Adjunctive Corticosteroids for Severe Community Acquired Pneumonia (SCAP): Something to Hang Your Hat On?

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1 Adjunctive Corticosteroids for Severe Community Acquired Pneumonia (SCAP): Something to Hang Your Hat On? Lauren Bjork, Pharm.D. PGY-2 Infectious Disease Pharmacy Resident South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy UT Health San Antonio Pharmacotherapy Grand Rounds January 25, 2019 Objectives 1. Discuss epidemiology, severity scoring and treatment of community acquired pneumonia (CAP) 2. Analyze role of acute inflammation and utility of adjunctive corticosteroids in CAP 3. Evaluate current literature to determine role of adjunctive corticosteroids in severe CAP (SCAP)

2 Community Acquired Pneumonia (CAP) 1. Definition 1 a. Pneumonia (PNA) not acquired in hospital or long-term care facility i. Lower-respiratory tract infection (LRTI) ii. Requires prompt administration of antimicrobial agents 2. Epidemiology 2-4 a. Incidence and Prevalence i. Approximately 5 to 6 cases of CAP per 1,000 persons per year 2,3 ii. Incidence increases significantly with age 1. Age years: ~18 cases per 1,000 persons per year 2. Age > 85 years: ~52 cases per 1,000 persons per year iii. In 2011, 35,380 CAP cases reported throughout all United States (U.S.) Department of Veterans Affairs (VA) Hospitals 4 1. Equivalent to 452 cases per 100,000 person-years 2. Over 50% of cases incurred in patients > 65 years old b. Economic Impact 4-5 i. Total costs exceed $10 billion annually in U.S. 5 ii. Annual expenditure of $750 million at VA hospitals in c. Morbidity and Mortality 6-10 i. LRTI = most common infectious cause of death world-wide 6 1. Fourth most common cause overall 2. PNA = 8 th leading cause of death in U.S. in ii. Mortality remains high despite advances in the following 8,9 1. Etiological investigation 2. Antimicrobial therapy 3. Improvements in supportive care iii. CAP = prominent precursor of sepsis and septic shock 8,9 1. Hypothalamic-pituitary-adrenal (HPA) axis activation à significant stress 2. Suggests factors other than infection involved with poor outcomes a. Bactericidal antimicrobials à pro-inflammatory b. Activation of excessive immune response of host iv. Morbidity especially concerning in elderly patients Negative impact on overall quality of life 2. Studies suggest ~ 16% decrease in quality of life in post-discharge year 3. Etiology 2,11 a. Streptococcus pneumoniae (S. pneumoniae) most common causative organism b. See Table 1 for common pathogens dependent on patient location Table 1. Common CAP Pathogens Outpatient or non-intensive care unit (ICU) Primarily gram-positive, atypical and viral pathogens: S. pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae ICU Primarily gram-positive pathogens or gramnegative bacilli (GNB): S. pneumoniae, Staphylococcus aureus, Legionella species, GNB 4. Prevention 13 a. Significant increase in pneumococcal vaccination in U.S. b. Relatively stable rates of mortality caused by PNA c. Age-adjusted death rate 16.8 vs 15.0 per 100,000 in 2010 compared to 2016 Bjork 2

3 5. Diagnosis 11,14 a. Clinical signs and symptoms: see Table 2 Table 2. Signs and Symptoms of CAP Cough Purulent sputum Dyspnea Pleuritic pain Fever or chills Malaise Altered mental status Tachypnea b. Imaging i. Standard: chest radiography (x-ray) ii. Alternative: chest computed tomography (CT) iii. Presence of infiltrate or consolidation in lungs Prediction Tools for Mortality and Severity of CAP 11, Prediction Tools a. Scoring tools categorize and predict severity of illness b. Designed to aid providers in determining proper level of care i. Determination of outpatient, inpatient or ICU admission ii. Used in combination with clinical judgement 2. CURB-65 and CRB-65 14,15 a. Quick and simple criteria easily implemented in clinical practice b. See Tables 3 and 4 for variables and associated mortality rates Table 3. CURB-65 and CRB-65 Mortality Prediction Tools 14 Prognostic variables (assign 1 point for each variable) Confusion (new onset) Urea nitrogen level > 20 mg/dl (7.14 mmol/l) * Respiratory rate 30 breaths/minute Blood pressure (systolic < 90 mmhg or diastolic 60 mmhg) Age 65 years * Excluded in CRB-65 Table Day Mortality by Score 15 CURB-65 CRB-65 Score Mortality Score Mortality % 0 2.3% 2 8.3% % % % 3. American Thoracic Society (ATS) Criteria for Severe CAP (SCAP) 11 a. Specifically designed to identify severe cases of CAP b. See Table 5 for ATS criteria for SCAP Table 5. ATS Criteria for Severe CAP (SCAP) 11 Minor Criteria Respiratory rate > 30 breaths/min. PaO 2/FiO 2 ratio < 250 Multilobar infiltrates Confusion/disorientation Uremia (BUN level, > 20 mg/dl) Leukopenia (WBC count, < 4000 cells/mm 3 ) Thrombocytopenia (PLT, < 100,000 cells/mm 3 ) Hypothermia (core temperature, < 36 C) Hypotension aggressive fluid resuscitation Major Criteria Invasive mechanical ventilation Septic shock with need for vasopressors 1 Major or > 3 Minor à ICU PaO2/FiO2 = partial pressure arterial oxygen/fraction inspired oxygen; BUN = blood urea nitrogen; WBC = white blood cell; PLT = platelet Bjork 3

