1. PNEUMONIA 2015

2. Objectives Definition Defense mechanisms Pathogenesis Pathology

3. Objectives Epidemiology Etiology Clinical manifestations, Dx Treatment, Prevention

4. Definition Pneumonia is an infection of the pulmonary parenchyma

5. New Classification of P. Community-acquired pneumonia (CAP) Community-acquired pneumonia (CAP) Hospital-acquired pneumonia (HAP) Hospital-acquired pneumonia (HAP) Ventilator-associated pneumonia (VAP) Ventilator-associated pneumonia (VAP) Health care–associated pneumonia (HCAP) Health care–associated pneumonia (HCAP)

6. Clinical Conditions and Pathogens in HCAP ConditionMRSAP. AAcinetobacterMDR Enterobacteriaceae Hospitalization for 48 h + + + + Hospitalization for 2 days in prior 3 months + + + + Nursing home or extended-care-facility residence + + + + Antibiotic therapy in preceding 3 months + +

7. Clinical Conditions and Pathogens in HCAP ConditionMRSA P. AAcinetobacterMDR Enterobacteriaceae Chronic dialysis + Home infusion therapy + Home wound care + Family member with MDR infection + +

8. Pathophysiology Proliferation of microbial pathogens at the alveolar level Proliferation of microbial pathogens at the alveolar level The host's response to those pathogens The host's response to those pathogens

9. Routes Of Infection Microaspiration Gross aspiration Inhalation of aerosol ( Aerosolization ) Hematogenous ( distant foci ) Hematogenous ( distant foci ) Direct spread ( contiguous foci ) : infected pleural or mediastinal space Direct spread ( contiguous foci ) : infected pleural or mediastinal space

10. Route Of Infection, Microaspiration Microaspiration of oropharyngeal secretion is the most common route. Most pulmonary pathogens originate in the oropharyngeal flora. ~ 50% of healthy adults aspirate oropharyngeal secretions into LRT during sleep.

11. Mechanical factors Defense Mechanisms Mechanical factors The hairs and turbinates of the nares The hairs and turbinates of the nares The branching architecture of the tracheobronchial tree : mucociliary clearance and local antibacterial factors The branching architecture of the tracheobronchial tree : mucociliary clearance and local antibacterial factors

12. Mechanical factors Defense Mechanisms Mechanical factors The gag reflex and the cough mechanism The gag reflex and the cough mechanism The normal flora adhering to mucosal cells of the oropharynx The normal flora adhering to mucosal cells of the oropharynx

13. Mechanical factors Defense Mechanisms Mechanical factors Resident alveolar macrophages Resident alveolar macrophages The host inflammatory response, rather than the proliferation of microorganisms, triggers the clinical syndrome of pneumonia The host inflammatory response, rather than the proliferation of microorganisms, triggers the clinical syndrome of pneumonia

14. The Host Inflammatory Response IL1, TNF : Fever IL1, TNF : Fever IL-8, G- CSF: stimulate the release of neutrophils and their attraction to the lung: IL-8, G- CSF: stimulate the release of neutrophils and their attraction to the lung: - Peripheral leukocytosis - Peripheral leukocytosis - Increased purulent secretions - Increased purulent secretions The newly recruited neutrophils : (ARDS) The newly recruited neutrophils : (ARDS)

15. The Host Inflammatory Response Erythrocytes can cross the alveolar-capillary membrane : hemoptysis Erythrocytes can cross the alveolar-capillary membrane : hemoptysis

16. The Host Inflammatory Response The capillary leak : * Radiographic infiltrate * Rales detectable on auscultation The capillary leak : * Radiographic infiltrate * Rales detectable on auscultation Alveolar filling : hypoxemia Alveolar filling : hypoxemia Increased SIRS : respiratory alkalosis Increased SIRS : respiratory alkalosis

17. The Host Inflammatory Response ↓ Compliance due to capillary leak ↓ Compliance due to capillary leak Hypoxemia Hypoxemia Increased respiratory drive Increased respiratory drive Increased secretions Increased secretions Infection-related bronchospasm Infection-related bronchospasm dyspnea dyspnea

