1. Community acquired pneumonia Bharat Awsare MD FCCP Division of Pulmonary and Critical Care Medicine Assistant Professor of Medicine Director, Medical Intensive Care Unit Thomas Jefferson University Hospital

2. Pneumonias – Classification Community Acquired CAP Health Care Associated HCAP Hospital Acquired HAP ICU Acquired ICUAP Ventilator Acquired VAP Nosocomial Pneumonias

3. CAP – Two Types of Presentations Classical Sudden onset of CAP High fever, shaking chills Pleuritic chest pain, SOB Productive cough Rusty sputum, blood tinge Poor general condition High mortality up to 20% in patients with bacteremia S.pneumoniae causative Gradual & insidious onset Low grade fever Dry cough, No blood tinge Walking CAP Low mortality 1-2%; except in cases of Legionellosis Mycoplasma, Chlamydiae, Legionella, Ricketessiae, Viruses are causative Atypical

4. Scope of the problem 5 million cases/year 10 million office visits 1 million admissions/year 100,000 ICU admissions Estimated cost: $12 billion* ◦ Inpatient (20%)$10 billion ◦ Outpatient (80%) $2 billion *Colice GL et al. Am J Resp Crit Care Med (2006)176:913-920.

5. Incidence of CAP per age (in 1000’s)

6. CAP mortality per age (in 1000’s)

7. Mortality in CAP Most common cause of severe sepsis 6 th leading cause of death ◦ Leading cause of death from infection Mortality has not changed in 4 decades ◦ Outpatient1% ◦ Inpatient5-10% ◦ ICU20-40%

8. Age adjusted death rates www.cdc.gov/mmwr

10. Risk factors Major ◦ COPD/smoking ◦ Alcoholism ◦ Chronic heart disease ◦ Diabetes 1/3 patients previously healthy Other risk factors ◦ Poor dentition ◦ Renal failure ◦ Hepatic disease ◦ CVA ◦ Immunodeficiency ◦ Malnutrition

11. Microbiology OutpatientInpatient (non-ICU)Inpatient (ICU) S pneumoniae M pneumoniae Legionella spp H influenzaeC pneumoniaeH influenzae C pneumoniaeH influenzaeGram negative bacilli M catarrhalisLegionella sppS aureus Viruses* * Influenza A and B Adenovirus Respiratory syncitial virus Parainfluenza 40-70% of patients with CAP have no organism identified (fastidious growth of S. pneumoniae, H. influenzae)

12. Modern methods to determine etiology of CAP Adults admitted with CAP over 1 year Microbiologic testing ◦ Sputum culture ◦ Blood culture ◦ Nasopharyngeal sampling ◦ Sputum samples analyzed by PCR ◦ Nasal samples analyzed by PCR ◦ Serologic testing for M pneumoniae and Chlamydophila pneumoniae, and viruses ◦ Urine antigen assay for S pneumoniae, Legionella

13. Results N = 184 Organism identified in 124 (67%) ◦ 35% of these had 2+ organisms For complete sampling, organism identified in 89% Sputum PCR increased yield over traditional methods

14. Bacterial and viral yields

15. Incidence of co-infections

16. Etiology in special situations Alcohol, poor dental hygiene: anaerobes Sick hunting dogs: blastomycosis Bats, bird droppings: histoplasmosis Travel to SW US: coccidiomycosis Birds: Chlamydia psittaci Rabbits: Francisella tularensis Farm animals, parturient cats: Coxiella burnetii (Q fever) Post-influenza: S. aureus, S. pneumoniae, S. pyogenes, H. influenzae

17. H1N1 outbreak April 2009 61 million affected 13,000 deaths 90% hospitalizations, 87% deaths occurred in patients less than 65 ◦ Obesity ◦ Pregnancy ◦ Asthma ◦ Young age

18. Community acquired MRSA New strain of MRSA (USA 300 strain) Not traditional risk factors for MRSA Often follow influenza viral infection ◦ Influenza with bilateral cavitary pneumonia Skin/soft tissue infection Risk factors ◦ Young age ◦ Close living conditions ◦ Skin contact, cuts/abrasions

19. Necrotizing pneumonia (CA-MRSA) Eur Respir J 2009; 34: 1470–1476

20. CA-MRSA virulence factors Panton-Valentine leukocidin (PVL) gene ◦ Skin/soft tissue infections ◦ Severe cavitary pneumonia Type IV mecA gene ◦ Resistance to beta lactams/methicillin

21. CA-MRSA therapy Antibiotics ◦ Vancomycin (reports of poor outcomes with monotherapy*) ◦ Linezolid Anti-toxin ◦ Clindamycin ◦ Linezolid *Micek et al. Chest 2005(128):2732.