4 4. Pneumonia Severity Index (PSI)/ Pneumonia Patient Outcomes Research Team (PORT) 16 a. More commonly used in clinical trials and not routine clinical practice b. See Figure 1 for scoring algorithm, Tables 6 and 7 for PSI score and associated mortality Observed Mortality by Score 5 Figure 1. PSI Risk Algorithm Table Day Observed Mortality by Score 16 Points Total Risk Class Mortality < 51 I 0.1% II 0.6% II 2.8% IV 8.2% > 130 V 29.2% Table 6. PSI/PORT Score 16 Characteristic Points Assigned Demographics Men Age (years) Women Age (years) 10 Nursing home resident + 10 Comorbidities Neoplastic disease + 30 Liver disease + 20 Heart failure + 10 Cerebrovascular disease + 10 Renal disease + 10 Physical Exam Findings Altered mental status + 20 Respiratory rate > 30/min + 20 Systolic blood pressure < 90 mmhg + 20 Temperature < 35 or > 40 C + 15 Pulse > 125/min + 10 Laboratory and Radiographic Findings Arterial ph < Blood nitrogen urea > 30 mg/dl + 20 Sodium < 130 mmol/l + 20 Glucose > 250 mg/dl + 10 Hematocrit < 30% + 10 Partial pressure arterial O 2 < 60 mmhg + 10 Pleural effusion + 10 Role of Inflammation and Markers of Infection 1. CAP may be associated with abnormal increase in inflammatory response 17,18 a. Poor outcomes with adequate antibiotic therapy b. Increased circulating inflammatory cytokines from alveolar macrophages i. Proinflammatory cytokines: interleukin (IL)-6, -8 and -10 ii. Natural immune response to infection à eliminate pathogens c. See Table 8 for pertinent clinical markers of inflammation and infection 2. Immune system can be potentially harmful 18 a. Excessive release of cytokines à lung damage b. Detrimental to patient stability 3. Non-survivors exhibit persistently elevated circulating cytokine levels 19 Bjork 4

5 Table 8. Pertinent Clinical Markers of Inflammation and Infection Markers of Inflammation Markers of Infection C-reactive protein (CRP) Non-specific: fever and leukocytosis Erythrocyte sedimentation rate (ESR) Specific: procalcitonin (PCT) Corticosteroids 1. Pathophysiology 20 a. Adrenal cortex naturally produces steroid hormones b. Involved in physiologic processes i. Stress and immune response ii. Regulation of inflammation iii. Carbohydrate metabolism and protein catabolism iv. Blood electrolyte levels v. Fluid balance 2. Immunomodulating Effects a. Mechanism of action 21 i. Pleiotropic ii. See Figure 2 depicting corticosteroids impact on immune cells INF = interferon IL = interleukin Th = helper Tc = cytotoxic NK = natural killer TNF = tumor necrosis factor Figure 2. Corticosteroids Impact on Immune Cells b. Local effect in lungs 20,22,23 i. In vitro 1. Decrease cytokine expression in human cells 2. Inhibit migration of phagocytic cells ii. In vivo 1. Diminish cytokine release, CRP and neutrophil counts 2. Impacts neutrophil migration and accelerates neutrophil apoptosis 3. May prevent respiratory failure c. Blocks Jarisch-Herxheimer-like reaction 20 i. Transient worsening à fever, chills, myalgia, tachycardia or hypotension ii. Caused by initiation of antibiotics in high bacterial load iii. High concentrations of cytokines à release of endotoxins iv. Probable mechanism of underlying benefit of steroids in infectious diseases Bjork 5