18. Pathogenesis Colonization of ph. Air Nonpulmonary site Contiguous site Microaspiration Inhalation Bloodstream Direct extension Disease

19. Pathology Edema (exudate and often of bacteria) (RBC + occasionally bacteria) Red hepatization (RBC + occasionally bacteria) (no new RBC, PMN dominant, Gray hepatization (no new RBC, PMN dominant, disappeared bacteria) disappeared bacteria) (macrophage reappears) Resolution (macrophage reappears)

20. Pathology Pneumococcal Pneumonia Lobar: Involvement an entire lung lobe, homogeneously Edema Edema Red hepatization Gray hepatization Resolution Bacterial CAP

21. Pathology Bronchopneumonia: Patchy Bronchopneumonia: Patchy consolidation in 1 or more lobes, in lower & post of lung with poorly demarcation. Bronchi Bronchioles Edema Edema Exudate

22. Pathology Because of the microaspiration mechanism, Because of the microaspiration mechanism, a bronchopneumonia pattern a bronchopneumonia pattern is most common in is most common in nosocomial pneumonias nosocomial pneumonias

23. Pathology Interstitial: Involvement of alveolar septa & connective tissue Patchy or diffuse Lymph, MQ & plasma cell in alveolar wall No exudate in the alveoli

24. Pathology Viral and Pneumocystis pneumonias Viral and Pneumocystis pneumonias Represent alveolar rather than Represent alveolar rather than interstitial processes interstitial processes

25. Pathology A bronchopneumonia pattern: most common in nosocomial pneumonias A bronchopneumonia pattern: most common in nosocomial pneumonias Lobar pattern: more common in bacterial CAP Lobar pattern: more common in bacterial CAP Alveolar rather than interstitial processes: Viral and Pneumocystis pneumonias Alveolar rather than interstitial processes: Viral and Pneumocystis pneumonias

26. Community-Acquired Pneumonia Etiology: Etiology: Streptococcus pneumoniae is most common

27. Microbial Causes of CAP, by Site of Care Outpatients Non-ICU ICU Streptococcus pneumoniae S. pneumoniae Mycoplasma pneumoniae M. pneumoniae Staphylococcus aureus Haemophilus influenzae Chlamydia pneumoniae Legionella spp. C. pneumoniae H. influenzae Gram-negative bacilli Respiratory virusesLegionella spp.H. influenzae Respiratory viruses Hospitalized Patients Pathogens are listed in descending order of frequency

28. CAP : Etiology “Typical" bacterial pathogens “Typical" bacterial pathogens “Atypical" organisms “Atypical" organisms

29. Typical" bacterial pathogens S. pneumoniae S. pneumoniae Haemophilus influenzae Haemophilus influenzae In selected patients: * S. aureus In selected patients: * S. aureus * Gram-negative bacilli : * Gram-negative bacilli : - Klebsiella pneumoniae - Klebsiella pneumoniae - Pseudomonas aeruginosa - Pseudomonas aeruginosa

30. Atypical Bacterial Pathogens Mycoplasma pneumoniae Mycoplasma pneumoniae Chlamydophila pneumoniae Chlamydophila pneumoniae Legionella spp. Legionella spp. Respiratory viruses : influenza viruses, adenoviruses, RSVs Respiratory viruses : influenza viruses, adenoviruses, RSVs

31. CAP, Etiology The atypical organisms: cannot be cultured on standard media, nor can they be seen on Gram's stain The atypical organisms: cannot be cultured on standard media, nor can they be seen on Gram's stain

32. CAP, Etiology A virus in up to 18% of cases of CAP that require admission to the hospital A virus in up to 18% of cases of CAP that require admission to the hospital ~10–15% of CAP cases are polymicrobial ~10–15% of CAP cases are polymicrobial

33. Etiology, Anaerobes An episode of aspiration days to weeks before presentation An episode of aspiration days to weeks before presentation ► Unprotected airway (alcohol or drug overdose, seizure) ► Unprotected airway (alcohol or drug overdose, seizure) + ► Significant gingivitis + ► Significant gingivitis

