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Pneumonia, Prednisone, Paradigm?Corticosteroids in Community-Acquired Pneumonia

Cam Roessner, PharmD StudentMay 28, 2015

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Learning Objectives

Describe the rationale for adjunctive corticosteroids in the treatment of community-acquired pneumonia

Evaluate and summarize the evidence for adjunctive corticosteroids in community-acquired pneumonia

Recognize the strengths and limitations of available evidence

Prioritize the role of corticosteroids in patients presenting with community-acquired pneumonia

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Outline

Background

Rationale for Corticosteroids in CAP

Rationale and Evidence for Corticosteroids in Infectious Diseases

Corticosteroid Controversy Review of Current Evidence Discussion and Opinion Remaining Questions

Summary

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Community-Acquired Pneumonia (CAP)

Infection of the lung parenchyma occurring in patients living independently in the community, including those hospitalized for other reasons for < 48hrs

Symptoms are variable between patients but often patients present with cough, sputum, and dyspnea in the setting of fever and crackles/rales on auscultation

Presence of lobar consolidation with decreased breath sounds and leukocytosis help to confirm the diagnosis

A microbiological cause is established with certainty in approximately 50%

Infection may bacterial, viral, fungal, or parasitic in origin

Limper, A. H. (2012)

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CAP – Common Infectious Causes

Bacteria Viruses Other

S. pneumoniae† Influenza A and B M. pneumoniae

H. influenzae† Respiratory syncytial virus C. pneumoniae

S. aureus Rhinovirus P. jirovecii

M. catarrhalis† Aspergillus spp.

P. aeruginosa

†Account for > 80% of cases of community-acquired pneumonia

Limper, A. H. (2012), Feldman, C., & Anderson, R. (2015)

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CAP – Incidence and Costs

Every year community-acquired pneumonia affects 2 to 4 million patients in the U.S., resulting in 500,000 hospital admissions

Hospitalized patients with CAP have a 30-day mortality rate of 10-12%, and in those who survive, the risk of mortality remains elevated at 1 year and up to 3-5 years in those with pneumococcal pneumonia

About 18% of patients are re-admitted to hospital within 30 days of discharge

The treatment of inpatient CAP in the U.S. is estimated to cost $8.6B annually, with a daily fixed cost of $1,448 $USD and an average stay cost of $13,009 $USD

NEJM 371(17), 1619-1628, Curr Med Res Op 25(9), 2151-2157

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CAP – Risk Factors

Virulence Factors Current or recent influenza virus

infection Bacterial-specific virulence

Drugs Acid-suppression Antipsychotics Corticosteroids

i.e. increased pneumonia risk with ICS in COPD patients

Patient Factors Age Decreased LOC Tobacco smoke Alcohol consumption Cystic fibrosis COPD HIV infection

Cochrane Sys Rev CD006829, European Respiratory Journal, 13(2), 349-355

Ellison, R. T., & Donowitz, G. R. (2015) 8

CAP – Why Corticosteroids?

Pathophysiology of Inflammation in Pneumonia

1. Alveolar and interstitial macrophages mediate the inflammatory response and produce cytokines when invading pathogens overcome their phagocytic abilities

2. Early-response cytokines include tumour necrosis factor-α (TNF- α) and IL-1

3. Cytokines and transcription factors promote pro-inflammatory recruitment of neutrophils to the lung AND anti-inflammatory safety measures aimed at preventing tissue destruction

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CAP – Why Corticosteroids?

In patients admitted with community-acquired pneumonia…

Excessive cytokine production (pro-inflammatory and anti-inflammatory) resulted in an increased risk of sepsis and mortality

The risk of mortality remained elevated at 3-6 months post-discharge

Archives of Internal Medicine, 167(15), 1655-1663,

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CAP – Why Corticosteroids?

