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 CAP3. Evaluate current literature to determine role of adjunctive corticosteroids in severe CAP (SCAP)

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Community Acquired Pneumonia (CAP) 1. Definition1

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. Epidemiology2-4 a. Incidence and Prevalence

i. Approximately 5 to 6 cases of CAP per 1,000 persons per year2,3 ii. Incidence increases significantly with age

1. Age 65 – 69 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) Hospitals4

1. Equivalent to 452 cases per 100,000 person-years 2. Over 50% of cases incurred in patients > 65 years old

b. Economic Impact4-5 i. Total costs exceed $10 billion annually in U.S.5 ii. Annual expenditure of $750 million at VA hospitals in 20114

c. Morbidity and Mortality6-10 i. LRTI = most common infectious cause of death world-wide6

1. Fourth most common cause overall 2. PNA = 8th leading cause of death in U.S. in 20167

ii. Mortality remains high despite advances in the following8,9 1. Etiological investigation 2. Antimicrobial therapy 3. Improvements in supportive care

iii. CAP = prominent precursor of sepsis and septic shock8,9 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 patients10 1. Negative impact on overall quality of life 2. Studies suggest ~ 16% decrease in quality of life in post-discharge year

3. Etiology2,11 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) ICU

Primarily gram-positive, atypical and viral pathogens: S. pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae

Primarily gram-positive pathogens or gram-negative bacilli (GNB): S. pneumoniae, Staphylococcus aureus, Legionella species, GNB

4. Prevention13 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

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5. Diagnosis11,14 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

1. Prediction Tools11, 14-16 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-6514,15 a. Quick and simple criteria easily implemented in clinical practice b. See Tables 3 and 4 for variables and associated mortality rates

* Excluded in CRB-65

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

PaO2/FiO2 = partial pressure arterial oxygen/fraction inspired oxygen; BUN = blood urea nitrogen; WBC = white blood cell; PLT = platelet

Table 3. CURB-65 and CRB-65 Mortality Prediction Tools14

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

Table 4. 30-Day Mortality by Score15

CURB-65 CRB-65 Score Mortality Score Mortality 0 – 1 2.0% 0 2.3% 2 8.3% 1 – 2 13.3% 3 – 5 22.3% 3 – 4 34.4%

Table 5. ATS Criteria for Severe CAP (SCAP)11 Minor Criteria Major Criteria Respiratory rate > 30 breaths/min. Invasive mechanical ventilation PaO2/FiO2 ratio < 250 Septic shock with need for vasopressors Multilobar infiltrates

1 Major or > 3 Minor à ICU

Confusion/disorientation Uremia (BUN level, > 20 mg/dL) Leukopenia (WBC count, < 4000 cells/mm3) Thrombocytopenia (PLT, < 100,000 cells/mm3) Hypothermia (core temperature, < 36°C) Hypotension – aggressive fluid resuscitation

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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

Table 7. 30-Day Observed Mortality by Score16

Points Total Risk Class Mortality < 51 I 0.1% 51 – 70 II 0.6% 71 – 90 II 2.8% 91 – 130 IV 8.2% > 130 V 29.2%

Role of Inflammation and Markers of Infection

1. CAP may be associated with abnormal increase in inflammatory response17,18 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 harmful18

a. Excessive release of cytokines à lung damage b. Detrimental to patient stability

3. Non-survivors exhibit persistently elevated circulating cytokine levels19

Observed Mortality by Score5

Figure 1. PSI Risk Algorithm

Table 6. PSI/PORT Score16

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 < 7.35 + 30

Blood nitrogen urea > 30 mg/dL + 20 Sodium < 130 mmol/L + 20 Glucose > 250 mg/dL + 10

Hematocrit < 30% + 10 Partial pressure arterial O2 < 60 mmHg + 10

Pleural effusion + 10

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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. Pathophysiology20 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 Effects20-23 a. Mechanism of action21

i. Pleiotropic ii. See Figure 2 depicting corticosteroids impact on immune cells

Figure 2. Corticosteroids Impact on Immune Cells

b. Local effect in lungs20,22,23

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 reaction20 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

INF = interferon IL = interleukin Th = helper Tc = cytotoxic NK = natural killer TNF = tumor necrosis factor

www.researchgate.net/figure/Fig-3-Mechanism-of-action-of-corticosteroids-Corticosteroids-diffuse-across-the-cell_fig1_258631989

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3. Indications for Use24 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. Classification25