34. Anaerobes Often complicated by : - Abscess formation - Significant empyemas - Parapneumonic effusions Often complicated by : - Abscess formation - Significant empyemas - Parapneumonic effusions

35. S. aureus Pneumonia Complicates influenza infection Complicates influenza infection MRSA strains, primary causes of CAP, relatively uncommon MRSA strains, primary causes of CAP, relatively uncommon Necrotizing pneumonia Necrotizing pneumonia

36. CAP, Etiology In more than half of cases, a specific etiology is never determined In more than half of cases, a specific etiology is never determined

37. Epidemiologic Factors, Possible Causes of CAP FactorPossible Pathogen(s) AlcoholismStreptococcus pneumoniae Oral anaerobes Klebsiella pneumoniae Acinetobacter spp. Mycobacterium tuberculosis COPD and/or smoking Haemophilus influenzae Pseudomonas aeruginosa Legionella spp. S. pneumoniae Moraxella catarrhalis Chlamydia pneumoniae

38. Epidemiologic Factors, Possible Causes of CAP FactorPossible Pathogen(s) Structural lung disease (e.g., bronchiectasis) P. Aeruginosa Burkholderia cepacia Staphylococcus aureus Dementia, stroke, decreased level of consciousness Oral anaerobes Gram-negative enteric bacteria

39. Epidemiologic Factors, Possible Causes of CAP FactorPossible Pathogen(s) Lung abscessCA-MRSA Oral anaerobes Endemic fungi M. tuberculosis Atypical mycobacteria Stay in hotel or on cruise ship in previous 2 weeks Legionella spp. Local influenza activityInfluenza virus S. Pneumoniae S. aureus

40. Epidemiologic Factors, Possible Causes of CAP FactorPossible Pathogen(s) Exposure to bats or birdsH. capsulatum Exposure to birdsChlamydia psittaci Exposure to rabbitsFrancisella tularensis Exposure to sheep, goats, parturient cats Coxiella burnetii

41. Epidemiology, CAP In the U.S: 4 million CAP cases annually In the U.S: 4 million CAP cases annually ~80% are treated on an outpatient basis ~80% are treated on an outpatient basis ~20% are treated in the hospital ~20% are treated in the hospital

42. CAP >600,000 hospitalizations >600,000 hospitalizations 64 million days of restricted activity 64 million days of restricted activity 45,000 deaths annually 45,000 deaths annually The overall yearly cost :$9–10 billion (U.S.) The overall yearly cost :$9–10 billion (U.S.) The incidence rates are highest at the extremes of age The incidence rates are highest at the extremes of age

43. Epidemiology, CAP Risk factors: Alcoholism Asthma Immunosuppression Institutionalization ≥ 70 y.

44. Epidemiology, R.F Pneumococcal pneumonia: Dementia Dementia Seizure disorders Seizure disorders Heart failure Heart failure cerebrovascular disease cerebrovascular disease Alcoholism Alcoholism Tobacco smoking Tobacco smoking COPD COPD HIV infection HIV infection

45. CA-MRSA Infection Skin colonization with CA-MRSA Skin colonization with CA-MRSA Skin infection with CA-MRSA Skin infection with CA-MRSA

46. The Enterobacteriaceae Patients who have recently been hospitalized and/or received antibiotic therapy Patients who have recently been hospitalized and/or received antibiotic therapy Comorbidities : Alcoholism Heart failure Renal failure Comorbidities : Alcoholism Heart failure Renal failure

47. P. aeruginosa Severe structural lung disease, such as: Severe structural lung disease, such as: - Bronchiectasis - Bronchiectasis - Cystic fibrosis - Cystic fibrosis - Severe COPD - Severe COPD

48. Legionella infection Diabetes Diabetes Hematologic malignancy Hematologic malignancy Cancer Cancer Severe renal disease Severe renal disease HIV infection HIV infection Smoking Smoking Male gender Male gender Recent hotel stay or ship cruise Recent hotel stay or ship cruise

49. CAP, Clinical Manifestations Fever Fever Tachycardic response Tachycardic response Chills and/or sweats Chills and/or sweats Cough :nonproductive or productive of mucoid, purulent, or blood-tinged sputum Cough :nonproductive or productive of mucoid, purulent, or blood-tinged sputum shortness of breath shortness of breath