6 3. Indications for Use 24 a. Many inflammatory, allergic, immunologic and malignant disorders b. Suggested benefit in some infectious conditions i. Meningitis 1. Mortality benefit in pneumococcal and cryptococcal meningitis 2. No clear benefit seen with other bacterial organisms ii. Septic shock iii. Immune reconstitution inflammatory syndrome (IRIS) iv. Severe pneumocystis and histoplasmosis PNA v. Severe chronic obstructive pulmonary disease (COPD) vi. Tuberculosis (TB) vii. Bacterial PNA 4. Classification 25 a. See Table 9 for a comparison of glucocorticoids and mineralocorticoids b. Glucocorticoids preferred in CAP due to anti-inflammatory effects Table 9. Comparison of Glucocorticoids and Mineralocorticoids Glucocorticoid Mineralocorticoid Mimic cortisol Mimic aldosterone Inflammation + immunosuppression Inflammation + immunosuppression > fluid retention effects < fluid retention effects 5. Formulations 26,27 a. Considerations: potency, duration of action and anti-inflammatory activity b. Refer to Appendix A (Table 20) for comparison of systemic glucocorticoid preparations 6. Adverse Effects 23,24,28-29 a. Corticosteroids may adversely impact any organ b. See Table 10 for systems adversely affected by corticosteroids Table 10. Systems Adversely Affected by Corticosteroids Cardiovascular Central Nervous System Dermatologic Endocrine Gastrointestinal (GI) Hematologic Hepatic Musculoskeletal Ophthalmologic Psychological Renal Respiratory c. Directly related to dose and duration of therapy 23 i. HPA-axis suppression ii. Increased infection risk 1. Inhibition of phagocytic cell function 2. Impairs immune response and wound healing iii. Short-term adverse events transient and reversible Hyperglycemia 2. Fluid retention 3. Hypertension 4. Neuropsychiatric (delirium, insomnia, irritability, psychosis) iv. Hyperglycemia associated with poor clinical outcomes in critically ill 29 v. Fluid retention à pulmonary congestion vi. Development of delirium à prolonged length of stay (LOS) Bjork 6

7 7. Potential Role in CAP a. Steroids utilized in CAP during 1950s after discovery of penicillin (1942) 30 b. Wagner et al (1956) showed benefit of hydrocortisone in pneumococcal PNA 30 c. Salluh et al (2006) demonstrated relative adrenal insufficiency in SCAP 31 i. Infection and immune response à endocrine alterations ii. Severe stress à relatively low cortisol levels d. Sibila et al (2008) found steroids decrease bacterial burden more than antibiotics alone 32 i. Animal models with severe PNA inoculated with Pseudomonas aeruginosa ii. Decreased IL-6 concentrations and bacteria in bronchoalveolar lavage fluid e. Corticosteroids minimize negative effects of severe inflammatory response CAP Management and Treatment Guidelines : Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) 12 a. Refer to Appendix B (Table 21) for antibiotic recommendations in patients with CAP b. No recommendation on corticosteroids : European Respiratory Society (ERS), in collaboration with the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) 33 a. Steroids not recommended (A3 = consistent evidence > 1 cohort study) i. Confalonieri et al. found benefit of hydrocortisone in SCAP 1. Reduction in hospital LOS and mortality 2. Reduction in CRP and delayed septic shock ii. Not enough literature in CAP patients à further investigation warranted : American Family Physician (AFP) 14 a. Corticosteroids x 5 7 days, initiated within 36 hours of admission for SCAP i. Decrease acute respiratory distress syndrome ii. Modestly reduce ICU and hospital stays iii. Reduce intravenous (IV) antibiotic treatment duration iv. Reduce time to clinical stability (TTCS) v. Do not increase major adverse events b. Typical regimen: methylprednisolone 0.5 mg/kg Q12H c. Evidence rating B = inconsistent or limited-quality patient-oriented evidence : Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 34 a. Corticosteroids x 5 7 days in hospitalized CAP patients b. Daily dose < 400 mg IV hydrocortisone or equivalent c. Grading of Recommendations Assessment, Development and Evaluation (GRADE) d. Conditional recommendation = we suggest, moderate quality of evidence Early Literature Review and Meta-Analyses of Corticosteroids in Severe CAP (SCAP) 1. Early literature review a. Confalonieri et al. (2005) 35 i. Small sample size (n = 44) ii. First randomized controlled trial (RCT) to suggest mortality benefit in SCAP b. Nafae et al. (2013) 36 i. Small sample size (n = 80) ii. Suggests mortality benefit in SCAP Bjork 7

8 2. Meta-Analyses a. Siemieniuk et al. (2015) 37 i. Corticosteroids only decreased mortality in SCAP ii. See Figure 2 for Forest Plot of SCAP trials All-cause In-hospital Mortality in Severe PNA CI = confidence interval Figure 2. Siemieniuk et al. (2015) 37 b. Stern et al. (2017) 20 i. Confirmed mortality benefit and reduced early clinical failure ii. See Table 11 for pertinent results in SCAP patients Table 11. Stern et al. (2017) Primary Outcomes 20 Anticipated Absolute Effects Relative Effect Number of Quality of Outcomes in in Study Population (95% CI) Participants Evidence adults with SCAP Control Steroids Risk Reduction (Studies) GRADE RR day mortality 131/ / (9 RCTs) Moderate ( ) Early clinical RR / / (5 RCTs) High failure ( ) c. Briel et al. (2017) 9 i. Reexamined individual patient data à no mortality benefit ii. See Table 12 for results in SCAP patients Table 12. Briel et al. (2017) Primary Outcomes 9 30-day mortality Placebo Corticosteroid Logistic Regression, Odds Ratio (n = 758) (n = 748) (95% CI), P-value PSI Class IV and V (%) 43 (11.6) 34 (8.4) 0.70 ( ), P = 0.14 SIRS Criteria > 2 (%) 33 (5.9) 22 (3.9) 0.59 ( ), P = 0.08 PSI = Pneumonia Severity Index; SIRS = Systemic Inflammatory Response System d. Wu et al. (2018) 38 i. Analyzed SCAP trials à reduced mortality ii. See Table 13 for in-hospital mortality results Table 13. Wu et al. (2018) Primary Outcome 38 Outcome in adults with Placebo Corticosteroid Relative Effect (95% CI) SCAP (n = 299) (n = 293) In-hospital mortality (%) 36 (12.04) 17 (5.80) 0.49 ( ) Bjork 8