Clinical Variables – Confusion, tachypnea, hypotension, impaired renal function, pleural effusion, and bacteremia were associated with an increased inflammatory response (increased IL-6 and IL -10 cytokines) and increased mortality In-hospital 30 days 90 days

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

Inflammatory Response in CAP

Normal IL-6 Excess IL-6 Normal IL-10 Excess IL-10

Time

Mor

talit

y

The European Respiratory Journal, 37(2), 393-399, American Journal of Respiratory and Critical Care Medicine, 177(11), 1242-1247

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Adjunctive Corticosteroids in Infectious Diseases

Bacterial meningitis

In experimental models, severity of subarachnoid inflammation (due to the immune response and bacterial lysis following antibiotic administration) lead to worse outcomes

Evidence (dexamethasone) Reduces mortality in patients with S.pneumoniae bacterial meningitis Reduces hearing loss and neurological sequelae in developed countries NOTE: Mortality benefit of dexamethasone in pneumococcal meningitis was due to a

reduced risk of systemic complications (i.e. septic shock, acute respiratory distress syndrome, and pneumonia) and NOT neurological seqeulae

NEJM 347(20), 1549-1556, The Cochrane Database of Systematic Reviews, 6, CD004405, Annals of Internal Medicine, 141(4), 327

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Adjunctive Corticosteroids in Infectious Diseases

Tuberculous meningitis Similar rationale to bacterial meningitis Evidence

Reduces mortality and disabling residual neurological deficits (i.e. ability to perform ADLs/IADLs) in HIV-negative patients with tuberculous meningitis

Pneumocystis pneumonia Clinical status of patients generally worsen within 3 days of starting anti-pneumocystis

therapy as killed pneumocystis organisms stimulate inflammation Evidence

Reduces mortality in HIV-positive patients with pneumocystis pneumonia and substantial hypoxemia (arterial oxygen partial pressure < 70mmHg)

NNT of 9 without HAART and 23 with HAART

Cochrane Database of Systematic Reviews, (1):CD002244, (4):CD006150

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Current Guideline Recommendations

Community-Acquired Pneumonia (IDSA) Hypotensive, fluid-resuscitated patients with severe CAP should be screened

for occult adrenal insufficiency. (Moderate recommendation; level II evidence.)

Corticosteroid replacement therapy in patients with severe CAP and septic shock can be used in documented adrenal insufficiency

New IDSA guidelines in development!

Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 44 Supplement 2, S27-72

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CAP – Why Not Corticosteroids?

I want to know if...

In patients with community-acquired pneumonia requiring hospitalization, when added to antibiotic therapy, do

corticosteroids result in improved outcomes when compared to antibiotics alone?

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Adjunct prednisone therapy for patients with community-acquired pneumoniaA multi-center, double-blind, randomized, placebo-controlled trial (Blum et al.)Lancet 2015; 385: 1511–18

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Population

N = 785 patients

Multi-center – Seven tertiary care hospitals in Switzerland

Inclusion Exclusion 18 years of age Hospital admission with CAP defined as the

presence of new infiltrate on CXR and at least one of:

Cough Sputum production Dyspnea Fever Leukocytosis or leukopenia

× Inability for informed consent× Active IVDU× Acute burn injury× GI bleed within 3 months× Known adrenal insufficiency× Severe immunosuppression× >0.5mg/d prednisone equivalent× Pregnancy/lactation

Lancet, 385(9977), 1511-1518

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Baseline Characteristics

Average Age: 74 years

Majority were male (62%)

No significant differences in days with symptoms (4), clinical presentation, lab values, PSI score, or comorbidities:

DM – 20% COPD – 19% vs. 15% CHF – 20% vs. 16% Renal Insufficiency – 32%

Half of patients were PSI class IV or V Average PSI score of around 90 – A score of 71-90 correlates with a mortality rate of 0.9%

Lancet, 385(9977), 1511-1518

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Intervention & Comparator

1:1 block randomization, with centrally managed computer-generated allocation concealment to:

1. prednisone 50mg PO once daily for 7 days (n=392)2. identical placebo PO once daily for 7 days (n=393)

Patients, physicians, investigators, and adjudicators were blinded

Empiric antibiotic therapy was started according to ERS/ESCMID guidelines (i.e. amoxi-clav +/- macrolide, ceftriaxone +/- macrolide, etc.) as soon as CAP was confirmed