50. CAP, Clinical Manifestations If the pleura is involved: pleuritic chest pain If the pleura is involved: pleuritic chest pain Up to 20%, GI symptoms : nausea, vomiting, and/or diarrhea Up to 20%, GI symptoms : nausea, vomiting, and/or diarrhea Other symptoms :fatigue, headache, myalgias, and arthralgias Other symptoms :fatigue, headache, myalgias, and arthralgias

51. CAP, Clinical Manifestations The clinical presentation may not be so obvious in the elderly: - May initially display new-onset or The clinical presentation may not be so obvious in the elderly: - May initially display new-onset or worsening confusion - Few other manifestations worsening confusion - Few other manifestations

52. CAP, Clinical Manifestations Severely ill patients who have septic shock secondary to CAP : - Hypotensive - May have evidence of organ failure Severely ill patients who have septic shock secondary to CAP : - Hypotensive - May have evidence of organ failure

53. CAP, Clinical Manifestations Pulmonary consolidation ± significant pleural effusion Signs : Pulmonary consolidation ± significant pleural effusion – use of accessory muscles –Tachypnea, use of accessory muscles –dull (consolidated) – Percussion: dull (consolidated) flat (pleural fluid) flat (pleural fluid) – – Tactile fremitus

54. CAP, Clinical Manifestations  Auscultation: - Crackles -Bronchial breath sounds -Pleural friction rub

55. D ifferential Diagnosis Acute bronchitis Acute bronchitis Acute exacerbations of chronic bronchitis Acute exacerbations of chronic bronchitis Heart failure Heart failure Pulmonary embolism Pulmonary embolism Radiation pneumonitis Radiation pneumonitis

56. Diagnosis Clinical Dx Clinical Dx Etiologic Dx : Etiologic Dx :

57. Clinical Diagnosis Physical exam Sens. 58% Spec. 67% CXR

58. Diagnosis : Imaging : CXR, CT TB Upper-lobe cavity TB Pneumatoceles S. aureus Air-fluid level Abscess Crescent sign Aspergilosis No etiologic inference can be made from CXR

59. Clinical Diagnosis For cases managed on an outpatient basis, the clinical and radiologic assessment is usually all that is done before treatment is started For cases managed on an outpatient basis, the clinical and radiologic assessment is usually all that is done before treatment is started

60. Diagnosis - Gram's Stain and Culture of Sputum - Gram's Stain and Culture of Sputum - B/C - B/C - Ag tests - Ag tests - PCR - PCR - serology - serology

61. Gram's staining S. pneumoniae S. pneumoniae S. aureus S. aureus Gram-negative bacteria Gram-negative bacteria To be adequate for culture, a sputum sample must have >25 neutrophils and 25 neutrophils and <10 squamous epithelial cells per low-power field

62. Gram's staining The sensitivity/specificity of the sputum Gram's stain/culture : highly variable The sensitivity/specificity of the sputum Gram's stain/culture : highly variable Proven bacteremic pneumococcal pneumonia: positive sputum cultures: 50% Proven bacteremic pneumococcal pneumonia: positive sputum cultures: 50%

63. Diagnosis

66. Dx: Blood Cultures The yield is disappointingly low, only ~5–14% : CAP The yield is disappointingly low, only ~5–14% : CAP Most frequently isolated pathogen is S. pneumoniae Most frequently isolated pathogen is S. pneumoniae Blood cultures are no longer considered de rigueur for all hospitalized CAP patients Blood cultures are no longer considered de rigueur for all hospitalized CAP patients

67. Dx: Blood Cultures Certain high-risk patients should have blood cultured : Certain high-risk patients should have blood cultured : Neutropenia secondary to pneumonia Neutropenia secondary to pneumonia Asplenia Asplenia Complement deficiencies Complement deficiencies Chronic liver disease Chronic liver disease Severe CAP Severe CAP

68. Ag Tests Legionella antigens in urine (Legionella pneumophila), only serogroup 1 Legionella antigens in urine (Legionella pneumophila), only serogroup 1 The sensitivity=90% The sensitivity=90% specificity= 99% specificity= 99%

