P4 Peptide in Community Acquired Pneumonia

The investigators will examine the response to P4 peptide of alveolar macrophages from bronchoalveolar lavage (BAL) and neutrophils from peripheral blood collected from patients with severe pneumonia admitted to the ITU.

The investigators expect to show improved phagocytosis, oxidative burst, cellular activation (flow cytometry, electron microscopy, cytokine production, transcriptomics) and bacterial killing when P4 is used to stimulate immune cells and this may lead to a novel approach to the treatment of severe infections.

The investigators will also examine the effect of P4 on alveolar macrophages and neutrophils from healthy volunteers in order to ensure comparability with previously published results and extend observations using S.pneumoniae to other causes of severe pneumonia including E.coli, Salmonellae, M.tuberculosis and Pseudomonas.

Augmented passive immunotherapy (API) is a novel potential treatment strategy to combat fulminant bacterial infections. It consists of two components

• a peptide that enhances bacterial uptake and killing by phagocytes.
• exogenous antibody (provided with intravenous immunoglobulin, a licensed medicinal product) which optimizes the phagocytosis. Previous studies of API have included extensive murine studies of acute and chronic bacterial infection with several different organisms. P4 has also been tested in aged mice and in mucosal administration.

The investigators will recruit patients with severe community acquired pneumonia on ICU and healthy volunteers using carefully established inclusion and exclusions criteria.

This research seeks to establish proof-of-concept for augmented passive immunotherapy in patients with severe pneumonia. Patients with mild to moderate pneumonia often respond to antibiotic therapy but those with severe community-acquired pneumonia who require admission to Intensive Care have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. These patients represent 6% of all admissions to Intensive Care Units in the UK. Strategies to improve clinical outcome for this group of patients are much needed and the investigators' research cohort has been selected to represent this group. The immunological characteristics of patients with overwhelming sepsis are likely to differ from patients with milder infection. Immune cells taken from patients with milder forms of sepsis may not respond to in vitro stimulation in the same way as cells taken from severely septic patients and therefore should not be used to establish proof-of-concept for a therapy intended for critically ill patients on Intensive Care.

Inclusion criteria

for ITU patients:

• Adults (>18y) with community acquired pneumonia.
• Diagnosis of CAP upon hospital admission requires: Radiographic shadowing unexplained by other causes plus Symptoms/signs consistent with acute lower respiratory tract infection.

Exclusion criteria

for ITU patients:

• Previous hospital admission within 14 days (implies hospital acquired).
• Immunocompromising comorbidity or therapy (e.g. HIV infection, chemotherapy).
• Pregnancy.
• Deemed inappropriate by responsible Intensivist. Already recruited in to an interventional study (where the study therapy may influence the results of this study).
• Failure to obtain consent.

Bronchoscopy Exclusion criteria (ITU patients):

• The patient does not require a bronchoscopy for clinical reasons
• The patient is not invasively ventilated therefore not requiring a bronchoscopy
• The patient condition deteriorates prior to bronchoscopy such that they might no longer tolerate the procedure (e.g. those progressing to require high frequency oscillation, prone-positioning, PEEP>15cmH2O or FiO2>0.8 for ventilation).
• Patient does not tolerate bronchoscopy, i.e. if there is oxygen desaturation to <90% for >60 seconds or haemodynamic disturbance during the procedure.
• The intensive care clinician responsible for the patient develops any new concerns about the safety of bronchoscopy or bronchoalveolar lavage.

Inclusion/ Exclusion Criteria for healthy volunteers:

• Adults (>18y).
• Able to give fully informed consent.
• Fluent English speaker.
• Non-smoking.
• Healthy adults without current illness.
• Contraindication to bronchoscopy or immunomodulatory medication.