9 3. Summary of existing literature a. Several small clinical studies assess utility of adjunctive corticosteroids in CAP 37 i. Signal towards possible mortality benefit in SCAP ii. Recent meta-analyses report conflicting results and conclusions b. Few clinical trials evaluate risk vs benefit of adjunctive corticosteroids in SCAP i. Varying interventions and outcomes ii. See Table 14 for summary of clinical trials assessing corticosteroids in SCAP Table 14. Summary of Clinical Trials Assessing Corticosteroids in Severe CAP (SCAP) SCAP Studies (Year) Corticosteroid Intervention and Duration Primary Benefit Marik (1993) 39 Hydrocortisone 10 mg/kg IV 30 min. before No impact on clinical antibiotics course Confalonieri (2005) 35 Hydrocortisone 200 mg IV x 1 à 10 mg/hour x 7D Reduced mortality El-Ghamrawy Improved time to clinical (2006) 40 Hydrocortisone 200 mg IV x 1 à 10 mg/hour x 7D cure; reduced LOS Mikami (2007) 41 Prednisolone 40 mg IV daily x 3D Improved TTCS Snijders (2010) 42 Prednisolone 40 mg IV/PO x 7D None; benefit cannot be excluded Fernandez-Serrano (2011) 43 Methylprednisolone 200 mg IV x 1 à tapering infusion (3.3 to 0.8 mg/hour) over 9D Reduced respiratory failure and TTCS Sabry (2011) 44 Hydrocortisone 200 mg IV x 1 à Reduced early clinical 12.5 mg/hour x 7D failure Sui (2013) 45 Methylprednisolone 8 mg Q12H x 7D Reduced LOS Nafae (2013) 36 Hydrocortisone 200 mg IV x 1 à 10 mg/hour x 7D Reduced mortality Blum (2015) 46 Prednisone 50 mg PO daily x 7D Reduced TTCS Torres (2015) 47 Methylprednisolone 0.5 mg/kg IV Q12H x 5D Reduced treatment failure Zhou (2015) 48 Methylprednisolone 120 mg daily x 7D Reduced LOS and Li (2016) 49 Methylprednisolone 80 mg daily x 7D respiratory failure IV = intravenous; D = day; LOS = length of stay; TTCS = time to clinical stability; PO = oral Clinical Question Should adjunctive corticosteroids be utilized in hospitalized patients with SCAP? Table 15. Snijders D, Daniels JM, de Graaff CS, van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med. 2010;181: Objective To assess efficacy of adjunctive prednisolone treatment in hospitalized CAP patients Methods Design Patient Population Randomized, double-blind, placebo-controlled trial at 1 site in Netherlands Inclusion Criteria Exclusion Criteria Patients age > 18 years hospitalized Immunosuppression or malignancy with CAP from Aug 2005 Jul 2008 Any likely infection other than CAP CAP definition: clinical symptoms of Pregnancy or breastfeeding CAP [cough, fever (> 38.5 C), pleuritic Conditions requiring corticosteroids chest pain] and new consolidations on Use of macrolides or prednisone > 15 chest radiograph mg for > 24 hours Bjork 9