22. Assessment of severity Physicians overestimate risk of death ◦ Unnecessary admissions ◦ Increased cost ◦ Potential for morbidity related to hospitalization Multiple tools available ◦ PORT/Pneumonia Severity Index ◦ CURB-65 ◦ ATS/IDSA

23. PORT Pneumonia Severity Index

25. ED’s using PSI reduced rate of hospitalization in low risk groups NO DIFFERENCES IN MORTALITY

26. CURB-65 algorithm

27. CRB-65 algorithm

30. ATS/IDSA: site of care decisions Severity scores should be used to identify patients for outpatient therapy ◦ CURB-65 ◦ PSI Scores should always be supplemented by physician determination of other factors ◦ Psychosocial factors ◦ Support resources ◦ Compliance ◦ Ability to tolerate oral therapy ◦ Failure of outpatient therapy

31. Laboratory testing (hospitalization) Chest X-ray CBC with differential Electrolytes BUN/creatinine Glucose Liver enzymes Oxygen saturation Gram stain/cultures of sputum (??) Blood cultures (??)

32. Chest x-ray Radiology + clinical scenario are gold standard for diagnosis Not mandatory (outpatient) Information provided ◦ Extent of disease ◦ Cavitation ◦ Complications (effusion) ◦ Alternate or co-existing diagnosis (neoplasm) Information not provided ◦ Causative organism

33. CXR PatternPossible Pathogens LobarS.pneumo, Kleb, H. influ, Gram Neg PatchyAtypicals, Viral, Legionella Interstitial Viral, PCP, Legionella, mycoplasma, chlamydia Cavitation Anerobes, Kleb, TB, S.aureus, Fungi, caMRSA, Nocardia Large effusionStaph, Anaerobes, Klebsiella Miliary patternMtb, Fungi Widened mediastinum with effusions Inhalational anthrax

34. Chest Xray in CAP

35. Cavitary pneumonia

36. Parapneumonic effusion

37. CXR – PA and Lateral Views

38. Round Pneumonic Consolidation

39. Special Forms of Pneumonia

40. Empyema

41. Microbiologic testing Utility for all CAP uncertain ◦ False negatives ◦ Not cost effective ◦ Diagnosis may not affect outcome IDSA/ATS recommendations ◦ Severe CAP (ICU) ◦ Optional for outpatient ◦ Diagnosis uncertain ◦ Structural lung disease ◦ Pleural effusion

43. Biomarkers for CAP Procalcitonin (available) C-reactive protein (available) Pro-adrenomedullin Co-peptin Natriuretic peptides Cortisol Pro-atrial natriuretic peptide Coagulation markers Brar NK and Niederman MS, Ther Adv Respir Dis (2011) 61-78

44. Procalcitonin Precursor of calcitonin No hormonal effects Increased with bacterial infection ◦ Toxin mediated (lipopolysaccaride) ◦ Cytokine mediated (IL-6, IL-1, TNF) ◦ Cell mediated response mediated Decreased with viral infection ◦ Cytokine mediated (IFN-gamma) Also increased with trauma, burns

45. Procalcitonin: Pros/cons Pros ◦ Helps reduce antibiotic duration ◦ Helps antibiotic exposure ◦ Helps convert to oral therapy ◦ May help with early discharge Cons ◦ Inadequate accuracy to discriminate bacterial vs. viral infection ◦ Accuracy too low to withhold therapy

46. Timing of antibiotics Multiple studies show delayed antibiotics associated with increased mortality (Houck et al 2004, Meehan et al 1997) 4 hour antibiotic was adopted as quality core measure Implementation of 4 hours had problems: ◦ Misdiagnosis of CAP* ◦ Inappropriate antibiotics* ◦ Antibiotic toxicity including C difficile *Kanwar et al. Chest 2007:1865-1869.

47. Timing of antibiotics IDSA/ATS guidelines recommendation ◦ First dose of antibiotics in ED (6-8 hrs) Earlier antibiotics probably better with severe sepsis

48. Factors influencing antibiotics Setting ◦ Outpatient ◦ Inpatient ◦ ICU Comorbidities Risk factors for certain pathogens Resistant pneumococcus Resistant gram negatives Pseudomonas Community acquired MRSA

50. Monotherapy vs. combination therapy Multiple recent studies show improved outcomes with combination therapy 1-5 Odds ratio of death with monotherapy ranged from 1.5-6x adjusted for severity Benefit most in those with severe CAP ◦ Benefit only seen when macrolides used 6 1 Waterer et al. Arch Int Med 2001(161):1837. 2 Baddour et al. Am J Respir Crit Care Med 2004(170):440. 3 Tessmer et al. J Antimicrob Chemother 2009(63):1025. 4 Rodriguez et al. Crit Care Med 2007(35):1493. 5 Restrepo et al.Eur Respir J 2009(33):153. 6 Martin-Loeches et al. Intensive Care Med 2010(36):612.