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

> fluid retention effects Inflammation + immunosuppression

< fluid retention effects

5. Formulations26,27 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 Effects23,24,28-29 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 therapy23 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 reversible28 1. Hyperglycemia 2. Fluid retention 3. Hypertension 4. Neuropsychiatric (delirium, insomnia, irritability, psychosis)

iv. Hyperglycemia associated with poor clinical outcomes in critically ill29 v. Fluid retention à pulmonary congestion vi. Development of delirium à prolonged length of stay (LOS)

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7. Potential Role in CAP30-32 a. Steroids utilized in CAP during 1950s after discovery of penicillin (1942)30 b. Wagner et al (1956) showed benefit of hydrocortisone in pneumococcal PNA30 c. Salluh et al (2006) demonstrated relative adrenal insufficiency in SCAP31

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 alone32 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 1. 2007: 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

2. 2011: 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 3. 2016: 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

4. 2017: 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

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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

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

c. Briel et al. (2017)9 i. Reexamined individual patient data à no mortality benefit ii. See Table 12 for results in SCAP patients

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 Outcome38

Outcome in adults with SCAP

Placebo (n = 299)

Corticosteroid (n = 293) Relative Effect (95% CI)

In-hospital mortality (%) 36 (12.04) 17 (5.80) 0.49 (0.29 – 0.85)

All-cause In-hospital Mortality in Severe PNA

Table 11. Stern et al. (2017) Primary Outcomes20

Outcomes in adults with SCAP

Anticipated Absolute Effects in Study Population

Relative Effect (95% CI)

Number of Participants

Quality of Evidence

Control Steroids Risk Reduction (Studies) GRADE

30-day mortality 131/1000 76/1000 RR 0.66 (0.47 – 0.92) 995 (9 RCTs) Moderate

Early clinical failure 422/1000 135/1000 RR 0.32

(0.15 – 0.70) 419 (5 RCTs) High

Table 12. Briel et al. (2017) Primary Outcomes9

30-day mortality Placebo (n = 758)

Corticosteroid (n = 748)

Logistic Regression, Odds Ratio (95% CI), P-value

PSI Class IV and V (%) 43 (11.6) 34 (8.4) 0.70 (0.44 – 1.13), P = 0.14 SIRS Criteria > 2 (%) 33 (5.9) 22 (3.9) 0.59 (0.33 – 1.06), P = 0.08

CI = confidence interval

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3. Summary of existing literature a. Several small clinical studies assess utility of adjunctive corticosteroids in CAP37

i. Signal towards possible mortality benefit in SCAP35-36 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 antibiotics

No impact on clinical course

Confalonieri (2005)35 Hydrocortisone 200 mg IV x 1 à 10 mg/hour x 7D Reduced mortality El-Ghamrawy (2006)40 Hydrocortisone 200 mg IV x 1 à 10 mg/hour x 7D Improved time to clinical

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 12.5 mg/hour x 7D

Reduced early clinical 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 respiratory failure Li (2016)49 Methylprednisolone 80 mg daily x 7D

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;181:975-82.42

Objective To assess efficacy of adjunctive prednisolone treatment in hospitalized CAP patients Methods

Design Randomized, double-blind, placebo-controlled trial at 1 site in Netherlands Patient Population

Inclusion Criteria Exclusion Criteria Patients age > 18 years hospitalized with CAP from Aug 2005 – Jul 2008

• Immunosuppression or malignancy • Any likely infection other than CAP • Pregnancy or breastfeeding • Conditions requiring corticosteroids • Use of macrolides or prednisone > 15

mg for > 24 hours

CAP definition: clinical symptoms of CAP [cough, fever (> 38.5°C), pleuritic chest pain] and new consolidations on chest radiograph

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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 Analysis

• Calculated sample size of 92 patients per group to detect 15% difference 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)

Results Baseline Characteristics

• 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

Primary Outcome

Clinical Cure Day 7

Prednisolone group (n = 104)

Placebo group (n = 109)

P- value

Odds Ratio (95% CI)

All patients, no. (%) 84/104 (80.8) 93/109 (85.3) 0.38 0.72 (0.35-1.49) CURB 65: 3-5, no. (%) 15/28 (46.4) 15/26 (57.7) 0.76 0.85 (0.29-2.48) PSI class IV-V, no. (%) 31/48 (64.7) 32/45 (71.1) 0.50 0.74 (0.31-1.77)

Secondary Outcomes

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) 0.55 1.39 (0.47-4.10) PSI class IV-V, no. (%) 24/48 (50.0) 26/45 (57.8) 0.45 0.73 (0.32-1.66) 30-day mortality CURB 65: 3-5, no. (%) 4/48 (14.3) 3/45 (11.5) 0.76 1.28 (0.26-6.35) PSI class IV-V, no. (%) 5/48 (10.4) 5/45 (11.1) 0.91 0.93 (0.25-3.46) Late failure All patients, no. (%) 20/104 (19.2) 10/109 (9.2) 0.04 2.36 (1.0 -5.31)

• 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

• Possible rebound inflammation in steroid group (higher CRP after 2 weeks)

Author’s Conclusion

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.