69. Ag Tests The pneumococcal urine antigen test : quite sensitive=80% and specific >90% The pneumococcal urine antigen test : quite sensitive=80% and specific >90% Although false-positive results in colonized children, the test is generally reliable Although false-positive results in colonized children, the test is generally reliable Both tests can detect antigen even after the initiation of appropriate antibiotic therapy and after weeks of illness Both tests can detect antigen even after the initiation of appropriate antibiotic therapy and after weeks of illness

70. PCR tests L. pneumophila L. pneumophila Mycobacteria Mycobacteria

71. Serology A fourfold rise in specific IgM antibody titer between acute- and convalescent- phase serum samples is generally considered diagnostic of infection with the pathogen in question A fourfold rise in specific IgM antibody titer between acute- and convalescent- phase serum samples is generally considered diagnostic of infection with the pathogen in question

78. Treatment, Site of care Hospital admission: – –Comorbid illness – –Confusion – –RR>28 – –BPs<90 mmHg – –Po2<60 mmHg or O2 sat <90% – –Multilobar pneumonia – –P.E. > 1 cm on lat. decubitus CXR

79. Severe CAP: CURB 65 Confusion Confusion Urea > 7mmol/L (20mg/dl) Urea > 7mmol/L (20mg/dl) RR >30/m RR >30/m BP: diast<60 mmHg, syst <90 mmHg BP: diast<60 mmHg, syst <90 mmHg

80. Empirical Antibiotic Treatment of CAP 1. Outpatients: 1. Outpatients: Previously healthy and no antibiotics in past 3 months Previously healthy and no antibiotics in past 3 months - A macrolide [clarithromycin or - A macrolide [clarithromycin or azithromycin ] azithromycin ] - Doxycycline - Doxycycline

81. Empirical Antibiotic Treatment of CAP 2. Outpatients: 2. Outpatients: Comorbidities or antibiotics in past 3 months : select an alternative from a different class: Comorbidities or antibiotics in past 3 months : select an alternative from a different class: - A respiratory fluoroquinolone - A respiratory fluoroquinolone - A ß lactam plus a macrolide - A ß lactam plus a macrolide (Doxy: alternative) (Doxy: alternative)

82. Empirical Antibiotic Treatment of CAP 2. Outpatients 2. Outpatients Comorbidities or antibiotics in past 3 months: Comorbidities or antibiotics in past 3 months: *preferred ß lactam: high-dose amoxicillin (1 g tid) or *preferred ß lactam: high-dose amoxicillin (1 g tid) or amoxicillin/clavulanate (2 g bid)] amoxicillin/clavulanate (2 g bid)] *alternatives: ceftriaxone, cefpodoxime, cefuroxime *alternatives: ceftriaxone, cefpodoxime, cefuroxime

83. Empirical Antibiotic Treatment of CAP 3. Inpatients, non-ICU 3. Inpatients, non-ICU A respiratory fluoroquinolone A respiratory fluoroquinolone A ß-lactamc plus a macrolide *[cefotaxime, ceftriaxone,ampicillin), A ß-lactamc plus a macrolide *[cefotaxime, ceftriaxone,ampicillin), ertapenem (in selected patients)] + *[clarithromycin or azithromycin] ertapenem (in selected patients)] + *[clarithromycin or azithromycin]

84. Empirical Antibiotic Treatment of CAP 4. Inpatients, ICU : 4. Inpatients, ICU : A ß-lactame plus Azithromycin or a fluoroquinolone A ß-lactame plus Azithromycin or a fluoroquinolone *[cefotaxime, ceftriaxone, ampicillin- sulbactam] *[cefotaxime, ceftriaxone, ampicillin- sulbactam]

85. Treatment, Antibiotics Duration :10-14d A longer course : Patients with bacteremia Metastatic infection Virulent pathogen, such as P. aeruginosa or CA-MRSA If initial treatment was ineffective Most cases of severe CAP