51. Beneficial effects of macrolides Atypical pathogen co-infection seen in 1/3 of pneumococcal CAP ◦ Quinolones, tetracyclines do not offer same benefit Anti-inflammatory properties ◦ Modification of heat shock protein-70 and p38 signaling pathways ◦ Improve chemotactic and phagocytic function of macrophages ◦ Mucociliary function enhancement Reduce virulence factors ◦ Toxin production ◦ Biofilm ◦ May reduce bacterial load with less cell wall lysis by beta- lactams = less pro-inflammatory response

52. Antimicrobial therapy Outpatient ◦ Previously healthy ◦ No antibiotics within last 3 months Macrolide Doxycycline

53. Antimicrobial therapy Outpatient ◦ Comorbidities ◦ Previous antibiotics within 3 months ◦ High resistance to S pneumoniae Respiratory fluoroquinolone Beta-lactam plus macrolide

54. Antimicrobial therapy Inpatient, non-ICU Beta-lactam plus macrolide Respiratory fluoroquinolone

55. Antimicrobial therapy Inpatient, ICU Beta lactam plus: ◦ Respiratory fluoroquinolone or ◦ Macrolide PCN allergic: ◦ Aztreonam plus fluoroquinolone

56. Antimicrobial therapy Pseudomonas is consideration Anti-pseudomonal/pneumococcal beta-lactam (Pip-tazo, cefepime, imipenem, meropenem) PLUS one of the following: ◦ Ciprofloxacin or Levofloxacin ◦ Azithromycin plus aminoglycoside ◦ Antipneumococcal fluroquinolone plus aminoglycoside PCN allergy: substitute aztreonam for beta-lactam

57. Antimicrobial therapy If CA-MRSA is consideration Add vancomycin or linezolid ◦ If vancomycin, consider clindamycin for anti- toxin therapy

58. Factors for switch to oral therapy Hemodynamic stability Clinical improvement ◦ Cough, dyspnea better ◦ Afebrile > 8 hours ◦ WBC normalizing Adequate oral intake No GI absorption issues Patients do not need to be observed overnight after switch to oral tx

59. Duration of antibiotics Treated for minimum 5 days (ATS), 7 days (BTS) Longer if resistant organism, extra-pulmonary disease Afebrile for 48-72 hours No more than 1 sign of clinical instability

60. Number of signs of instability correlate with mortality, readmission Halm EA, et al.. Arch Intern Med 2002; 162:1278–84.

62. Does everyone need follow up chest Xray? Cohort study in 3398 patients 1.1% risk of lung cancer at 90 days 2.3% risk of lung cancer at 5 years Multivariate analysis ◦ Age > 50 most strongly associated ◦ Male sex ◦ Smoking Conclusion: follow-up CXR not necessary in patients <50 years old Should be done at 7-12 weeks Tang et al. Arch Intern Med 2011;171:1193.

63. Long term consequences of CAP Survivors of CAP had sustained increased mortality for 2+ years 1 CAP survivors had 1 year mortality 2.5x greater than age/sex matched controls 2 IL-6 and IL-10 elevation at discharge associated with increased 90d mortality 3 1 Brancati et al. Lancet 1993(342):30. 2 Kaplan et al. Arch Intern Med 2003(163):317. 3 Yende et al. Am J Respir Crit Care Med 2008(177):1242.

64. Long term consequences of CAP Medicare database 158,960 CAP pts 794,333 hospitalized controls matched for age, sex, race Kaplan et al. Arch Intern Med 2003(163):317.

65. CAP was associated with lower 10 year survival compared to age matched control

66. Possible mechanisms to explain long term mortality Cardiovascular disease effects 1 Associations between CAP and acute coronary events 2 Associations between CAP and subsequent cardiovascular events 3 Destabilize atheromatous plaques Induce procoagulant state 1 Koivula et al. Arch Intern Med 1999(159):1550. 2 Ramirez et al. Clin Infect Dis 2008(47):182. 3 Smeeth et al. NEJM 2004(351):2611.

67. QUESTIONS?