Extended Steroid in CAP(e)

VA Cooperative Study #574 is designed to prospectively evaluate the efficacy of prolonged
glucocorticoid (methylprednisolone) treatment on short- (in hospital) and long-term (after
hospital discharge), morbidity and mortality in Veteran patients admitted to the ICU
(including intermediate care unit) with severe community-acquired pneumonia (CAP).

CAP is the sixth most common cause of death (acute mortality) in the United States and the
leading cause of community-acquired infection requiring intensive care unit (ICU) admission.
Despite significant advancements in medical care, there has been little change in crude
mortality from respiratory tract infection for more than 5 decades (1950-2000). In the
United States alone, over 1.3 million people were admitted to the hospital in 2002 with
severe CAP (262 per 10,000 population) with an estimated inpatient cost of approximately
$4.4 billion. In addition, severe CAP patients surviving hospitalization experience a
significant increase in long-term morbidity (cardiovascular complications, impaired
functional status, and recurrent hospitalizations) and a sizable mortality up to 1 year (up
to 25%) that is independent of patient's chronic health condition.

Dysregulated systemic inflammation, characterized by persistent elevation in circulating
inflammatory cytokine levels over time, is the central pathogenetic process contributing to
short- and long-term morbidity and mortality in patients with severe CAP. Even when patients
survive ICU and hospital admission, elevation in inflammatory cytokine lasts for greater
than 3 weeks, and interleukin (IL)-6 levels at hospital discharge predict subsequent
mortality. Endogenous and exogenous glucocorticoids are the most important physiologic
inhibitors of inflammation. In a meta-analysis of four, small, published studies that
included a total of 198 patients with severe CAP, prolonged glucocorticoid treatment was
associated with a significant reduction in short-term mortality (RR = 0.40, 95%CI 0.18-0.89;
p = 0.03; I2 12%). This Cooperative Studies Program study will be the first large-scale,
prospective, randomized clinical trial evaluating the efficacy of prolonged
methylprednisolone in the treatment of severe CAP.

In this study, at each site, patients with severe CAP will be randomized in a 1:1 ratio to
receive methylprednisolone or placebo in a double-blind fashion. The investigators have
chosen a total duration of treatment of 20 days (7 days full dose followed by slow reduction
over 13 days) to forestall relapse of systemic inflammation and allow recovery of the
suppressed hypothalamic-pituitary-adrenal (HPA) axis. All patients will also receive
standardized management of CAP in accordance with current practice guidelines. Randomization
will be stratified separately within each participating site by whether or not the patient
requires mechanical ventilation at the time of randomization. Patients will be followed
clinically for 180 days. The primary outcome is all cause 60-day mortality. Secondary
outcomes are (1) in-hospital morbidity-mortality, including ventilator-free days, multiorgan
dysfunction syndrome (MODS)-free days, duration of ICU and hospital stay, and hospital
discharge; and (2) posthospital discharge morbidity-mortality, including cardiovascular
complications, functional and general health status in the first 180 days,
rehospitalization, and mortality at 1 year. Serial blood samples will also be collected and
stored for future translational research relating longitudinal inflammation markers to
clinical outcomes.

Based on published studies and VA Decision Support System, the investigators estimate the
all cause 60-day mortality in severe CAP patients admitted to ICU is 28%. The investigators
hypothesize that prolonged methylprednisolone treatment will reduce the 60-day mortality
from 28% to 21% (a 25% relative reduction). A total of 1406 patients (703 per group) will be
required to give 85% power to detect this hypothesized improvement, using a two-sided 5%
significance level test. Adjusting for 1% attrition, the target sample size is 1420.
Assuming 5 years of accrual and an intake rate of 8 patients per year per VAMC, the
investigators will need 36 participating VAMCs.

Treatment of severe CAP is of particular importance to the VA health care system because of
the large patient population and because a single episode of severe CAP is associated with
significant short- and long-term morbidity and mortality. In fiscal year 2006, 17,890
patients were admitted to the VA hospital system with a diagnosis of CAP. Of these, 3727
(21%) required ICU admission during their hospital stay. For ICU-admitted patients,
mortality rates in the hospital at 60, 90, 180, and 365 days were 26%, 34%, 37%, 44%, and
51%, respectively. They had on average a hospital stay of 17.7 days with hospital costs of
$49,936, and 48% of them were readmitted within 12 months of hospital discharge. This study
will investigate the effects of an off-patent, inexpensive treatment that, based on strong
experimental and translational evidence and the encouraging findings of preliminary trials,
has the potential of significantly decreasing mortality and morbidity. Equally important,
this study will advance knowledge on the relationship between inflammation and long-term
outcome in severe CAP. Given that methylprednisolone is off-patent, there is little
incentive for the pharmaceutical industry to fund this study. The VA system with its
Cooperative Studies Program is uniquely suited to conduct the study.