10 Intervention Randomization 1:1 to prednisolone 40 mg (IV or PO) once daily or placebo x 7 days Outcomes Primary: clinical cure at day 7 Cure = resolution or improvement of CAP signs and symptoms (s/s) without need for additional or alternative therapy Secondary: clinical cure at day 30, 30-day mortality, LOS, TTCS, early (< 72 hours) and late clinical failure (> 72 hours) Failure = persistence or progression of all s/s, development of new infection, chest radiograph deterioration, death or discontinuation due to adverse events Statistical Calculated sample size of 92 patients per group to detect 15% difference Analysis between groups at day 7 with 80% power and alpha = 0.05 Based on previous CAP study with 93.3 vs 75.9% clinical success with/without steroids, respectively Kaplan-Meier method: analyze time from admission to discharge and TTCS Hazard and odds ratios reported with 95% confidence intervals (CI) Baseline Characteristics Primary Outcome Secondary Outcomes Results N = 213; mean age of 63.5 years, 57.9% male and slightly imbalanced groups Higher mean baseline CRP in prednisolone group (259 vs 215 mg/l) and increased prevalence of chronic heart disease in placebo group SCAP patients evenly distributed prednisolone vs placebo, respectively o CURB-65 score > 3: 28 (13.1%) vs 26 (12.2%) patients o PSI class IV V: 48 (46.2%) vs 45 (41.3%) patients Clinical Cure Prednisolone Placebo group P- Odds Ratio Day 7 group (n = 104) (n = 109) value (95% CI) All patients, no. (%) 84/104 (80.8) 93/109 (85.3) ( ) CURB 65: 3-5, no. (%) 15/28 (46.4) 15/26 (57.7) ( ) PSI class IV-V, no. (%) 31/48 (64.7) 32/45 (71.1) ( ) Clinical Cure Day 30 Prednisolone group Placebo group P- value Odds Ratio (95% CI) CURB 65: 3-5, no. (%) 13/28 (46.4) 10/26 (38.5) ( ) PSI class IV-V, no. (%) 24/48 (50.0) 26/45 (57.8) ( ) 30-day mortality CURB 65: 3-5, no. (%) 4/48 (14.3) 3/45 (11.5) ( ) PSI class IV-V, no. (%) 5/48 (10.4) 5/45 (11.1) ( ) Late failure All patients, no. (%) 20/104 (19.2) 10/109 (9.2) ( ) No significant differences in TTCS, LOS and early treatment failure in SCAP Safety Adverse Event Prednisolone group Placebo group P- value Hyperglycemia (%) 2.3% 0.9% 0.27 Confusion (%) 1.9% 1.4% 0.72 Superinfection (%) 2.1% 1.9% 0.10 Author s Conclusion Possible rebound inflammation in steroid group (higher CRP after 2 weeks) Prednisolone for 7 days does not improve outcomes in hospitalized CAP patients and should not be routinely recommended due to association with increased late failure and lack of efficacy. Benefit in more severely ill patients cannot be excluded. Bjork 10

11 Discussion Critique Strengths Limitations Randomized, double-blind design Single site in Netherlands CURB-65 and PSI scores provided Low number of SCAP patients CRP level assessed and monitored Antibiotic regimens based on Assessed CAP etiology Netherland guidelines 50 Excluded use of macrolides Take Home Points Subjectivity of primary outcome Primarily non-scap patients with average baseline CRP of 236 mg/l No difference in clinical cure at day 7 or 30 No mortality benefit or differences in safety outcomes between groups Ungeneralizable to SCAP patients in U.S. Table 16. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with communityacquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: (STEP Trial) 46 Objective To evaluate whether treatment with prednisone for seven days in patients with CAP as compared to placebo reduces time to clinical stability (TTCS) Methods Design Patient Population Intervention Outcomes Statistical Analysis Randomized, double-blind, placebo-controlled trial at 7 sites in Switzerland Inclusion Criteria Exclusion Criteria Patients age > 18 years hospitalized Active intravenous drug use with CAP from Acute burn injury CAP definition: new infiltrate on chest Adrenal insufficiency radiograph and presence of > 1 acute GI bleed within 3 months respiratory s/s (cough, sputum Condition requiring > 0.5 mg/kg/day production, dyspnea, temperature prednisone equivalent 38.0 C, auscultatory findings of Pregnancy or breastfeeding abnormal breath sounds and Severe immunosuppression leukocyte count > 10 or < 4 g/l) Active TB or cystic fibrosis Randomized 1:1 to receive prednisone 50 mg PO daily or placebo x 7 days, initiated within 24 hours upon hospital arrival Primary: TTCS (days until stable vital signs x 24 hours) Temperature < 37.8 C, heart rate < 100 beats/min, respiratory rate < 24 breaths/min, systolic blood pressure > 90 mmhg without vasopressors, baseline mental status, oral intake and adequate oxygenation on room air Secondary: effective hospital discharge, recurrent PNA, readmissions, ICU admission, 30-day all-cause mortality, duration of total and IV antibiotics, disease activity score, CAP complications, side effects of corticosteroids and time to hospital discharge Patients admitted to ICU: ICU LOS, time to ICU transfer and discharge, duration of vasopressor treatment and duration of mechanical ventilation Assumed mortality rate of 10% in placebo vs 7.5% in corticosteroid group over 14-day follow-up with 75% of survivors being clinically stable after 7 days Estimated 25% decrease in non-stability with corticosteroids at day 7 Calculated sample size of 800 patients followed for > 14 days à 85% power Primary outcome: intention-to-treat and per protocol population Bjork 11