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Discussion Critique Strengths Limitations

• Randomized, double-blind design • CURB-65 and PSI scores provided • CRP level assessed and monitored • Assessed CAP etiology

• Single site in Netherlands • Low number of SCAP patients • Antibiotic regimens based on

Netherland guidelines50 • Excluded use of macrolides • Subjectivity of primary outcome

Take Home Points

• 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 community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–8. (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 Randomized, double-blind, placebo-controlled trial at 7 sites in Switzerland Patient Population

Inclusion Criteria Exclusion Criteria Patients age > 18 years hospitalized with CAP from 2009 – 2014

• Active intravenous drug use • Acute burn injury • Adrenal insufficiency • GI bleed within 3 months • Condition requiring > 0.5 mg/kg/day prednisone equivalent • Pregnancy or breastfeeding • Severe immunosuppression • Active TB or cystic fibrosis

CAP definition: new infiltrate on chest radiograph and presence of > 1 acute respiratory s/s (cough, sputum production, dyspnea, temperature ≥ 38.0°C, auscultatory findings of abnormal breath sounds and leukocyte count > 10 or < 4 g/L)

Intervention Randomized 1:1 to receive prednisone 50 mg PO daily or placebo x 7 days, initiated within 24 hours upon hospital arrival

Outcomes 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

Statistical Analysis

• 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

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• Prespecified subgroup analyses: multivariable Cox proportional hazards model • Secondary outcomes: unadjusted and adjusted (age and PSI) estimates; 95% CI

Results Baseline Characteristics

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

Primary Outcome TTCS (days)

Prednisone (n = 392)

Placebo (n = 393) Hazard Ratio [HR]

(95% CI) p-value Median (interquartile range)

Intent-to-treat 3.0 (2.5 – 3.4) 4.4 (4.0 – 5.0) 1.33 (1.15-1.50) <0.0001 Per-protocol 3.0 (2.5 – 3.2) 4.4 (4.0 – 5.0) 1.35 (1.16-1.56) <0.0001 PSI class IV – V 4.0 (3.4 – 4.5) 5.6 (5.0 – 7.0) 1.29 (1.05-1.59) – • 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

Secondary Outcomes

Prednisone (n = 392)

Placebo (n = 393)

HR or difference (95% CI) p-value

Time to hospital discharge, days 6.0 (6.0 – 7.0) 7.0 (7.0 – 8.0) 1.19 (1.04-1.38) 0.012

IV antibiotic treatment, days 4.0 (3.0 – 6.0) 5.0 (3.0 – 7.0) -0.89 (-1.57-0.20) 0.011

• 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 0.23 – 1.02, p = 0.056)

Safety • Incidence of corticosteroid related adverse events: 24% in prednisone group vs 16% in placebo group, difference 1.77 (95% CI 1.24-2.52, p = 0.0020)

• Driven by in-hospital hyperglycemia requiring new insulin regimen Author’s Conclusion

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

• 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

satisfaction scoring Take Home Points

• 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.

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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;313:677–86.47

Objective To assess the effect of corticosteroids in patients with severe community acquired pneumonia and high associated inflammatory response.

Methods Design Randomized, double-blind, placebo-controlled trial at 3 Spanish teaching hospitals Patient Population

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

• 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

CAP definition: clinical symptoms suggesting CAP (cough, fever, pleuritic chest pain or dyspnea) and new chest radiographic infiltrate

Intervention Randomized 1:1 to methylprednisolone 0.5mg/kg IV Q12H or placebo x 5 days, started within 36 hours of hospital admission

Outcomes 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

Statistical Analysis

• 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

Baseline Characteristics

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 PaO2/FiO2 < 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)

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Discussion

1. Few RCTs assess use of corticosteroids solely in SCAP patients35,36,39-49 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