Treatment was optimized after the susceptibility patterns were known

Lancet, 385(9977), 1511-1518

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Outcomes

Primary Outcome Time to clinical stability – Number of days until stable vital signs (≤ 37.8ᵒC, HR < 100,

RR < 24, SBP ≥ 90mmHg with no vasopressors, baseline mental status, oral intake, adequate oxygenation on room air) for 24h or longer (all criteria needed to be met)

Secondary Outcomes• Time to effective discharge• Recurrence of pneumonia• Re-admission to hospital• ICU admission• All-cause mortality

• Duration of total and IV antibiotic treatment• CAP Score at day 5 and 30• Incidence of complications• Side-effects of corticosteroids• Time to earliest possible discharge

Lancet, 385(9977), 1511-1518

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Follow-Up

Until death or 30 days post-discharge

No patients were lost to follow-up for the primary outcome

At Presentation/Hospital Baseline blood samples, nasal swabs for viral PCR, and clinical variables, including those

used to calculate a pneumonia severity index (PSI) Routine laboratory markers of inflammation on days 1, 3, 5, 7 and before discharge Four glucose measurements per day

Community At 30 days, a phone follow-up assessed for infections, recurrent pneumonia, re-

admission to hospital, new onset diabetes or insulin dependence, and new onset hypertension

Lancet, 385(9977), 1511-1518

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Results

Secondary Outcome Prednisone vs. Placebo Hazard Ratio (95% CI) P-valueTime to effective hospital discharge

6 days (6.0 – 7.0) vs. 7 days (7.0 – 8.0)

1.19 (1.04 – 1.38) 0.012

IV Antibiotic Duration Mean difference of -0.89 days for prednisone arm (-1.57 to -0.20)

0.011

Primary Outcome Prednisone vs. Placebo Hazard Ratio (95% CI) P-valueIntention-to-treat 3 days (2.5 – 3.4) vs. 4.4 days

(4.0 – 5.0)1.33 (1.15 – 1.50) < 0.0001

Per-protocol 3 days (2.5 – 3.2) vs. 4.4 days (4.0 – 5.0)

1.33 (1.16 – 1.56) < 0.0001

Lancet, 385(9977), 1511-1518

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Results

Probability of Attaining Clinical Stability

Lancet, 385(9977), 1511-1518

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Results

Side Effects of Corticosteroids

Adverse Event Prednisone vs. Placebo

Risk Increase (95% CI) P-value NNH

Any 24% vs. 16% 1.58 (1.14 – 2.17) 0.002 11

In-hospital hyperglycemia needing new insulin

19% vs. 11% 1.77 (1.22 – 2.92) 0.001 12

• Hyperglycemia• In-hospital and needing insulin start• New insulin dependence at day 30

• Hypertension

• Nosocomial infections• Weight gain• Gastrointestinal bleeding• Delirium

Lancet, 385(9977), 1511-1518

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Commentary: Strengths

Largest trial to date of adjunctive corticosteroids for community-acquired pneumonia Reduced risk of a type II error, although not powered to detect a difference in mortality

Randomization, allocation concealment, and blinding was well done

Patients were analyzed according to the group they were randomized to (ITT) as well as according to treatment protocol (per-protocol)

Length of follow-up was reasonable (data has been collected for 180 days)

No patients were lost to follow-up for the primary outcome and only 4 (0.5%) were lost at 30 days

Amoxi-clav or ceftriaxone +/- clarithromycin were the antibiotics of choice (>90%)

Time to clinical stability can be considered a patient-important outcome (although the definition itself is a composite of surrogate markers)

Lancet, 385(9977), 1511-1518

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Commentary: Limitations

Patients had lower severity pneumonia than previous studies (Average PSI score of 93 and 86) At baseline, average temperature, heart rate, respiratory rate, and blood pressure were stable already! About 65% of patients in each group had ≤ 2 instability criteria at baseline