12 Baseline Characteristics Primary Outcome Secondary Outcomes Safety Author s Conclusion Prespecified subgroup analyses: multivariable Cox proportional hazards model Secondary outcomes: unadjusted and adjusted (age and PSI) estimates; 95% CI Results N = 785; well-balanced groups, median age of 74 years and 62% male High burden of comorbidities (diabetes, COPD and chronic renal insufficiency) 49.2% high-risk PSI classes IV and V (SCAP) with average CRP of ~160 mg/l Prednisone Placebo Hazard Ratio [HR] TTCS (days) (n = 392) (n = 393) p-value (95% CI) Median (interquartile range) Intent-to-treat 3.0 ( ) 4.4 ( ) 1.33 ( ) < Per-protocol 3.0 ( ) 4.4 ( ) 1.35 ( ) < PSI class IV V 4.0 ( ) 5.6 ( ) 1.29 ( ) No evidence of effect modification in prespecified subgroups based on median age, initial median CRP concentration, previous history of COPD, severity of CAP (PSI score I III vs IV V) or blood culture positivity Prednisone (n = 392) Placebo (n = 393) HR or difference (95% CI) p-value Time to hospital discharge, days 6.0 ( ) 7.0 ( ) 1.19 ( ) IV antibiotic treatment, days 4.0 ( ) 5.0 ( ) ( ) No difference between groups in total duration of antibiotic treatment, rates of recurrent PNA, readmission to hospital and ICU admittance Overall CAP associated complications tended to be lower in prednisone group than placebo group at 30 days with OR = 0.49 (95% CI , p = 0.056) Incidence of corticosteroid related adverse events: 24% in prednisone group vs 16% in placebo group, difference 1.77 (95% CI , p = ) Driven by in-hospital hyperglycemia requiring new insulin regimen Prednisone treatment for 7 days in CAP patients admitted to hospital shortens TTCS without increased complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. Discussion Critique Strengths Limitations Largest RCT of corticosteroids in hospitalized CAP patients Prespecified subgroup analyses to assess for confounders Assessed infecting pathogen and antimicrobial use No patients lost to follow-up Provided rationale for selection of intervention and outcomes satisfaction scoring Take Home Points Primary outcome may not be extrapolated to other outcomes Most patients met < 3 baseline instability criteria Limited amount of ICU, bacteremic and septic patients Not powered to assess mortality No formal cost-benefit or patient Included ~50% SCAP patients with average baseline CRP of 160 mg/l Overall reduction in TTCS by 1.4 days and 1.6 days in SCAP Shorter LOS and antibiotic duration with increased risk of hyperglycemia Fairly generalizable to SCAP patients in U.S. Bjork 12

13 Table 17. Torres A, Sibila O, Ferrer M, 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: Objective To assess the effect of corticosteroids in patients with severe community acquired pneumonia and high associated inflammatory response. Methods Design Patient Population Intervention Outcomes Statistical Analysis Baseline Characteristics Randomized, double-blind, placebo-controlled trial at 3 Spanish teaching hospitals Inclusion Criteria Exclusion Criteria Patients age > 18 years hospitalized with CAP from Jun 2004 Feb 2012 Criteria for SCAP Defined by modified ATS criteria or PSI risk class V C-reactive protein (CRP) level > 150 mg/l at admission CAP definition: clinical symptoms suggesting CAP (cough, fever, pleuritic chest pain or dyspnea) and new chest radiographic infiltrate Prior treatment with chronic or recent systemic corticosteroids Nosocomial PNA Severe immunosuppression Preexisting medical condition with life expectancy < 3 months Uncontrolled diabetes mellitus GI bleed within 3 months Condition requiring acute treatment of > 1 mg/kg/d of methylprednisolone H1N1 influenza A PNA Randomized 1:1 to methylprednisolone 0.5mg/kg IV Q12H or placebo x 5 days, started within 36 hours of hospital admission Primary: treatment failure composite outcome (early vs late) Early: clinical deterioration indicated by development of shock, need for invasive mechanical ventilation or death within 72 hours of treatment Late: radiographic progression, persistent severe respiratory failure, development of shock, need for invasive mechanical ventilation or death between 72 and 120 hours after treatment initiation Secondary: in-hospital mortality, TTCS, ICU LOS and hospital stays and adverse events related to corticosteroids Assumed treatment failure rate of 35% in placebo group Alpha = 0.05 and 80% power to detect 20% absolute reduction in treatment failure by methylprednisolone compared to placebo Calculated sample size of 60 patients per group Primary outcome: intention-to-treat and per protocol population 95% CI: differences between groups and logistic regression: sensitivity analysis Outcomes adjusted for baseline variables and predefined covariates (year of admission and center) and any imbalanced variables between groups at baseline Results N = 120; similar between groups except lower levels of PCT and IL-10 and fewer patients with septic shock in methylprednisolone group Median age of 65 years, 62% male, mean CRP = 259 mg/l, 73% PSI class IV or V, 75% admitted to ICU and 68% with PaO 2/FiO 2 < 250 mmhg Antimicrobial treatment and timing of first dose similar between groups 97% of patients received adequate antibiotic treatment according to guidelines and microbiological results (49 patients with known etiology) Bjork 13

