Systemic Inflammatory Response to CCRE
Systemic Inflammatory Response to CCRE
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.
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.
Inclusion Criteria:

 1. Subjects must be 18-50 years of age to be eligible for study participation

 2. Subjects must be willing to and able to provide informed consent and participate in
 all study procedures

 3. Normal lung function, defined as (Knudson 1976/1984 predicted set):

 -  1. Forced Vital Capacity (FVC) of > 80% of that predicted for gender, ethnicity,
 age and height

 -  2. Forced Expiratory Volume in the first second (FEV1) of > 80% of that predicted
 for gender, ethnicity, age and height

 -  3. FEV1/FVC ratio of > 0.75 of that predicted for gender, ethnicity, age and
 height

 4. Oxygen saturation of > 94% Normal blood pressure (Systolic between 150 - 90, Diastolic
 between 90-60 mm Hg)

 5. Symptom Score (defined in section "f") no greater than 6 (out of a possible 24) for
 total symptom score with a value no greater than 2 for any one score.

 Exclusion Criteria:

 1. Any chronic medical condition considered by the PI as a contraindication to the
 exposure study including significant cardiovascular disease, diabetes requiring
 medication, chronic renal disease, or chronic thyroid disease.

 2. Physician directed emergency treatment for asthma exacerbation within the preceding 3
 months.

 3. Moderate or Severe asthma

 4. Exacerbation of asthma more than 2x/week that would be characteristic of a person of
 moderate or severe persistent asthma as outlined in the current NHLBI guidelines for
 diagnosis and management of asthma.

 5. Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a
 clearly recognized viral induced asthma exacerbation) which would be characteristic of
 a person of moderate or severe persistent asthma as outlined in the current NHLBI
 guidelines for diagnosis and management of asthma

 6. Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest
 tightness) which would be characteristic of a person of moderate or severe persistent
 asthma as outlined in the current NHLBI guidelines for diagnosis and management of
 asthma. (Not to include prophylactic use of albuterol prior to exercise).

 7. History of intubation for asthma

 8. Daily use of NSAIDs, or inability to withhold NSAIDs for 4 days prior to dosing.

 9. Use of medications that may impact the results of the study to include, but not
 limited to, systemic corticosteroids, beta blockers.

 10. Cigarette smoking > 1 pack per month.

 11. BMI>35.

 12. Pregnant or breast feeding women will not be included.

 13. Subjects who are employed within the past 6 months in an occupation with high risk for
 endotoxin exposure, such as grain storage sites or swine containment.

 14. Subjects will be deferred after any acute, non-chronic medical condition requiring
 treatment, such as bronchitis, pneumonia or febrile illness for a minimum of 4 weeks
 after complete resolution of symptoms.

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