Primary endpoint was combined (fever, tachycardia, tachypnea, normotensive, etc.) Concurrent medications were not discussed at all – some could impact patient “stability” (i.e. beta-blockers,

antipyretics, antiemetic)

Did not evaluate patients for a history of pneumococcal or influenza vaccinations, interventions thought to have a beneficial impact on pneumonia severity and mortality outcomes

What about patient risk factors for community-acquired pneumonia? Smoking and alcohol consumption were not discussed and are not a part of the risk scoring systems used (i.e. CAP

score)

Did not perform a sub-group analysis specific to an infectious organism – S.pneumoniae was the most commonly identified organism (12.% vs. 12.7%)

Are corticosteroids more effective against certain infectious etiologies? S.pneumonia?Lancet, 385(9977), 1511-1518, Archives of Internal Medicine, 167(18), 1938-1943, The American Journal of Medicine, 115(6), 454-461

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Conclusions

Benefit on time to clinical stability regardless of age, CRP concentration, or severity of pneumonia (PSI score)

Trend towards increased benefit in patients with sepsis

Although complications were few (i.e. empyema, ARDS, pneumonia persistence) they tended to be (non-significant) lower in the treatment group

Discharged on average 1 day sooner, a previously described outcome with dexamethasone in community-acquired pneumonia

Short-term administration resulted in higher rates of hyperglycemia requiring insulin treatment however, other adverse effects were similar between groups

Lancet, 385(9977), 1511-1518, Jama, 313(7), 677-686

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Effect of Corticosteroids on Treatment Failure AmongHospitalized Patients With Severe Community-AcquiredPneumonia and High Inflammatory ResponseA Randomized Clinical Trial (Torres et al.)JAMA. 2015;313(7):677-686

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Design & Population

Multicenter, randomized, double-blind, placebo controlled trial

N = 120 patients at 3 Spanish teaching hospitalsInclusion Exclusion ≥ 18 years of age Clinical symptoms suggestive of CAP (cough,

fever, pleuritic chest pain, dyspnea) New infiltrate on CXR Severe pneumonia or PSI score of V CRP > 150mg/L at admission

× Prior treatment with corticosteroids× Nosocomial pneumonia× Severe immunosuppression× Medical condition with life expectancy < 3

months× Uncontrolled diabetes× GI bleed within 3 months× > 1mg/kg/d baseline methylprednisolone

Jama, 313(7), 677-686

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Baseline Characteristics

Average age of ≈65 years

Majority were male (62%)

Less patients with septic shock in treatment group 17% vs. 31% Remaining clinical variables were similar

On average patients had a more sever presentation Higher respiratory rate and heart rate on average than study by Blum et al.

A majority were PSI class IV and V (≥70%) Average PSI score of 108 between the two groups – A PSI score of correlates with a

mortality rate of 9.3% (the study by Blum et al. had a PSI-related risk of 0.9%!)

Jama, 313(7), 677-686

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Intervention & Comparator

1:1 randomization to pre-numbered boxes containing dosing units of either:1. methylprednisolone 0.5mg/kg IV q12h for 5 days started within 36 hours of

admission (n=61)2. identical placebo IV q12h for 5 days started within 36 hours of admission (n=59)

Patients, investigators, and adjudicators were blinded

Empiric antibiotic therapy was started according to IDSA 2007 community-acquired pneumonia guidelines (i.e. ceftriaxone + macrolide, fluoroquinolone)

Jama, 313(7), 677-686

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Outcomes

Primary Outcome Rate of treatment failure – Early treatment failure (<72 hours of treatment), late

treatment failure (72 – 120 hours), or both Definition – Development of shock, need for invasive mechanical ventilation, or death

(late also included radiographic progression and persistence of severe respiratory failure)

Secondary Outcomes• Time to clinical stability• Length of ICU and hospital stay• In-hospital mortality