Primary Outcome Treatment Failure Methylprednisolone

group (n = 61) Placebo group

(n = 59) P-

value Difference

(95% CI) Total, no. (%) 8 (13) 18 (31) 0.01 18 (3 - 32) Early, no. (%) 6 (10) 6 (10) 0.95 0 (-10 - 11) Mech. ventilation 4 (7) 5 (8) 0.74 2 (-8 - 11) Septic shock 2 (3) 3 (5) 0.68 2 (-5 - 9) Death 2 (3) 2 (3) > .99 0 (-6 - 7) Late, no. (%) 2 (3) 15 (25) .001 22 (10 - 34) Radiographic prog. 1 (2) 9 (15) .007 14 (4 - 23) Resp. failure 1 (2) 5 (8) 0.11 7 (-1 - 15) Mech. ventilation 1 (2) 4 (7) 0.20 5 (-2 - 12) Septic shock 0 (0) 4 (7) 0.06 7 (0 - 13) Mech. = mechanical; resp. = respiratory

Secondary Outcomes In-hospital

mortality, no. (%)

Methylprednisolone group (n = 61)

Placebo group (n = 59)

P- value

Difference, % (95% CI)

6 (10) 9 (15) 0.37 5 (-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

• 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

Take Home Points

• 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

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Table 18. Comparison of Largest RCTs Assessing Corticosteroids in Severe CAP (SCAP) Study SCAP Criteria Intervention Treatment Guideline Primary Outcome Results Snijders et al42

CURB-65 > 2 and PSI IV - V

Prednisolone 40 mg PO/IV x 7 days Netherlands50 No difference in clinical

cure at day 7 Blum et al46 PSI IV – V Prednisone 50 mg PO

x 7 days ERS/ESCMID Reduced TTCS

Torres et al47 PSI V or

modified ATS

Methylprednisolone 0.5 mg/kg IV Q12H x 5 days

IDSA/ATS Reduced in-hospital treatment failure

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 definitions35,36,39-49 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 studies35,36,39-49 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 corticosteroids35,36,39-49 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 mortality35,36

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 patients35,36,39-49 a. Reduction in treatment failure rates (reduction in late > early failure)47 b. Reduction in total IV antibiotic use46 c. Improvement in TTCS by ~ 1 day46 d. Reduction in hospital LOS by ~ 1 day40,45,46,48 e. Likely cost-effective and relatively safe46,47

7. Potential harms of adjunctive corticosteroid therapy in SCAP patients35,36,39-49 a. Hyperglycemia requiring insulin during hospitalization42,46 b. Concern for rebound inflammation after discontinuation of corticosteroids42 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

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Table 19. Ongoing RCTs of Adjunctive Corticosteroids in Severe CAP (SCAP) Patients Acronym (Country) Patient Population Intervention Primary Outcome

ESCAPe51 (United States)

Hospitalized veterans with SCAP

Methylprednisolone bolus x 1 à 40 mg x 7 days à 20 mg x 7 days à 6-day taper (12 and 4 mg/day)

All-cause 60-day mortality

Santeon-CAP52 (Netherlands)

Hospitalized CAP and SCAP patients Dexamethasone 6 mg PO x 4 days Hospital LOS

Peking Union53 (China) SCAP Methylprednisolone 80 mg x 3 days

à 40 mg x 3 days All-cause 30-day mortality

CAPE COD54 (France) SCAP

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*

All-cause 28-day mortality

REMAP-CAP55 (Netherlands)

ICU patients with SCAP

Hydrocortisone 50 mg IV Q6H up to 7 days

All-cause 60-day mortality

PO = by mouth; CI = continuous infusion; IV = intravenous; LOS = length of stay * Duration of treatment is chosen upon patient initial improvement Conclusions and Recommendations 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 24 – 36 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

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Appendix A

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

Moderate III Aminoglycoside + azithromycin 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

Table 20. Comparison of Systemic Glucocorticoid Preparations26,27

Steroids Equivalent Potency (mg)

Glucocorticoid Activity

Mineralocorticoid Activity

Anti-inflammatory Activity (hours)

Short-acting (t ½ = 8 – 12 hours) Cortisone 20 0.8 0.8 1 Hydrocortisone 25 1 1 1 Intermediate-acting (t ½ = 18 – 36 hours) Prednisone 5 4 0.8 4 Prednisolone 5 4 0.8 5 Methylprednisolone 4 5 0.5 5 Triamcinolone 4 5 0 5 Long-acting (t ½ = 36 – 54 hours) Betamethasone 0.6 25 0 35 Dexamethasone 0.75 30 0 30