Establishing standard definitions and data collection methodologies for validated outcomes measures in asthma clinical research Identifying promising outcomes measures for asthma clinical research that require further developmentSzefler SJ et al. Asthma outcomes: Biomarkers. JACI. 2012; 129( 3Suppl):S9-23.
Core outcome - A set of asthma outcomes considered by NIH and other agencies as requirement for funding support : Multi-allergen screening to define atopySzefler SJ et al. Asthma outcomes: Biomarkers. JACI. 2012; 129( 3Suppl): S9-23.
Standard definitions have been developed, method for measurement can be specified, validity has been proved but whose inclusion in funded clinical asthma research will be optional - CBC to measure total eosinophils - Fractional exhaled nitric oxide ( Feno) - Sputum eosinophils - Urinary leukotrienes - Total and allergen-specific IgESzefler SJ et al. Asthma outcomes: Biomarkers. JACI. 2012; 129( 3Suppl): S9-23.
Have potential to : expand/ improve current aspects of disease monitoring and improve translation of basic and animal model-based asthma research into clinical research. They are not yet standardized and need more development and validation - Sputum PMN leukocytes - Cortisol measures - Airway imaging - Breath markers - System-wide studies ( genomics, proteomics)Szefler SJ et al. Asthma outcomes: Biomarkers. JACI. 2012; 129(3Suppl): S9-23.
Nitric Oxide ( NO) is an pollutant emitting from vehicle and cigarette smoke A biological mediator in animal and human Produced by human lungs Roles of NO: - Vasodilator - Bronchodilator - Neurotransmitter - Inflammatory mediatorPalmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-666.Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994; 78: 915-918.
Highly reactive molecule/ free radical and has oxidant property Bactericidal and cytotoxicity for tumor cell Pathophysiology of NO in airway and lung: - A pro-inflammatory mediator lead to airway hyper-responsiveness Reid DW, Johns DP, Feltis B, Ward C, Walters EH. Exhaled nitric oxide continues to reflect airway hyperresponsiveness and disease activity in inhaled corticosteroid- treated adult asthmatic patients. Respirology. 2003; 8: 479-486.
FENO used as quantitative method of airway nitric oxide ( NO), produced by NO synthases Noninvasive, simple, and safe method An indirect marker for eosinophilic airway inflammation Support diagnosis of eosinophilic asthma Determining corticosteroid responsiveness ( more consistently than other methods) Evaluation of adherence to anti-inflammatory drugsDweik RA et al. An official ATS clinical practice guideline: Interpretation of exhaled nitric oxide levels ( (FENO) for clinical applications. Am J Respir Crit Care Med. 2011; 184: 602-615.
Low FENO ( < 25 ppb in adult, < 20 ppb in kids) - Less likely eosinophilic inflammation & responsiveness to corticosteroid High FENO ( > 50 ppb in adult, > 35 ppb in kids) - More likely for eosinophilic inflammation & in symptomatic patient, more response to corticosteroid
Significant increase in FENO - Greater than 20% ( if value > 50 ppb) - More than 10 ppb ( if value < 50 ppb) Significant decrease in FENO - Greater than 20% (if value > 50 ppb) - More than 10 ppb ( if value < 50 ppb)
Not associated with neutrophilic airway Inflammation Children younger than 4 years False negative in patient already treated with ICS
Age , FENO increase 5% per year ( important in children) Height Atopic symptoms Smoking Anti-inflammatory drugs Measurement technique Exhalation flow rate Nasal NO contamination NO analyzer usedBorrill Z, Clough D, Truman N, Morris J, Langley S, Singh D, A comparison of exhaled nitric oxide measurements performed using three different analyzers. Respir Med 2006; 100: 1392-1396.Buchvald F et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. JACI 2005;115: 1130-1136.
To study association between exhaled nitric oxide, asthma and atopy in a variety clinically relevant phenotypes in a cohort of 6-year-old children
The New Zealand Asthma and Allergy Cohort Study At Wellington and Christchurch From 1997-2001 Participants: - Mothers were recruited randomly by midwives ( previous study) - Questionnaires were administered by nurses at start, 3, 15, 24, 36, 48 & 60 mo of age - Home visit at 3 & 15 months & others by telephone - Outcomes were measured at 15, 36, 48 & 60 monthsEpton M, Town G, Ingham T, et al. The New Zealand infant cohort study : assembly, demographics and investigations. BMC Public Health 2007; 7: 26.Pediatr Allergy Immunol 2012; 23: 59-64.
Participants: - Between the ages of 6-7 years - Questionnaires & clinical assessments : - FENO measurement - SPT to food & environmental allergens - Blood for total & specific IgEMeasurement of exhaled nitric oxide : - Using Aerocrine NIOX chemiluminescence analyser at flow rate 50 ml/s - Range of detection from 2- 200 p.p.b. - FENO was measured according to American Thoracic Society / European Respiratory Society guidelines - Before NO measurement, mothers were asked whether the child had a cold, respiratory infection or had exercised a last hour before Pediatr Allergy Immunol 2012; 23: 59-64.