*Definition of time to clinical stability was similar to the previous study

Jama, 313(7), 677-686

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Follow-Up

At Presentation: Sputum, urine, blood (× 2), and nasopharyngeal swabs CBC, renal and liver function tests, electrolytes, blood glucose, and CRP IL-6, -8, -10, procalcitonin, and CRP were obtained on treatment days 1, 3, and 7

Patients were evaluated daily for treatment failure and time to clinical stability until day 7 to assess for rebound inflammation following corticosteroid discontinuation

Jama, 313(7), 677-686

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Results

Secondary Outcome Methylprednisolone vs. Placebo

Mean Difference/Risk Reduction (95% CI)

P-value

Time clinical stability 4 days (3 – 6) vs. 5 days (3 – 7)

1 day (-0.4 – 2.4) 0.28

In-hospital mortality 10% vs. 15% 0.64 (0.23 – 1.81) 0.37

Primary Outcome Methylprednisolone vs. Placebo

Risk Reduction (95% CI) P-value NNT

Intention-to-treat 13% vs. 31% 0.43 (0.19 – 0.99) 0.02 6

Early (0-72h) 10% vs. 10% 0.97 (0.31 – 3.00) 0.95 N/A

Late (72-120h) 3% vs. 25% 0.13 (0.03 – 0.56) 0.001 5

Jama, 313(7), 677-686

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Results

Percentage of Patients Failing Treatment

Jama, 313(7), 677-686

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Results

Causes of Treatment Failure

Jama, 313(7), 677-686

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Results

Incidence of other adverse events (GI bleed, infection, delirium, AKI, acute hepatic injury) were similar between groups

Likely not powered to detect differences in adverse events

Adverse Event Methylprednisolone vs. Placebo

Risk Increase (95% CI) P-value

Hyperglycemia 18% vs. 12% 1.52 (0.59 – 3.92) 0.34

Jama, 313(7), 677-686

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Commentary: Strengths

Patients were analyzed according to the group they were randomized to (ITT) and according to treatment protocol (per-protocol)

Randomization, allocation concealment, and blinding was well done

Addressed more baseline risk factors for community-acquired pneumonia including current smoking status

Adjusting for baseline differences (rates of septic shock in placebo group) still resulted in reduced treatment failure with methylprednisolone

Primary outcome addressed morbidity and mortality associated with treatment failure (shock, ventilation, death)

BUT, what can we make of reduced late (72-120h) radiographic progression, the outcome driving statistical significance? Does it lead to worse outcomes?

Jama, 313(7), 677-686, Jama, 313(7), 673-674

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Commentary: Limitations

Treatment failure is a composite endpoint

Initial antibiotic adequacy was lower in the placebo group (94%) when compared to the methylprednisolone group (100%) after culture results were known

Poor applicability due to inclusion of patients with a high inflammatory response (CRP > 150mg/L) – 24% of screened patients were excluded for CRP < 150mg/L

Did not evaluate patients for a history of pneumococcal or influenza vaccinations, interventions thought to have a beneficial impact on severity and mortality outcomes

Follow-up was only done in hospital, post-discharge complications were not assessed

Low proportion of patients received a macrolide combination (24% vs. 23%) Anti-inflammatory action of macrolides? Mortality benefit with macrolides? About 63% received a macrolide in the study by Blum et al…

No subgroup analysis according to infectious cause – S.pneumoniae was the most common infectious agent (20% vs. 26%)

Jama, 313(7), 677-686, Critical Care Medicine, 42(2), 420-432

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Conclusions

Included more information on baseline characteristics (i.e. smokers), but…

Trial was small (n=120), and although it offers some insight into the treatment of a specific patient group, enrollment was difficult for this subset (took 8 years) and resulted in a lack of power to detect possible differences

Patients community-acquired pneumonia with a greater inflammatory response showered lower risk of treatment failure, although it is hard to apply the benefit of reduced radiographic progression

Does it mean lower incidence of acute respiratory distress syndrome? Reduce inflammatory response to a Jarisch-Herxeimer reaction?

Is it applicable when only about 24% of patients received macrolides (a common guideline and resource recommendation for hospitalized CAP in North America)?

