Systemic Inflammatory Response to CCRE
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      Purpose: The purpose of this study is to classify volunteers as endotoxin-responders or
      non-responders following inhalation of 20,000 EU Clinical Center Reference Endotoxin (CCRE).
      Endotoxin is a commonly encountered bioaerosol and component of indoor and outdoor air
      pollution. For reasons that remain unclear, some individuals appear to be more susceptible to
      the inflammatory effects of inhaled endotoxin than are others, possibly owing to single
      nucleotide polymorphisms in the Toll-like receptor 4 (TLR4) gene that influence TLR4
      signaling and function. These susceptible individuals represent a population of particular
      interest for further mechanistic studies of the effects of endotoxin and for therapeutic
      trials. Susceptibility to inhaled endotoxin will be determined by measuring change in
      peripheral blood neutrophil counts, a biomarker of systemic inflammation, following inhaled
      CCRE. In our previous work, the investigators have found that inhalation of 20,000 EU CCRE is
      well tolerated and induces measurable increase in neutrophil content of peripheral blood in
      susceptible individuals. Our hope is that this CCRE inhalation protocol can be employed to
      screen large populations for susceptibility to the inflammatory effect of inhaled endotoxin.
    

Detailed description: 
      This is a single center, screening study involving recruitment of 18 normal volunteers (NV).
      The protocol is powered to compare absolute neutrophil count (ANC) in the blood 6 hours after
      inhalational challenge with CCRE compared baseline. In addition, as secondary endpoints, the
      investigators will evaluate inflammatory cytokine levels in systemic circulation and access
      for the presence of genes thought to be related to endotoxin response. Visits will be
      conducted by a study coordinator or other study staff, physical exams will be performed by
      the PI or other study physician.

      Eighteen subjects will be recruited. There will be no gender or ethnic restrictions, and
      subjects will be healthy volunteers. Prior to enrollment in this study, subjects will have
      participated in our protocol 98-0799 (screening and database study for the CEMALB). Data such
      as medical history and allergy skin testing collected during the screening protocol will be
      included with data in this study. Subjects with positive allergy skin testing will not be
      excluded. Spirometry will be performed to determine the current level of lung function.

      In order to identify those individuals who appear more susceptible to the systemic
      inflammatory effects of endotoxin exposure, subjects will undergo inhaled endotoxin challenge
      at the baseline visit followed 6 hours later by blood draw for complete blood count with
      differential to allow for calculation of absolute neutrophil count (ANC). Subjects will be
      considered "responders" if their peripheral ANC increases by at least 20% following inhaled
      endotoxin challenge.
    

Intervention name(s): CCRE
Intervention type(s): Drug
Intervention description(s): Endotoxin challenge: Subjects will undergo inhalation of 20,000 EU CCRE. The CCRE will be inhaled by subjects as a nebulized preparation using an ultrasonic nebulizer until the challenge solution is completely spent (generally 10 minutes).
Other intervention name(s): endotoxin, lipopolysaccharide (LPS)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: healthy