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Asthma biomarkers: FENO
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Asthma Biomarkers; FENO …

Asthma Biomarkers; FENO

Presented by Theerapan Songnuy, MD.

March1, 2013

Published in Health & Medicine
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  • 1. Theerapan Songnuy, M.D.
  • 2.  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.
  • 3.  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.
  • 4.  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.
  • 5.  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.
  • 6.  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.
  • 7.  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.
  • 8.  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.
  • 9.  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
  • 10.  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)
  • 11.  Not associated with neutrophilic airway Inflammation Children younger than 4 years False negative in patient already treated with ICS
  • 12.  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.
  • 13. www.ergonomidesign.se
  • 14. Pediatr Allergy Immunol 2012; 23: 59-64.
  • 15.  To study association between exhaled nitric oxide, asthma and atopy in a variety clinically relevant phenotypes in a cohort of 6-year-old children
  • 16.  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.
  • 17. 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.
  • 18.  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.
  • 19.  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.
  • 20.  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.
  • 21. At birth 3-mo. 15-mo. 6 yr. 6 yr. 1064 1011 681 1105 (96.3%) (91.4%) 846 (62%) Attend Lab complete FENO test Pediatr Allergy Immunol 2012; 23: 59-64.
  • 22. Pediatr Allergy Immunol 2012; 23: 59-64.
  • 23. Pediatr Allergy Immunol 2012; 23: 59-64.
  • 24. Pediatr Allergy Immunol 2012; 23: 59-64
  • 25. Pediatr Allergy Immunol 2012; 23: 59-64
  • 26. Pediatr Allergy Immunol 2012; 23: 59-64
  • 27.  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
  • 28. JACI. 2011; 127 ( 5) : 1165-72.e5.
  • 29.  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
  • 30.  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.
  • 31. 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.
  • 32. Participants :Enrolled F/U until age 12 y FENO measurement 430 277 505 ( 64%) (85%) JACI. 2011; 127 ( 5) : 1165-72.e5.
  • 33.  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
  • 34.  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
  • 35. 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
  • 36. 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
  • 37. 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
  • 38. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 39. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 40. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 41. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 42. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 43. JACI. 2011; 127 ( 5) : 1165-72.e5
  • 44.  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
  • 45.  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
  • 46. THANK YOU VERY MUCH