Inclusion Criteria:

- Patient's origin. Patients are classified as having CAP if they are admitted directly
from outside the hospital, including private residence, nursing home, rehabilitation
center, other long-term care facility (health care-associated pneumonia-HCAP).

- Clinical diagnosis of CAP.

- Have radiographically confirmed pneumonia (new or progressive pulmonary infiltrate(s)
on chest radiograph or chest computed tomography scan consistent with bacterial
pneumonia) AND Have acute illness ( 7 days' duration) with at least three of the
following clinical signs or symptoms consistent with a lower respiratory tract
infection:

New or increased cough Purulent sputum or change in sputum character Auscultatory findings
consistent with pneumonia (e.g., rales, egophony, findings of consolidation) Dyspnea,
tachypnea, or hypoxemia (O2 saturation <90% on room air or PaO2 <60 mmHg) Fever greater
than 38 C oral (>38.5 C rectally or tympanically) or hypothermia (<35 C) White blood cell
count greater than 10,000 cells/mm3 or less than 4,500 cells/mm3 Greater than 15% immature
neutrophils (bands) irrespective of WBC count

- Diagnosis of severe CAP. Pneumonia of sufficient severity to require admission to the
ICU (including intermediate care unit) and meeting >1 major or > 3 minor modified
Infectious Diseases Society of America (IDSA)/American

Thoracic Society (ATS) criteria.:

- 1 Major Criteria

1. Use of invasive or noninvasive mechanical ventilation

2. Vasopressors for shock despite adequate fluid resuscitation

3. Arterial pH < 7.30 -OR > 3 Minor Criteria

1. New onset of confusion or disorientation

2. Hypothermia (core temperature 36 C)

3. Respiratory rate 30 breaths/min

4. Hypotension requiring aggressive fluid resuscitation

5. Uremia (BUN 20 mg/dL)

6. PaO2: FiO2 ratio 250 or SaO2:FiO2 ratio 250

7. Leukopenia (WBC count < 4000 cells/mm3)

8. Platelet count < 100,000 cells/mm3 or > 400,000 cells/mm3

9. Multilobar infiltrates

Exclusion Criteria:

- Patient's age 17 years or younger.

- Vasopressor-dependent shock requiring moderate-to-high dose vasopressor (i.e.,
norepinephrine 0.3 mcg/Kg/min) treatment for greater than 2 hours in patient
that is adequately fluid-resuscitated (at least 4 liters of crystalloids) WITH
central venous pressure (CVP) equal to or greater than 8 mm Hg for nonventilated
patients and equal to or greater than 12 mm Hg for ventilated patients. (See
explanation below)*

- Major gastrointestinal bleeding requiring transfusion of 5 units or more of
packed red blood cells within 3 months of current hospitalization.

- Any condition requiring 20 mg of prednisone equivalent/day for greater than 14
days, over the last 3 months.

- COPD with acute exacerbation requiring glucocorticoid treatment at hospital
admission. Patients with short-term glucocorticoid use (e.g., methylprednisolone
up to 300 mg within 5 days of randomization) will not be excluded.

- Patients enrolled in another experimental (interventional) protocol.

- Pregnancy, confirmed by urine or serum test.

- Presence of postobstructive pneumonia or cystic fibrosis.

- Clinical history consistent with aspiration of gastric content (i.e., loss of
consciousness or seizure).

- Active tuberculosis or fungal infection.

- Moribund patient (i.e., not expected to live more than 24 h) or with recent
(within 7 days) cardiopulmonary arrest, or with (known or suspected)
irreversible cessation of all brain function, or comfort measure status.

- Presence of preexisting medical condition that is irreversible and expected to
be fatal within 3 months.

- Patients with severe immunosuppression (i.e., HIV with CD4 <200),
neutropenia (less than 1000 neutrophils) not related to pneumonia, acute
burn injury, or receiving immunosuppressive or cytotoxic therapy for any
reason.

- Chronic severe cognitive impairment caused by dementia or central nervous
system pathologies (tumor, cerebro-vascular accident, infections, or head
injuries) as defined by the site investigator by obtaining medical history
and reviewing medical record.

- The physician doesn't feel the patient is a viable candidate for the study
(e.g., presence of hypersensitivity or previous severe adverse reaction to
cosyntropin or any glucocorticoid, history of adrenal insufficiency or
chronic systemic steroid use placing the patient at risk for relative
adrenal insufficiency).