Corticosteroids in Severe CAP

Mervyn Mer Department of Medicine & ICU Johannesburg Hospital University of the Witwatersrand

Introduction
Much controversy and debate regarding the use of corticosteroids (CS) in clinical medicine CS use in CAP controversial and unclear

Introduction
Definition of Pneumonia

Inflammatory condition of the lung parenchyma, caused by an infectious agent/s

Introduction
Community-acquired pneumonia common Leading infectious cause of death Consistently among top 5 causes of death in both developed and under-developed countries At least 20% cases CAP will require hospitalisation - 25% of these will require ICU admission Mortality of up to 50%
Almirall J, et al. Eur Resp J 2000; 15: 757-763 Alvarez-Lemma F, Torres A. Curr Opin Crit Care 2004; 10: 369-74

Introduction
Mortality rates CAP relatively unchanged past half century
Evans GM, Gainsford WF. Lancet 1938; 2: 14-19

Landmark study: Austrian and Gold 1964 - deaths occurring within 1st 5 days of rx not due to failure to eradicate micro-organism - suggested due to specific inflammatory response of host
Austrian R, Gold J. Ann Intern Med 1964; 60 :759-770

Introduction
...inflammatory response of the host may be more important than the specific microorganism causing the infection or the type of antibiotic administered

Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-84

Mechanism of Action
CS modulate the inflammatory response

Inhibit the production of key substances in the inflammatory pathway which contribute to vascular permeability, oedema, leucocyte migration and fibrin deposition

Mechanism of Action
CS modulate the inflammatory response
- halt activation of various transcription

factors including NF- KB - occurs via an inhibitory action on histone acetylation and stimulation of histone deacetylation
Barnes PJ. Allergy 2001; 56: 928-36

Marik P. Chest 2009

CS stimulate

Histone deacetylation

AP-1

CS/GR

CBP / p300
HAT

NF-KB

STATs

CS inhibit

Histone acetylation

Feldman C, et al. SAMJ 2007; 97: 1295-1306

Severe CAP

CURB-65 score

Treatment of Severe CAP

Amoxicillin-clavulanate or 2nd or 3rd generation cephalosporin & Aminoglycoside & Macrolide / azalide
Alternative : Flouroquinolone + another agent
Management of CAP in Adults Guideline. Feldman C, et al. SAMJ 2007; 97: 1295-1306

ATS / IDSA Guideline on CAP

Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72

ATS / IDSA Guideline on CAP

Hypotensive, fluid resuscitated patients with severe CAP should be screened for occult CIRCI
Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72

History
Initial description 1956 Effects of hydrocortisone upon course pneumococcal pneumonia treated with penicillin
Wagner HNJ, et al. Bull John Hopkins Hosp 1956; 98: 197-215

Severe Community Acquired Pneumonia (CAP)

Pneumonia leading cause of community-acquired infection requiring ICU admission Mortality remains high despite advances in antimicrobials & supportive measures

Severe CAP
Randomized multicentre study in patients with severe CAP in ICU who received low-dose CS (HC) associated with - significant reduction length of hospital stay - significant reduction in mortality
Confalonieri M, et al. AJRCCM 2005; 171: 242-248

Hydrocortisone in Severe CAP : Outcome

Outcome variable ICU mortality Hospital mortality 60-d mortality Length of ICU stay, d Length of hospital stay, d Duration of MV Placebo 7 (30%) 7 (30%) 8 (38%) 18 (3-45) 21 (3-72) 10 (2-44) Hydrocortisone 0 (0%) 0 (0%) 0 (0%) 10 (4-33) 13 (10-53) 4 (1-27) p Value 0.009 0.009 0.001 0.01 0.03 0.007

Confalonieri M , et al. AJRCCM 2005; 171: 242-48

Hydrocortisone in Severe CAP

Patients treated HC also showed significant improvements in - PaO2 : FiO2 ratio - chest radiograph score - MODS score - CRP reduction Dose : 200mg iv bolus followed by 10mg / hr x 7d
Confalonieri M ,et al. AJRCCM 2005; 171: 242-248

Recent Reviews
Severe CAP : approach to therapy - CS promising adjunct
Pineda L, et al. Expert Opin Pharmacother 2007; 8: 593-606

CS infusion in patients with severe CAP - powerful immunomodulatory effects - seems to be associated with significant reduction in morbidity, mortality, hospitalisation
Confalonieri M, Trevisan R. Recenti Prog Med 2006; 97: 32-36

Recent Reviews
Associated inflammatory response in pneumonia: role of adjunctive corticosteroids - adjunctive treatment with CS probably indicated in severe CAP
Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-184

An update on the diagnosis of adrenal insufficiency & the use of corticotherapy in critical illness - possible role for CS in severe CAP
Thomas Z, et al. Ann Pharmacother 2007; 41: 1456-65

CS and Severe CAP

Systematic review 2008 No evidence adverse outcomes or harm Moderate doses of CS safe Consider particularly in patients with COPD or asthma receiving antimicrobials
Salluh JIF, et al. Critical Care 2008; 12: R76

CS & CAP Requiring Hospitalisation

Prospective randomized controlled Japanese study Aim : assess effectiveness CS as adjunctive therapy in CAP requiring hospitalization 31 adult patients Adrenal function evaluated
Mikami K, et al. Lung 2007 185 (5): 249-55