14 Primary Methylprednisolone Placebo group P- Difference Treatment Failure Outcome group (n = 61) (n = 59) value (95% CI) Total, no. (%) 8 (13) 18 (31) (3-32) Early, no. (%) 6 (10) 6 (10) (-10-11) Mech. ventilation 4 (7) 5 (8) (-8-11) Septic shock 2 (3) 3 (5) (-5-9) Death 2 (3) 2 (3) >.99 0 (-6-7) Late, no. (%) 2 (3) 15 (25) (10-34) Radiographic prog. 1 (2) 9 (15) (4-23) Resp. failure 1 (2) 5 (8) (-1-15) Mech. ventilation 1 (2) 4 (7) (-2-12) Septic shock 0 (0) 4 (7) (0-13) Mech. = mechanical; resp. = respiratory Secondary Methylprednisolone Placebo group P- Difference, In-hospital Outcomes group (n = 61) (n = 59) value % (95% CI) mortality, no. (%) 6 (10) 9 (15) (-6-17) No significant differences between groups for TTCS, hospital or ICU LOS Safety No significant differences between groups (includes hyperglycemia, GI bleed, superinfection, delirium, acute kidney injury and hepatic failure); well tolerated Hyperglycemia: 18% in methylprednisolone and 12% in placebo group (P = 0.34) Author s Conclusion In SCAP patients with high inflammatory response, acute use of methylprednisolone decreased treatment failure. If replicated, these findings would support use of corticosteroids as adjunctive treatment. Discussion Critique Strengths Limitations Take Home Points SCAP patients with high initial systemic inflammatory response Inflammation associated with high rates of treatment failure in CAP Assessed proper antibiotic use Adjusted for potential confounders Benefit from less radiographic progression consistent with previous, less robust literature Relatively short follow-up period No rules to adjust antibiotics based on clinical evaluation à no difference in duration of antibiotic therapy Slow patient accrual: 49% of those evaluated did not meet inclusion Treatment failure in placebo group lower than expected à less power Care of patients may have evolved during long enrollment period Included only SCAP patients with high markers of inflammation (CRP) Reduced treatment failure driven by improvement in late failure rates No mortality benefit or differences in safety outcomes between groups Most generalizable to SCAP patients in U.S. compared to previous trials Discussion 1. Few RCTs assess use of corticosteroids solely in SCAP patients 35,36,39-49 a. Primarily subgroup analyses of all CAP patients i. Lack of power to determine differences ii. Difficult to interpret and generalize secondary outcomes b. See Table 18 for comparison of three largest RCTs assessing corticosteroids in SCAP Bjork 14

15 Table 18. Comparison of Largest RCTs Assessing Corticosteroids in Severe CAP (SCAP) Study SCAP Criteria Intervention Treatment Guideline Primary Outcome Results Snijders CURB-65 > 2 Prednisolone 40 mg et al 42 Netherlands and PSI IV - V PO/IV x 7 days No difference in clinical cure at day 7 Blum Prednisone 50 mg PO et al 46 PSI IV V x 7 days ERS/ESCMID Reduced TTCS Torres et al 47 Methylprednisolone 0.5 mg/kg IV Q12H IDSA/ATS PSI V or modified ATS Reduced in-hospital treatment failure x 5 days PSI = pneumonia severity index; ATS = American Thoracic Society; ERS/ESCMID = European Respiratory Society/ European Society for Clinical Microbiology and Infectious Diseases; IDSA = Infectious Diseases Society of America; TTCS = time to clinical stability 2. SCAP criteria varied significantly based upon study definitions 35,36,39-49 a. Severity scoring tools each have benefits and limitations b. Most scoring systems not commonly used in clinical practice 3. Various corticosteroid regimens utilized in studies 35,36,39-49 a. No consistent drug, dose or duration to determine optimal regimen b. Lack of detailed rationale for specific intervention 4. Various antimicrobial regimens used in combination with corticosteroids 35,36,39-49 a. Limited information on antibiotic selection in combination with CAP etiology b. Optimal antibiotic regimens prevent morbidity and mortality 5. Uncertainty of mortality benefit in SCAP patients receiving adjunctive corticosteroids a. Confalonieri et al. and Nafae et al. found significant reduction in mortality 35,36 i. Difficult to interpret results 1. Small sample 2. Ungeneralizable ii. Uncertain risk bias b. Possible reduction in mortality à need further evaluation in RCTs 6. Apparent benefits of adjunctive corticosteroid therapy in SCAP patients 35,36,39-49 a. Reduction in treatment failure rates (reduction in late > early failure) 47 b. Reduction in total IV antibiotic use 46 c. Improvement in TTCS by ~ 1 day 46 d. Reduction in hospital LOS by ~ 1 day 40,45,46,48 e. Likely cost-effective and relatively safe 46,47 7. Potential harms of adjunctive corticosteroid therapy in SCAP patients 35,36,39-49 a. Hyperglycemia requiring insulin during hospitalization 42,46 b. Concern for rebound inflammation after discontinuation of corticosteroids 42 c. No significant adverse events found in primary literature i. Cardiac ii. Gastrointestinal iii. Neuropsychiatric iv. Superinfections Future Directions 1. Update in progress: 2007 IDSA/ATS CAP Treatment Guideline 2. See Table 19 for currently ongoing RCTs assessing adjunctive corticosteroids in SCAP Bjork 15

