Community Acquired Pneumonia (CAP) by Paras Patel MD. Assistant Professor of Internal Medicine, Division of Infectious disease. ETSU

Alphabet Soup for Pneumonia HAP: Hospital-acquired pneumonia ≥ 48 h from admission VAP: Ventilator-associated pneumonia ≥ 48 h from endotracheal intubation HCAP: Healthcare-associated pneumonia Long-term care facility (NH), hemodialysis, outpatient chemo, wound care, etc. CAP: Community-acquired pneumonia Outside of hospital or extended-care facility 2

Community Acquired Pneumonia Definition: … an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph, or auscultatory findings consistent with pneumonia, in a patient not hospitalized or residing in a long term care facility for > 14 days before onset of symptoms. Bartlett. Clin Infect Dis 2000;31:347-82.

Community Acquired Pneumonia Epidemiology: 4-5 million cases annually ~500,000 hospitalizations ~45,000 deaths Mortality 2-30% <1% for those not requiring hospitalization Cdc.gov/data 2007.

Community Acquired Pneumonia Epidemiology: (contd) fewest cases in 18-24 yr group probably highest incidence in <5 and >65 yrs mortality disproportionately high in >65 yrs

Community Acquired Pneumonia Mortality # in 1000s NCHS Data: www.cdc.gov/nchswww/data/nvsr47_9.pdf

Age-specific Rates of Hospital Admission by Pathogen Marsten. Community-based pneumonia incidence study group. Arch Intern Med 1997;157:1709-18 7

CAP – Pathogenesis Inhalation, aspiration and hematogenous spread are the 3 main mechanisms by which bacteria reaches the lungs Inhalation Aspiration Hematogenous Infectious agents gain entry to the lower respiratory tract through aspiration of upper airway resident flora, inhalation of of aerosolized materal and less frequently metastatic seeding of the lung from blood.

Pathogenesis Primary inhalation: when organisms bypass normal respiratory defense mechanisms or when the Pt inhales aerobic GN organisms that colonize the upper respiratory tract or respiratory support equipment Aspiration: occurs when the Pt aspirates colonized upper respiratory tract secretions Stomach: reservoir of GNR that can ascend, colonizing the respiratory tract. Hematogenous: originate from a distant source and reach the lungs via the blood stream. Microaspiration: S. pneumo Inhalation: TB, viruses, Legionella Aspiration: anaerobes Bloodborne: Staph endocarditis, septic emboli Direct extension: Amebiasis, trauma

Community Acquired Pneumonia Risk Factors for pneumonia age smoking asthma immunosuppression institutionalization COPD PVD Dementia HIV/AIDS Pneumonia has been noted to occur with increased frequency in patients with a variety of underlying diseases as above. The incidence of invasive pneumococcal pneumonia is 100 to 300 times higher in HIV infected patients. And the incidence of H. influenzae infection may be up to 100 fold higher in this population. ID Clinics 1998;12:723. Am J Med 1994;96:313

Community Acquired Pneumonia Risk Factors in Patients Requiring Hospitalization older, unemployed common cold in the previous year asthma, COPD; steroid or bronchodilator use Chronic disease amount of smoking Farr BM. Respir Med 2000;94:954-63 Farr BM. Respir Med 2000;94:954-63.

Community Acquired Pneumonia Risk Factors for Mortality age bacteremia (for S. pneumoniae) extent of radiographic changes degree of immunosuppression amount of alcohol Fine. JAMA 1996;275:134-41.

Community Acquired Pneumonia Microbiology Legionella spp. 2-8% S. aureus: 3-5% Gram negative bacilli: 3-5% Viruses: 2-13% S. pneumoniae: 20-60% H. influenzae: 3-10% Chlamydia pneumoniae: 4-6% Mycoplasma pneumonaie: 1-6% Bartlett. NEJM 1995;333:1618-24. 40-60% - NO CAUSE IDENTIFIED 2-5% - TWO OR MORE CAUSES Bartlett. NEJM 1995;333:1618-24

Streptococcus pneumonia (Pneumococcus) Most common cause of CAP About 2/3 of CAP are due to S.pneumoniae These are gram positive diplococci Typical symptoms (e.g. malaise, shaking chills fever, rusty sputum, pleuritic chest pain, cough) Lobar infiltrate on CXR May be Immuno suppressed host 25% will have bacteremia – serious effects Predisposing factors: anorexia, ETOH, HIV, sickle cell disease, splenectomy, hematologic diseases

Atypical Pneumonia Pneumonia #2 cause (especially in younger population) Commonly associated with milder Sx’s: subacute onset, non-productive cough, no focal infiltrate on CXR Mycoplasma: younger Pts, extra-pulm Sx’s (anemia, rashes), headache, sore throat Chlamydia: year round, URI Sx, sore throat Legionella: higher mortality rate, water-borne outbreaks, hyponatremia, diarrhea

Viruses and Pneumonia Pneumonia in the normal host Adults or Children Influenza A and B, RSV, Adenovirus, Para Influenza Pneumonia in the immuno-compromised Measles, HSV, CMV, HHV-6, Influenza viruses Can cause a primary viral pneumonia. Cause partial paralysis of “mucociliary escalator” - increased risk of secondary bacterial LRTI. S.aureus pneumonia is a known complication following influenza infection.