Jama, 313(7), 677-686, NEJM 354(16), 1671-1684, Travel Medicine and Infectious Disease, 11(4), 231-237

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Corticosteroids in the Treatment of Community-AcquiredPneumonia in AdultsA Meta-Analysis (Nie et al.)PLoS One. 2012; 7(10): e47926

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Design & Results

Nine RCTs and quasi-RCTs involving 1001 patients with CAP receiving either adjunctive corticosteroids or placebo in addition to standard treatment

Four trials included only patients with severe CAP

Hydrocortisone, dexamethasone, prednisolone, or methylprednisolone were used with a duration ranging from 1 to 9 days

Primary outcome measure was mortality (8 trials, n=970) OR 0.62 (95% CI 0.37-1.04), p=0.07, I2=13%, NSS

GI bleeding and infection rates were not different, however hyperglycemia was more common in the corticosteroid groups

PLoS One. 2012; 7(10): e47926

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Severe CAP & Prolonged Therapy

A subgroup analysis showed a significant association between severe community-acquired pneumonia and reduced mortality with adjunctive corticosteroids

OR 0.26 (95% CI 0.11-0.64), p=0.003, I2=0%

Prolonged courses of treatment (> 5 days) also resulted in reduced mortality OR 0.51 (95% CI 0.26-0.97), p=0.04, I2=37%

Keep in mind: Only 4 trials assess severe community-acquired pneumonia Only 5 trials looked at prolonged treatment

7 days (4) 9 days (1)

PLoS One. 2012; 7(10): e47926

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Conclusions

Although Blum et al. showed a benefit regardless of pneumonia severity, the 2012 meta-analysis by Nie et al. demonstrated a mortality benefit in severe CAP or those given prolonged corticosteroid treatment > 5 days

Other than an increased risk of hyperglycemia in the corticosteroid group, rates of GI bleeding and superinfection were the same

Heterogeneity was low, but is it reasonable to combine data from 4 different continents (Europe, North America, Africa, and Asia) where antibiotic/antiviral usage, etiologies, resistance rates, and populations likely differ?

Perhaps it is better left to a large, specific, well-designed RCT?

PLoS One. 2012; 7(10): e47926

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Corticosteroids for Community-Acquired PneumoniaPutting it all together

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Discussion

It is still unclear what cohort of patients will benefit most, as there are many variables that can affect pneumonia risk, severity, and morbidity/mortality

Clinical criteria needs to be more specific to better answer the question

If the question of corticosteroids and mortality in CAP is to be adequately addressed, much larger RCTs need to be conducted

More power to detect differences in a more representative patient sample

Although there is unclear evidence for a mortality benefit in any severity of CAP, even a 1 day reduction in hospital stay carries significant cost savings, however, at the expense of in-hospital hyperglycemia requiring insulin

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Remaining Questions

What about patients with CAP and septic shock with adrenal insufficiency?

Do corticosteroids reduce the incidence of acute respiratory distress syndrome secondary to CAP?

Are corticosteroids more effective in Staphylococcus aureus pneumonia than in Streptococcus pneumonia? What about viral pneumonia? Atypical pneumonia?

Does immunization or smoking status play a large role?

Outpatient vs. Inpatient vs. ICU?

Chest, 136(6), 1631-1643

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Summary

The most recent randomized controlled trial evidence suggests reduced in-hospital instability, length of stay, and treatment failure when using short term corticosteroids for the treatment of community-acquired pneumonia. Even though a recent meta-analysis suggest a possible mortality benefit in severe pneumonia and with prolonged treatment, it is difficult to apply the meaning of these endpoints to patients in clinical practice.

At best there is evidence for potential cost savings due to reduced length of stay, but weighed against the risk of in-hospital hyperglycemia requiring insulin

Until a more definitive conclusion is drawn, there is no clear role for corticosteroids in the treatment of community-acquired pneumonia and they should not be routinely used

Lancet 2015; 385: 1511–18, Jama, 313(7), 677-686, PLoS One. 2012; 7(10): e47926

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Questions?