16 Table 19. Ongoing RCTs of Adjunctive Corticosteroids in Severe CAP (SCAP) Patients Acronym (Country) Patient Population Intervention Primary Outcome ESCAPe 51 Methylprednisolone bolus x 1 à Hospitalized All-cause 60-day 40 mg x 7 days à 20 mg x 7 days (United States) veterans with SCAP mortality à 6-day taper (12 and 4 mg/day) Santeon-CAP 52 (Netherlands) Peking Union 53 (China) CAPE COD 54 (France) Hospitalized CAP and SCAP patients SCAP SCAP Dexamethasone 6 mg PO x 4 days Methylprednisolone 80 mg x 3 days à 40 mg x 3 days Hydrocortisone 200 mg/day CI x 4 or 7 days à 100 mg/day CI x 2 or 4 days à 50 mg/day x 2 or 3 days* Hydrocortisone 50 mg IV Q6H up to 7 days REMAP-CAP 55 ICU patients with (Netherlands) SCAP PO = by mouth; CI = continuous infusion; IV = intravenous; LOS = length of stay * Duration of treatment is chosen upon patient initial improvement Conclusions and Recommendations Hospital LOS All-cause 30-day mortality All-cause 28-day mortality All-cause 60-day mortality Recommendation: adjunctive corticosteroids should be utilized for majority of SCAP patients 1. Patient selection a. ATS criteria may better identify SCAP patients than PSI or CURB-65 score b. Key factors in patients with SCAP that may benefit from corticosteroids i. CAP of bacterial etiology ii. High inflammatory markers (CRP, IL-6, -8 and -10 and ESR) iii. Respiratory decompensation iv. ICU admission upon hospital arrival v. Concomitant sepsis or septic shock c. Patients that may not benefit from adjunctive corticosteroids i. CAP of non-bacterial etiology ii. Previous recent or chronic steroid use iii. History of recent severe GI bleed iv. Severe underlying immunosuppression v. Pregnancy or breastfeeding 2. Corticosteroid selection a. Preferred agents i. Methylprednisolone 40 mg IV daily ii. Prednisone 50 mg PO daily b. Time to administration and duration i. Administer within hours of hospital arrival ii. Short term treatment to prevent adverse drug events iii. Duration: 5 7 days based upon patient response and clinical status Bjork 16

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20 Appendix A Table 20. Comparison of Systemic Glucocorticoid Preparations 26,27 Steroids Equivalent Glucocorticoid Mineralocorticoid Anti-inflammatory Potency (mg) Activity Activity Activity (hours) Short-acting (t ½ = 8 12 hours) Cortisone Hydrocortisone Intermediate-acting (t ½ = hours) Prednisone Prednisolone Methylprednisolone Triamcinolone Long-acting (t ½ = hours) Betamethasone Dexamethasone Appendix B Table 21. Recommended Empiric Antibiotics for CAP IDSA Guidelines (2007) 12 Outpatient Treatment Recommendation Level of Evidence Previously healthy and no use of antimicrobials in past 3 months Macrolide Strong I Doxycycline Weak III Comorbidities (i.e. heart, lung, liver or renal disease; diabetes; alcoholism; malignancies; asplenia; immunosuppression; or use of antimicrobials in past 3 months) OR macrolide resistant S. pneumoniae Respiratory (resp.) fluoroquinolone* Strong I Beta-lactam + macrolide Strong I Inpatients, non-intensive care unit (ICU) Treatment Recommendation Level of Evidence Resp. fluoroquinolone Strong I Beta-lactam + macrolide Strong I Inpatients, ICU Treatment Recommendation Level of Evidence Beta-lactam + azithromycin or resp. fluoroquinolone Strong II, I Penicillin allergic: resp. fluoroquinolone + aztreonam Recommended Special Concerns Recommendation Level of Evidence Pseudomonas Anti-pneumococcal, anti-pseudomonal beta-lactam with any of the following: Ciprofloxacin or levofloxacin Aminoglycoside + azithromycin Moderate III Aminoglycoside + resp. fluoroquinolone Penicillin allergic: aztreonam instead of beta-lactam Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) + vancomycin or linezolid Moderate III *Respiratory fluoroquinolones (cover S. pneumoniae): levofloxacin, moxifloxacin and gemifloxacin Bjork 20