86. Treatment, Antibiotics A switch to oral treatment is appropriate as long as: The patient can ingest and absorb the drugs The patient can ingest and absorb the drugs Hemodynamically stable Hemodynamically stable Showing clinical improvement Showing clinical improvement

87. Discharge Patients may be discharged : Once they are clinically stable Have no active medical problems Not requiring ongoing hospital care

88. Follow up Fever & Leukocytosis usually resolve within 2-4 days Fever & Leukocytosis usually resolve within 2-4 days Physical findings may persist longer Physical findings may persist longer CXR abnormalities are slowest to resolve : 4–12 weeks to clear CXR abnormalities are slowest to resolve : 4–12 weeks to clear

89. Follow up For a patient whose condition is improving and who (if hospitalized) has been discharged, a follow-up radiograph can be done ~4–6 weeks later For a patient whose condition is improving and who (if hospitalized) has been discharged, a follow-up radiograph can be done ~4–6 weeks later If relapse or recurrence is documented, particularly in the same lung segment, the possibility of an underlying neoplasm must be considered If relapse or recurrence is documented, particularly in the same lung segment, the possibility of an underlying neoplasm must be considered

90. Failure To Improve Clinical stability within 3-7 d P.R< 100 “ “ 2 d RR < 24 “ “ 3 d T < 37.2 c “ “ 3 d Cough “ “ 4-7 d If no improvement = Failure

91. Failure to Improve Patients who are slow to respond to therapy should be reevaluated at about day 3 (sooner if their condition is worsening rather than simply not improving) Patients who are slow to respond to therapy should be reevaluated at about day 3 (sooner if their condition is worsening rather than simply not improving) Is this a noninfectious condition? Is this a noninfectious condition? If this is an infection, is the correct pathogen being targeted? If this is an infection, is the correct pathogen being targeted? Is this a superinfection with a new nosocomial pathogen? Is this a superinfection with a new nosocomial pathogen?

92. Failure to Improve Resistant pathogen Resistant pathogen A sequestered focus (e.g., a lung abscess or empyema) A sequestered focus (e.g., a lung abscess or empyema) The wrong drug The wrong drug The wrong dose or frequency of administration The wrong dose or frequency of administration

93. Failure to Improve A different pathogen (e.g., M. tuberculosis or a fungus) A different pathogen (e.g., M. tuberculosis or a fungus) Nosocomial superinfections—both pulmonary and extrapulmonary Nosocomial superinfections—both pulmonary and extrapulmonary

94. Complications Respiratory failure Respiratory failure Shock and multiorgan failure Shock and multiorgan failure Bleeding diatheses Bleeding diatheses Exacerbation of comorbid illnesses Exacerbation of comorbid illnesses Metastatic infection Metastatic infection lung abscess lung abscess Complicated pleural effusion Complicated pleural effusion

95. Complications Metastatic infection : Metastatic infection : - Brain abscess - Brain abscess - Endocarditis - Endocarditis Abscess, Aspiration pneumonia : polymicrobial Abscess, Aspiration pneumonia : polymicrobial

97. Prognosis Young patients without comorbidity do well and usually recover fully after ~2 weeks. Young patients without comorbidity do well and usually recover fully after ~2 weeks. Older patients and those with comorbid conditions can take several weeks longer to recover fully. Older patients and those with comorbid conditions can take several weeks longer to recover fully.

98. Prognosis The overall mortality rate for the outpatient group is <1%. The overall mortality rate for the outpatient group is <1%. For patients requiring hospitalization, the overall mortality rate is estimated at 10%, with ~50% of the deaths directly attributable to pneumonia. For patients requiring hospitalization, the overall mortality rate is estimated at 10%, with ~50% of the deaths directly attributable to pneumonia.

99. Prevention No smoking Vaccination: pneumococcal & influenza Prevention of aspiration

100. Prevention Influenza outbreak, and unprotected patients: vaccination immediately + chemoprophylaxis with either oseltamivir or zanamivir for 2 weeks— i.e., until vaccine-induced antibody levels are sufficiently high Influenza outbreak, and unprotected patients: vaccination immediately + chemoprophylaxis with either oseltamivir or zanamivir for 2 weeks— i.e., until vaccine-induced antibody levels are sufficiently high