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References

Limper, A. H. (2012). Overview of Pneumonia. In L. Goldman, & A. I. Schafer, Goldman's Cecil Medicine, Twenty-Fourth Edition (pp. 587-596). Philadelphia: Elsevier.

Feldman, C., & Anderson, R. (2015). Community-acquired pneumonia: Pathogenesis of acute cardiac events and potential adjunctive therapies. Chest, doi:10.1378/chest.15-0484; 10.1378/chest.15-0484

Raut, M., Schein, J., Mody, S., Grant, R., Benson, C., & Olson, W. (2009). Estimating the economic impact of a half-day reduction in length of hospital stay among patients with community-acquired pneumonia in the US. Current Medical Research and Opinion, 25(9), 2151-2157. doi:10.1185/03007990903102743; 10.1185/03007990903102743

Nannini, L. J., Lasserson, T. J., & Poole, P. (2012). Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. The Database of Systematic Reviews, 9, CD006829. doi:10.1002/14651858.CD006829.pub2; 10.1002/14651858.CD006829.pub2

Almirall, J., Bolibar, I., Balanzo, X., & Gonzalez, C. A. (1999). Risk factors for community-acquired pneumonia in adults: A population-based case-control study. The European Respiratory Journal, 13(2), 349-355.

Ellison, R. T., & Donowitz, G. R. (2015). Acute Pneumonia. In J. E. Bennett, R. Dolin, & M. J. Blaser, Mandell's Priniciples and Practice of Infectious Diseases (pp. 823-846). Philadelphia: Elsevier.

Kellum, J. A., Kong, L., Fink, M. P., Weissfeld, L. A., Yealy, D. M., Pinsky, M. R., et al. (2007). Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the genetic and inflammatory markers of sepsis (GenIMS) study. Archives of Internal Medicine, 167(15), 1655-1663. doi:10.1001/archinte.167.15.1655

Yende, S., D'Angelo, G., Kellum, J. A., Weissfeld, L., Fine, J., Welch, R. D., et al. (2008). Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. American Journal of Respiratory and Critical Care Medicine, 177(11), 1242-1247. doi:10.1164/rccm.200712-1777OC; 10.1164/rccm.200712-1777OC

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References

Martinez, R., Menendez, R., Reyes, S., Polverino, E., Cilloniz, C., Martinez, A., et al. (2011). Factors associated with inflammatory cytokine patterns in community-acquired pneumonia. The European Respiratory Journal, 37(2), 393-399. doi:10.1183/09031936.00040710; 10.1183/09031936.00040710

de Gans, J., & van, d. B. (2002). Dexamethasone in adults with bacterial meningitis. N Engl J Med, 347(20), 1549-1556. doi:10.1056/NEJMoa021334 Brouwer, M. C., McIntyre, P., Prasad, K., & van de Beek, D. (2013). Corticosteroids for acute bacterial meningitis. The Cochrane Database of Systematic Reviews, 6,

CD004405. doi:10.1002/14651858.CD004405.pub4; 10.1002/14651858.CD004405.pub4 van de Beek, D., & de Gans, J. (2004). Dexamethasone and pneumococcal meningitis. Annals of Internal Medicine, 141(4), 327. Prasad, K., & Singh, M. B. (2008). Corticosteroids for managing tuberculous meningitis. The Cochrane Database of Systematic Reviews,(1):CD002244. doi(1),

CD002244. doi:10.1002/14651858.CD002244.pub3; 10.1002/14651858.CD002244.pub3Ewald, H., Raatz, H., Boscacci, R., Furrer, H., Bucher, H. C., & Briel, M. (2015). Adjunctive corticosteroids for pneumocystis jiroveci pneumonia in patients with HIV infection. The Cochrane Database of Systematic Reviews, 4, CD006150. doi:10.1002/14651858.CD006150.pub2; 10.1002/14651858.CD006150.pub2

Mandell, L. A., Wunderink, R. G., Anzueto, A., Bartlett, J. G., Campbell, G. D., Dean, N. C., et al. (2007). Infectious diseases society of America/American thoracic society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 44 Suppl 2, S27-72. doi:10.1086/511159