Other bacteria Anaerobes Aspiration-prone Pt, putrid sputum, dental disease Gram negative Klebsiella - alcoholics Branhamella catarrhalis - sinus disease, otitis, COPD H. influenza

S. aureus CAP – Dangerous This CAP is not common; Multi lobar Involvement Post Influenza complication, Class IV or V Compromised host, Co-morbidities, Elderly CA MRSA – A Problem; CA MSSA also occurs Empyema and Necrosis of lung with cavitations Multiple Pyemic abscesses, Septic Arthritis Hypoxemia, Hypoventilation, Hypotension common Vancomycin, Linezolid are the drugs for MRSA

Diagnosis and Management

Clinical Diagnosis Suggestive signs and symptoms CXR or other imaging technique Microbiologic testing

Signs and Symptoms Fever or hypothermia Cough with or without sputum, hemoptysis Pleuritic chest pain Myalgia, malaise, fatigue GI symptoms Dyspnea Rales, rhonchi, wheezing Egophony, bronchial breath sounds Dullness to percussion Atypical Sx’s in older patients

Clinical Diagnosis: CXR Demonstrable infiltrate by CXR or other imaging technique Establish Dx and presence of complications (pleural effusion, multilobar disease) May not be possible in some outpatient settings CXR: classically thought of as the gold standard

May show hyper-expansion, atelectasis or infiltrates Chest Radiograph May show hyper-expansion, atelectasis or infiltrates Normal Pneumonia 23

Infiltrate Patterns Pattern Possible Diagnosis Lobar S. pneumo, Kleb, H. flu, GN Patchy Atypicals, viral, Legionella Interstitial Viral, PCP, Legionella Cavitary Anaerobes, Kleb, TB, S. aureus, fungi Large effusion Staph, anaerobes, Kleb

Clinical Diagnosis: Recommended testing Outpatient: CXR, sputum Cx and Gram stain not required Inpatient: CXR, Pox or ABG, chemistry, CBC, two sets of blood Cx’s If suspect drug-resistant pathogen or organism not covered by usual empiric abx, obtain sputum Cx and Gram stain. Severe CAP: Legionella urinary antigen, consider bronchoscopy to identify pathogen In general, sputum gram stain cannot be used to focus initial empiric antibioic therapy, but could be used to broaden initial antibiotic therapy. IDSA consensus group believes that a properly collected and examined Gram’s stain of expectorated sputum is helpful for focusing initial empiric therapy in CAP. A lower respiratory tract sample that is not heavily contaminated by oral secretions will typically have fewer than 10 squamous epithelial cells and > 25 neutrophils per LPF. Limitations: not all Pts can provide an adequate sample, interpretation-observer dependent, etc.

Community Acquired Pneumonia Who should be hospitalized?

To Admit or Not? Pneumonia Severity & Deciding Site of Care Using objective criteria to risk stratify & assist in decision re outpatient vs inpatient management PSI CURB-65 Caveats Other reasons to admit apart from risk of death Not validated for ward vs ICU Labs/vitals dynamic 27

Pneumonia Severity Index Class Points Mortality* Site of Care I <51 0.1% OutPatient II 51-70 0.6% III 71-90 2.8% In or OutPatient IV 91-130 9.5% Inpatient V >130 26.7%

CURB 65 Rule – Management of CAP BP SBP <90 DBP <60 RR > 30 BUN > 30 Confusion Age > 65 CURB 0 or 1 Home Rx CURB 2 Short Hosp CURB 3 Medical Ward CURB 4 or 5 ICU care

Who Should be Hospitalized? Class I and II Usually do not require hospitalization Class III May require brief hospitalization Class IV and V Usually do require hospitalization Severity of CAP with poor prognosis RR > 30; PaO2/FiO2 < 250, or PO2 < 60 on room air Need for mechanical ventilation; Multi lobar involvement Hypotension; Need for vasopressors Oliguria; Altered mental status