SPT: - Allergens: Der p, cat, dog, horse, cockroach mix, rye grass, olive tree, Aspergillus fumigatus, peanus, Alternaria tenuis, egg white, & cow’s milk ( Dome/ Hollister-Stier, Spokane, WA, USA) - Mean wheal diameter was measured - A positive reaction defined as a mean wheal diameter of 3 mm or greater - Atopy defined as positive one or more reaction to SPT Pediatr Allergy Immunol 2012; 23: 59-64.
Wheezing, asthma & family history definitions - Mother/caregiver was asked for child’s wheezing at each visit - Wheezing classified as: - Early transient ( occur from birth to 3 y ) - Late onset ( from 3-6 y) - Persistent wheeze ( from birth-6 y) - Current asthma ( previous doctor’s diagnosis of asthma at any time & current wheeze, inhaler use - A family history of allergic disease ( a parental report of either parent having a history of asthma, allergic rhinitis or eczema ) Pediatr Allergy Immunol 2012; 23: 59-64.
IgE measurement - Total IgE - Specific IgE - These were measured by IMMULITE 2000 Siemens Medical, Deerfield, IL, USA - Atopy defined as any sIgE 0.35 kU/l or more Pediatr Allergy Immunol 2012; 23: 59-64.
FENO is closely related to specific IgE to aeroallergens among allergic children The main factor of airway inflammation is sIgE to aeroallergen & to Der p that children have continually exposed at a high level FENO is not elevated in non-allergic asthma Children
Whether FENO was increased in children with allergic sensitization or asthma Whether specific allergen exposure increased FENO level in sensitized , but not in un-sensitized children Whether sedentary behavior increased FENO, independent of allergen exposures JACI. 2011; 127 ( 5) : 1165-72.e5
Children whose mothers reside in Boston Metropolitan area Between Sep 1994-Aug 1996 ( cohort study)* Children whose mothers: - Age at least 18 y - History of hay fever, asthma, or allergy in at least one of the child’s parents - Families were not screened if NB was admitted in NICU, maternal gestational age < 36 wk or he/she had a congenital anomaly *Gold DR, Burge HA, Carey V, Milton DK, Platts-Mills T, Weiss ST. Predictors of repeated wheeze in the first year of life : The relative roles of cockroach, birth weight, acute lower respiratory illness , and matrnal smoking. Am J Respir Crit Care Med. 1999; 160(1): 227-36. JACI. 2011; 127 ( 5) : 1165-72.e5.
A series of home visit: - At age 2-3 months, 7 y, 12 yQuestionnaires : by trained research assistants ( home visit) - Demographics - Home characteristics - Environmental exposures - Tobacco use - Health outcomesQuestionnaires : by telephone every 6 months JACI. 2011; 127 ( 5) : 1165-72.e5.
Participants :Enrolled F/U until age 12 y FENO measurement 430 277 505 ( 64%) (85%) JACI. 2011; 127 ( 5) : 1165-72.e5.
Home visit & dust sample collection - Measurement of bed dust mite ( by Eureka Mighty-Mite vacuum cleaner : Model 3621; Eureka Co. , Bloomington IN) modified to hold 19*90 mm cellulose extraction thimbles - All layers of the bedding were vacuumed for 10 min - Allergen concentrations (ug/g dust) for Der p1,Der f1, Fel d1, Bla g2 quantified by ELISA - Cut off point : for Der p 1, Der f1 greater than 10 ug/g for Cat allergen greater than 8 ug/g for Cockroach above detectable levels JACI. 2011; 127 ( 5) : 1165-72.e5
Assessment of allergic sensitization - Specific IgE to common ( outdoor & indoor) allergens were done using the UniCap 250 system in 189 children - Positive test was greater than 0.35 IU/ml - Specific IgE + SPT + FENO in 208 children JACI. 2011; 127 ( 5) : 1165-72.e5
Assessment of TV watching /video game playing - Collecting data every 6 months by telephone - Using the closest time to FENO measurement - Assess hour of weekday & weekend separately - Categories: ( none, 1-5 hr, 6-10 hr, 11-15 hr, or 16-20 hr) - Also ask for “ physical activity” day/weekDefinition of respiratory symptom outcomes - Collecting every 6 months by telephone - Outcomes: current asthma; any wheeze; dry cough at night; current rhinitis JACI. 2011; 127 ( 5) : 1165-72.e5
Spirometry:- Albuterol was administered ( 180 ug; 2 puffs with spacer) & wait 10 min- Apply spirometry before & after medication- Positive bronchodilator response : 12% increase in FEV1 JACI. 2011; 127 ( 5) : 1165-72.e5
Measurement of FENO :- FENO level by using a portable electrochemical device ( NIOX MINO); Aerocrine AB- Validated by chemiluminescene technology; +-5 ppb- Subject breathed in through an NO scrubbing filter & exhaled out into the room air twice- Then inhaled a third time through the filter & exhaled into the FENO analyzer- Flow rate of 50 ml/s without a nose clip- The last 3 seconds of exhalation was assessed- This procedure was done 3 times, the median value was used JACI. 2011; 127 ( 5) : 1165-72.e5
The first study to investigate the independent impact of home allergens and sedentary home behavior on FENO in high risk children for allergies & asthma - Sensitization : predictor of airway inflammation - Allergic sensitization : key factor in NO production - Sedentary behavior has positive association with FENO
FENO : used as a biomarker in assessment and management of airway inflammatory disease FENO is a noninvasive, ease of repeat measurement, & easy use in patients