CS & CAP Requiring Hospitalisation

Results - shorter duration of iv antibiotics if received CS - vital signs stabilized earlier in steroid group - differences most prominent in moderate-severe subgp. - prevalence of relative adrenal insufficiency high : 43% Conclusion - in moderate-severe CAP, CS promote resolution of clinical symptoms & reduce duration iv antibiotic rx
Mikami K, et al. Lung 2007 185 (5): 249-55

CS and Severe CAP

Spanish retrospective observational study Cohort of patients hospitalised with severe CAP (classes IV & V Prognostic Severity Index score) 308 patients evaluated - 238 (77%) rx standard antimicrobial therapy - 70 (23%) received antibiotics & systemic steroids Clinical characteristics similar
Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956

CS and Severe CAP

Median dose of CS : - 45.7mg / 24 hours methylprednisolone Results - systemic steroids were independently associated with a decreased mortality ( odds ratio 0.287; 95% CI 0.113-0.732 ) Conclusion - mortality decreased in patients with severe CAP who received simultaneous administration of systemic steroids along with antibiotic therapy
Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956

CS and Severe CAP

Severe sepsis Adrenal insufficiency - common - up to 2/3rds of patients with severe CAP admitted to ICU
Salluh J, et al. Intensive Care Med 2006; 32: 595-598

Role of CS in Paediatrics
Severe Mycoplasma Pneumoniae Pneumonia MP responsible for 10-40% cases paediatric CAP Occasionally progression to severe pneumonia despite appropriate antibiotic therapy Retrospective evaluation effect prednisolone Dose : 1mg/kg x 3-7 days, tapered over 7 days
Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8

Role of CS in Paediatrics
Severe Mycoplasma Pneumoniae Pneumonia Results - recipients afebrile within 24 hours - improvement in clinical status and radiographically Conclusion - CS rx temporally associated with clinical & radiographic improvement - may be helpful for reducing morbidity
Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8

CS in Other Pulmonary Infections

Data indicating benefit Pneumocystis Jirovecii pneumonia Tuberculosis Varicella-zoster virus Hantavirus Influenza virus Severe acute respiratory syndrome (SARS)
Rano A, et al. Curr Opin Infect Dis 2006; 19: 179-184

Cheng VCC, et al. J Infect 2004; 49: 262-273

Mer M, et al. Chest 1998; 114: 426-31

Critical Determinants
Timing Dose Duration

Factors Affecting Response to CS Treatment

Factors Affecting Treatment Response
Prevention of Potential Complications
Infection Surveillance Avoidance of Paralysis Corticosteroid Treatment Avoidance of Rebound Inflammation

Timing of Initiation

Dosage

Duration of Treatment

Cortisol Levels and CAP

Cortisol levels predictors of severity and outcome in CAP Similar to PSI Better than routinely measured laboratory parameters ( CRP, procalcitonin, leukocytes) Free cortisol not superior to total cortisol wrt prognostic accuracy in CAP
Christ-Crain M. Am J Respir Crit Care Med 2007; 176: 913-20

New Data
Corticosteroids not effective in CAP RDBP trial, 213 hospitalised patients 7 days of adjunctive prednisolone (40mg dly) - did not improve outcome - increased late failure in nonsevere CAP
Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82

New Data
Limitations
73% patients CURB-65 2 Abrupt cessation of CS (rebound) Benefit in more severely ill patients cannot be excluded Underpowered No assessment of adrenal function Editorial: CS if admitted ICU with severe CAP with either shock or ALI
Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82 Meduri GU, Confalonieri M. Am J Respir Crit Care Med 2010; 181: 880-82

Recent Meta-analyses
Corticosteroid treatment Patients with severe sepsis (n = 1228) Acute lung injury-acute respiratory distress syndrome (n = 648) Conclusions - CS of benefit
Annane D, et al. JAMA 2009; 301: 2362-2375 Tang B, et al. Crit Care Med 2009; 37: 1594-1603

Aggregate Data Randomised Trials

CS in patients with pneumonia requiring ICU Many with septic shock & / or acute lung injury Significant reduction in short term mortality - relative risk 0.40; p=0.03 Small size of trials
Confalonieri M, et al. Am J Respir Crit Care Med 2005; 171:242-248 Nawab Q, et al. Am J Respir Crit Care Med 2007;175: A594 Annane D, et al. JAMA 2002; 288: 862-871 Meduri GU, et al. Chest 2007; 131:954-963

Consensus Guidelines
Patients admitted to ICU with severe CAP with either shock or acute lung injury - CS indicated

Marik PE, et al. Crit Care Med 2008; 36:1937-1949

Corticosteroids for Pneumonia

Cochrane Database Systems Review 2011 6 studies, 437 participants CS improve oxygenation and reduce need for mechanical ventilation in severe pneumonia Hastened resolution of symptoms Adverse events related to CS infrequent
Chen Y, et al. Cochrane Database Syst Rev 2011: CD007720

Future
ESCAPe Trial Extended Steroid (in) CAP(e) Patients admitted to ICU with severe CAP Randomised trial; 1400 patients Prolonged use low dose MP

Conclusion
Encouraging data regarding use of CS in severe CAP They should be used in this setting Dose Avoid in non-severe CAP Timing, dose, duration are critical variables

Never underestimate the power of steroids

Umberto Meduri

In the ICU People Die, Steroids Never Do