CAP – Criteria for ICU Admission Major criteria Invasive mechanical ventilation required Septic shock with the need of vasopressors Minor criteria (least 3) Confusion/disorientation Blood urea nitrogen ≥ 20 mg% Respiratory rate ≥ 30 / min; Core temperature < 36ºC Severe hypotension; PaO2/FiO2 ratio ≤ 250 Multi-lobar infiltrates WBC < 4000 cells; Platelets <100,000

Traditional Treatment Paradigm Conservative start with ‘workhorse’ antibiotics Reserve more potent drugs for non-responders

New Treatment Paradigm Hit hard early with appropriate antibiotic(s) Short Rx. Duration; De-escalate where possible

The Effect of the Traditional Approach 50 Inappropriate therapy (%) 45 40 34 30 17 20 10 CAP HAP HAP on CAP Kollef, et al. Chest 1999;115:462–474

New data – Don’t Wait for Results ! Switching after susceptibility results p<0.001 Adequate treatment within ‘a few hours’ Mortality (%) n=75 For the subgroup of patients whose inadequate initial treatment was corrected based on in vitro susceptibility data, the 21-day mortality rate was 52% (39 of 75), compared with only 18% in the subgroup that received adequate treatment within a few hours of BSI onset (OR 2.18; 95% CI 1.58, 3.01; p<0.001). Inadequate antimicrobial therapy within the first 72 h of infection is a predictor of mortality (OR 6.28; 95% CI 3.18, 12.42; p<0.001). 21-day mortality rate was highest among the 16 patients treated from the start with fluoroquinolones (44.4% OR 4.05; 95% CI 1.89, 8.65; p<0.001). 21-day mortality rate was lowest in patients treated from the start with carbapenems (5.5%; OR 0.14; 95% CI 0.02, 1.03; p=0.01). Tumbarello, et al. Antimicrob Agents Chemother 2007;51:1987–1994 35

New data – The Speed of Delay ! (Class 4,5) Delay in treatment (hours) from hypotension onset Survival (%) Each hour of delay carries 7.6% reduction in survival Kumar, et al. Crit Care Med 2006;34:1589–1596

CAP – Complications Hypotension and septic shock 3-5% Pleural effusion; Clear fluid + pus cells 1% Empyema thoracis pus in the pleural space Lung abscess – destruction of lung . Single (aspiration) anaerobes, Pseudomonas Multiple (metastatic) Staphylococcus aureus Septicemia – Brain abscess, Liver Abscess Multiple Pyemic Abscesses

IDSA: Outpt Management in Previously Healthy Pt Organisms: S. pneumo, Mycoplasma, viral, Chlamydia pneumo, H. flu Recommended abx: Advanced generation macrolide (azithro or clarithro) or doxycycline If abx within past 3 months: Respiratory quinolone (moxi-, levo-, gemi-), OR Advanced macrolide + amoxicillin, OR Advanced macrolide + amoxicillin-clavulanate

IDSA: Outpt Management in Pt with comorbidities Comorbidities: cardiopulmonary dz or immunocompromised state Organisms: S. pneumo, viral, H. flu, aerobic GN rods, S. aureus Recommended Abx: Respiratory quinolone, OR advanced macrolide Recent Abx: Respiratory quinolone OR Advanced macrolide + beta-lactam

IDSA: Inpt Management-Medical Ward Organisms: all of the above plus polymicrobial infections (+/- anaerobes), Legionella Recommended Parenteral Abx: Respiratory fluoroquinolone, OR Advanced macrolide plus a beta-lactam Recent Abx: As above. Regimen selected will depend on nature of recent antibiotic therapy.

IDSA: Inpt Management-Severe/ICU One of two major criteria: Mechanical ventilation Septic shock, OR Two of three minor criteria: SBP≤90mmHg, Multilobar disease PaO2/FIO2 ratio < 250 Organisms: S. pneumo, Legionella, GN, Mycoplasma, viral, ?Pseudomonas PIF ratio: index of severity of hypoxemia. Used as part of the definition of ALI (acute lung injury) and ARDS. ALI, PIF=200-300 ARDS, PIF <200

IDSA: Inpt Management: Severe/ICU No risk for Pseudomonas IV beta-lactam plus either IV macrolide, OR IV fluoroquinolone Risk for Pseudomonas Double therapy: selected IV antipseudomonal beta-lactam (cefepine, imipenem, meropenem, piperacillin/tazobactam), plus IV antipseudomonal quinolone -OR- Triple therapy: selected IV antipseudomonal beta-lactam plus IV aminoglycoside plus either IV macrolide, OR IV antipseudomonal quinolone

Switch to Oral Therapy Four criteria: Improvement in cough and dyspnea Afebrile on two occasions 8 h apart WBC decreasing Functioning GI tract with adequate oral intake If overall clinical picture is otherwise favorable, can can switch to oral therapy while still febrile.

