prophylaxis, adequate hydration, nutrition, diabetes, and aspiration risk –Less attention to other key management issues (eg. adequate fluid management, appropriate recognition of associated cardiovascular compromise, early ambulation ) 4hrs? 8hrs?

18. LONG-TERM CONSEQUENCES OF COMMUNITY-ACQUIRED PNEUMONIA Substantial continuing excess mortality for more than 2 years after surviving an episode of CAP –No specific cause was identified –As comorbid illnesses represents one of the key potential causes Cardiovascular disease effect –Acute inflammation is known to destabilize atheromatous plaques as well as inducing a procoagulant state –The inflammatory response (IL-6 and IL-10) at discharge –The possibility that an episode of CAP accelerates underlying cardiovascular disease

19. LONG-TERM CONSEQUENCES OF COMMUNITY-ACQUIRED PNEUMONIA Further studies are desperately needed Drug candidates for study are those recommended for secondary cardiovascular disease prevention –HMB CoA reductase inhibitors, aspirin, antiinflammatory strategies Profound shift in our current treatment paradigms –Treating CAP as an acute illness to one that has long-term health implications

20. Figure 1. Major determinants of outcome in community-acquired pneumonia. CONCLUSION