Effect of a 10,000 EU Dose of Endotoxin in Allergic and Mildly Asthmatic Adults
Effect of a 10,000 EU Dose of Endotoxin in Allergic and Mildly Asthmatic Adults
The purposes of this pilot safety study are to identify a dose of inhaled Clinical Center
 Reference Endotoxin (CCRE) that is well tolerated by allergic subjects that induces
 measurable increases in neutrophil content of induced sputum that can be employed to screen
 large populations for susceptibility to the inflammatory effect of inhaled endotoxin.
Twenty-four or forty-eight hours (study day 1) prior to the inhalation challenge, subjects
 will undergo a physical examination of the ears, nose, throat and chest and will have an
 assessment of vital signs (temperature, pulse, respiratory rate, blood pressure), oxygen
 saturation, symptom score assessment and undergo spirometry to rule out acute illness prior
 to challenge. All female volunteers will undergo a urine pregnancy test. A similar
 examination will take place immediately prior to inhalation challenge with 10,000 EU of CCRE,
 as well as 30, 60, 120, 180, 240, 300 and 360 minutes and 24 hours after challenge (with the
 exception of a pregnancy test which will only be administered prior to sputum induction on
 study day 1). Induced sputum will be 24 to 48 hours prior to challenge, and again six hours
 after challenge on Study day 2. Sputum will be analyzed for PMN content, CD14 expression on
 airway macrophages and monocytes, soluble CD14 levels, cytokine levels in sputum and products
 of inflammatory cells (eosinophil, cationic protein, myeloperoxidase). Blood will be
 collected for a CBC and differential when the pre- challenge induced sputum is obtained and
 again 6 hours after challenge. Subjects will then be escorted to the GCRC for overnight
 admission. While on the GCRC, vital signs will be obtained every 2 hours till bedtime, then
 once a shift. Spirometry will not be obtained while the subject is in the GCRC, however the
 subject will be given symptom scoring cards. The next morning (study day 3) subjects will be
 discharged and escorted to the CEMALB for a final set of vital signs, spirometry, symptom
 scoring, and an examination by a study physician.

 Each volunteer will be given a symptom scoring sheet for each day up to 96 hours (4 days)
 after challenge.

 Each sheet will include the name and phone number of the study coordinator and study MD.
 Sample home symptom scoring sheets and instructions are included with this protocol.

 Between 48 and 96 hours after challenge, each volunteer will be called to determine their
 status, inquiring about symptoms, symptom scoring, and need for medication and/or physician
 visits.

 Between 7 and 10 days of the challenge dose, each subject will be asked to return for a study
 discontinuation visit. At that time temperature, pulse, systolic and diastolic BP,
 respiratory rate, FVC and FEV1 and SpO2 (oxygen saturation), and symptoms scores will be
 assessed and, if abnormal, medical evaluation as directed by the study physician will be
 undertaken.
Inclusion Criteria:

 -  Inclusion criteria

 -  Specific allergy to at least one of the following allergen preparations: (House Dust
 Mite f, House dust mite p, Cockroach, Tree mix, Grass Mix, Weed Mix, Mold Mix 1, Mold
 Mix 2, Rat, Mouse, Guinea Pig, Rabbit, Cat or Dog) confirmed by positive immediate
 skin test response.

 -  FEV1 of at least 80% of predicted and FEV1/FVC ratio of at least .75 (without use of
 bronchodilating medications for 12 hours), consistent with lung function of persons
 with no more than mild episodic or mild persistent asthma.

 -  History of nasal allergy, including episodic, perennial, or seasonal sneezing, nasal
 congestion or cough, or such symptoms associated with specific exposures (such as cat
 or dog)

 Criteria for classification as having asthma with allergic rhinitis vs. allergic rhinitis
 alone:

 -  History of episodic wheezing, chest tightness, or shortness of breath consistent with
 asthma, or physician diagnosed asthma.

 -  Provocative concentration of methacholine producing a 20% fall in FEV1 (PC20
 methacholine) of less than 10 mg/ml by the method used (see below).

 Exclusion Criteria:

 -  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.

 -  Physician directed emergency treatment for an asthma exacerbation within the preceding
 12 months.

 -  Use of systemic steroid therapy within the preceding 12 months for an asthma
 exacerbation. All use of systemic steroids in the last year will be reviewed by a
 study physician.

 -  Use of inhaled steroids, cromolyn or leukotriene inhibitors (Montelukast or
 zafirkulast) initiated within the past month (except for use of cromolyn exclusively
 prior to exercise). Patients must be on a stable regimen of therapy and shown to be
 stable.

 -  Use of daily theophylline within the past month.

 -  Pregnancy or nursing a baby.

 -  Cigarette smoking > 1 pack per month.

 -  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.

 -  Exacerbation of asthma more than 2x/week 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.

 -  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).

 -  Dosing level of an inhaled steroid must be consistent with mild episodic asthma as
 outlined by the NHLBI NAEPP guidelines. Any dose of inhaled steroid typically used for
 moderate or severe asthma will result in exclusion from the protocol.

 -  Viral upper respiratory tract infection within 2 weeks of challenge.

 -  Any acute infection requiring antibiotics within 2 weeks of challenge.