Duration of Therapy Minimum of 5 days Afebrile for at least 48 to 72 h No > 1 CAP-associated sign of clinical instability Longer duration of therapy If initial therapy was not active against the identified pathogen or complicated by extra pulmonary infection

Prevention Smoking cessation Vaccination per ACIP recommendations Influenza Inactivated vaccine for people >50 yo, those at risk for influenza compolications, household contacts of high-risk persons and healthcare workers Intranasal live, attenuated vaccine: 5-49yo without chronic underlying dz Pneumococcal Immunocompetent ≥ 65 yo, chronic illness and immunocompromised ≤ 64 yo Vaccination may be done either at hospital discharge or during outpatient treatment ACIP: Advisory Committee on Immunization Practices

Epidemiology of Pneumococcal Infection in Immunocompromised Adults Streptococcus pneumoniae remains a leading cause of serious illness, including bacteremia, meningitis, and pneumonia among adults in the United States. An estimated 4,000 deaths occur annually in USA primarily among adults. For adults aged 18–64 years with hematologic cancer, the rate of IPD in 2010 was 186 per 100,000, and for persons with human immunodeficiency virus (HIV) the rate was 173 per 100,000 (CDC, unpublished data, 2012). The disease rates for adults in these groups can be more than 20 times those for adults without high-risk medical conditions.

PCV13 has been used for children since 2010, when it replaced an earlier version targeting seven serotypes (PCV7; Prevnar, Pfizer) that had been in use since 2000. The routine use of PCV7 in infants and young children resulted in significant reductions in IPD caused by vaccine serotypes in children, and because of indirect effects, also in adults. Rates of IPD caused by vaccine serotypes in adults aged 18–64 years without HIV decreased from six cases to one case per 100,000 during 2000–2007. However, even after indirect effects of the pediatric immunization had been realized fully, the incidence of IPD caused by the serotypes included in PCV7 remained high in HIV-infected persons aged 18–64 years at 64 cases per 100,000 persons with acquired immunodeficiency syndrome (AIDS) . Moreover, 50% of IPD cases among immunocompromised adults in 2010 were caused by serotypes contained in PCV13; an additional 21% were caused by serotypes only contained in PPSV23.

In two randomized, multicenter immunogenicity studies conducted in the United States and Europe, immunocompetent adults aged ≥50 years received a single dose of PCV13 or PPSV23. In adults aged 60–64 years and aged >70 years, PCV13 elicited opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) that were comparable with, or higher than, responses elicited by PPSV23. OPA GMTs elicited by PCV13 in adults aged 50–59 years for all 13 serotypes were comparable with the corresponding GMTs elicited by administration of PCV13 in adults aged 60–64 years.

PCV13 Vaccine in Adults PCV13 was licensed by the Food and Drug Administration (FDA) for prevention of IPD and otitis media in infants and young children in February 2010, supplanting PCV7 One dose of PCV13 is recommended by ACIP for children aged 6–18 years with high-risk conditions such as functional or anatomic asplenia, immunocompromising conditions, cochlear implants, or CSF leaks. In December 2011, FDA licensed PCV13 for prevention of pneumonia and IPD in adults aged ≥50 years . Approval of PCV13 for adults was based on immunogenicity studies that compared antibody responses to PCV13 with antibody responses to PPSV23

ACIP Recommendations for PCV13 and PPSV23 Use Pneumococcal vaccine-naïve persons. ACIP recommends that adults aged ≥19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, and who have not previously received PCV13 or PPSV23, should receive a dose of PCV13 first, followed by a dose of PPSV23 at least 8 weeks later (Table). Subsequent doses of PPSV23 should follow current PPSV23 recommendations 5 years after the first PPSV23 dose for persons aged 19–64 years with functional or anatomic asplenia and for persons with immunocompromising conditions.

Previous vaccination with PPSV23. Adults aged ≥19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, who previously have received ≥1 doses of PPSV23 should be given a PCV13 dose ≥1 year after the last PPSV23 dose was received. For those who require additional doses of PPSV23, the first such dose should be given no sooner than 8 weeks after PCV13 and at least 5 years after the most recent dose of PPSV23

CAP – So How Best to Win the War? Early antibiotic administration within 4-6 hours Empiric antibiotic Rx. as per guidelines (IDSA / ATS) PORT – PSI scoring and Classification of cases Early hospitalization in Class IV and V Decrease smoking cessation - advice / counseling Arterial oxygenation assessment in the first 24 h Blood culture collection in the first 24 h prior to Abx. Pneumococcal & Influenza vaccination; Smoking X

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