Dexamethasone in community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a common infection. Approximately 20
percent of all episodes of pneumonia result in hospitalization. It is the
leading cause of community-acquired infection requiring intensive care unit
(ICU) admission. Especially elderly patients may have a severe illness with a
high morbidity and mortality rate. In pulmonary infections, the release of
cytokines and other inflammatory mediators from alveolar macrophages serves as
a mechanism by which invading pathogens are eliminated. However, this reaction
of the innate immune system can be potentially harmful when excessive release
of circulating inflammatory cytokines causes damage to the patient,
particularly the lung. Interest in the role of corticosteroids in the
pathophysiology of critical illness has existed since the early part of the
20th century. On ICU, early treatment with corticosteroids to attenuate
systemic inflammation is widespread. At the same time, outside the ICU little
evidence is available on the effect of treatment with corticosteroids in
patients diagnosed with CAP. Theoretically, early initiated administration of
corticosteroids in the course of a CAP can lower systemic and pulmonary
inflammation. This may lead to earlier resolution of pneumonia and a reduction
of complications (sepsis, mortality).

The present study is designed to confirm the beneficial effects of adjunctive
dexamethasone therapy in a larger sample of patients with pneumonia,
additionally aiming at assessing what patients benefit from dexamethasone
treatment mostly. To do so, a large multicenter study will be conducted
comparing a 4 days dexamethasone 6 mg per os course with placebo in 600
patients and with predefined subgroup analyses planned.

Primary Objective:
- To confirm the effect of dexamethasone on clinical outcome in patients
admitted with CAP.

Secondary Objectives:
- To study what patients admitted with CAP benefit most from dexamethasone
therapy. Predefined subgroup analysis based on:
o disease severity score (PSI 1-3 vs. PSI 4-5);
o CRP level at admission;
o causative microorganism (Pneumococcus antigentest positive vs. negative);
o cytokine response (IL-6 and IL-10) over time;
o cortisol level over time;
o procalcitonin over time.

Prospective, randomized, double-blinded, placebo controlled, multiple centre,
intervention study.

Patients presenting with a community-acquired pneumonia, eligible for inclusion
in the study, are treated with one bolus of dexamethasone 6 mg (1 tablet of 6
mg) on the emergency department and dexamethasone 6 mg once daily for the
following 3 days.

Burden: In this study participants are required to take one tablet (either
dexamethasone or placebo) daily during the first four days of admission. Data
collected for this study are in part data collected in routine clinical care.
Blood samples are taken daily as part of routine care. Additional blood
samples are collected for the study at timepoints that venapuncture is
performed as part of routine clinical care. Participants are requested to fill
a quality of life questionnaire twice. We refer to Appendix 6 for an overview
of blood sampling and other tests. In this appendix a distinction is made
between routine clinical care and study related procedures.

Risks: Participants taking placebo are not expected to run a study related
risk. Some adverse side effects have been attributed to corticosteroids, like
hyperglycaemia or opportunistic infections. In the recent Ovidius study the
most frequently observed side effects of dexamethasone was hyperglycaemia.
There was no increased need of glucose lowering therapy in the treatment group.
. For a detailed description we refer to section 7.1
Potential Benefits: The aim of the study is to confirm the faster recovery of
patients treated with dexamethasone, leading to a reduced length of stay.
Additionally we hope to demonstrate a reduced mortality in patients admitted
with more severe pneumonia (PSI 4-5).