Blum, C. A., Nigro, N., Briel, M., Schuetz, P., Ullmer, E., Suter-Widmer, I., et al. (2015). Adjunct prednisone therapy for patients with community-acquired pneumonia: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet, 385(9977), 1511-1518. doi:10.1016/S0140-6736(14)62447-8; 10.1016/S0140-6736(14)62447-8

Johnstone, J., Marrie, T. J., Eurich, D. T., & Majumdar, S. R. (2007). Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia. Archives of Internal Medicine, 167(18), 1938-1943. doi:10.1001/archinte.167.18.1938

Herzog, N. S., Bratzler, D. W., Houck, P. M., Jiang, H., Nsa, W., Shook, C., et al. (2003). Effects of previous influenza vaccination on subsequent readmission and mortality in elderly patients hospitalized with pneumonia. The American Journal of Medicine, 115(6), 454-461.

Meijvis, S. C., Hardeman, H., Remmelts, H. H., Heijligenberg, R., Rijkers, G. T., van Velzen-Blad, H., et al. (2011). Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: A randomised, double-blind, placebo-controlled trial.Lancet, 377(9782), 2023-2030. doi:10.1016/S0140-6736(11)60607-7; 10.1016/S0140-6736(11)60607-7Torres, A., Sibila, O., Ferrer, M., Polverino, E., Menendez, R., Mensa, J., et al. (2015).

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References

Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. Jama, 313(7), 677-686. doi:10.1001/jama.2015.88; 10.1001/jama.2015.88dex

Wunderink, R. G. (2015). Corticosteroids for severe community-acquired pneumonia: Not for everyone. Jama, 313(7), 673-674. doi:10.1001/jama.2015.115; 10.1001/jama.2015.115

Sligl, W. I., Asadi, L., Eurich, D. T., Tjosvold, L., Marrie, T. J., & Majumdar, S. R. (2014). Macrolides and mortality in critically ill patients with community-acquired pneumonia: A systematic review and meta-analysis. Critical Care Medicine, 42(2), 420-432. doi:10.1097/CCM.0b013e3182a66b9b; 10.1097/CCM.0b013e3182a66b9b

Steinberg, K. P., Hudson, L. D., Goodman, R. B., Hough, C. L., Lanken, P. N., Hyzy, R., et al. (2006). Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. The New England Journal of Medicine, 354(16), 1671-1684. doi:10.1056/NEJMoa051693

Belum, G. R., Belum, V. R., Chaitanya Arudra, S. K., & Reddy, B. S. (2013). The jarisch-herxheimer reaction: Revisited. Travel Medicine and Infectious Disease, 11(4), 231-237. doi:10.1016/j.tmaid.2013.04.001; 10.1016/j.tmaid.2013.04.001

Nie, W., Zhang, Y., Cheng, J., & Xiu, Q. (2012). Corticosteroids in the treatment of community-acquired pneumonia in adults: A meta-analysis. PloS One, 7(10), e47926. doi:10.1371/journal.pone.0047926; 10.1371/journal.pone.0047926

Meduri, G. U., Annane, D., Chrousos, G. P., Marik, P. E., & Sinclair, S. E. (2009). Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest, 136(6), 1631-1643. doi:10.1378/chest.08-2408; 10.1378/chest.08-2408

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Severe Community-Acquired Pneumonia

Minor criteria• Respiratory rate > 30 breaths/min• PaO2/FiO2 ratio ≤250• Multi-lobar infiltrates• Confusion/disorientation• Uremia (BUN level ≥20 mg/dL)• Leukopenia (WBC count <4000 cells/mm3)• Thrombocytopenia (platelet count <100,000

cells/mm3)• Hypothermia (core temperature <36ᵒC)• Hypotension requiring aggressive fluid

resuscitation

Major Criteria• Invasive mechanical ventilation• Septic shock with need for vasopressors

Criteria for severe community-acquired pneumonia*

*Require 3 minor criteria or 1 major