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Con l’ossido nitrico gestisco l’asma dei miei bambini molto meglio!

Usare i markers della flogosi atopica migliora la terapia dell’asma. E’ vero?

A. Kantar

Mito?A patient with a diagnosis of asthma tells her physician, “I'm really concerned about side effects and expense. Will thesemedications be safe and effective for me?”. The physician orders an asthmapharmacogenomic profile and a week later prescribesmedications according to the results of the profile.

Wechsler Am J Respir Crit Care Med 2005

One drug, many genomes

Many drugs, one genome

Phenotype:The visibile properties of an organism that are produced by the interaction of genotype and the environment

Webster’s New Collegiate Dictionary

In asthma “environmental stimuli” (allergens, viruses and just as importantly, various pharmacologic agents) differentially interact with this genetic makeup of the individual to produce the clinical, immunologic, and /or pathophysiologicphenotype that we observe.

How to deal with Management ?Utilize characteristics, biomarkers, and genetics to “profile” asthma ‘severity’ and controlSelect medications based on “driving factors” of disease presentation and predictors of responseMonitor response, assess reasons for treatment failure, and adjust therapy accordingly

Stratifying Phenotypes in the Heterogeneity of Airway Inflammation

Mucosal biopsyBAL

SputumBlood/urine

Markers in exhaled air

NO: in practice

EBC: promising

FENO Interpretation and Application

response to ICSin titrating/reducing ICSto monitor adherenceto predict relapseto guide managementto predict EIBto evaluate allergen exposure

Response/Reproducibility of FENO after ICS

Reproducibility of response

12 adult asthmatics*

FENO >80 ppb2 wks of 200ug/d BDP1> wk No therapy periods

*3 withdrawn failed to to return to baseline value

1 wk 1< wk <6

FEV1 No changes

Silkoff Chest 2001

FENO & Asthma Outcomes

Bates JACI 2003

Dose-Response of FENO after ICS

020406080

100120140160

FENO PC20 FEV1 Diff

basalplaceboBDP 100ugBDP 400ugBDP 800ug

Dose-response15 adult asthmaticsFENO >60 ppb4 wks follow-up1 wk therapy regimea) Placebob) BDP 100µgc) BDP 400µgd) BDP 800µg

Silkoff Chest 2001

Dose-Response of FENO after ICS

Silkoff Chest 2001

Therapy-Resistant FENO Elevation

42 Children 6-18 yrsStable for 3 moFENO>20ppb (Aerocrione)

Inhalation technique

ICS response

Pijnenburg Clin Exp Allergy 2005

Therapy-Resistant FENO Elevation

FENO before and 2 wks after increasing ICS in 36 atopic children

All were able to demonstrate optimalinhalation technique

Median ICS 400µg 1200µgBUD-equivalent (100-800)

Pijnenburg Clin Exp Allergy 2005

12-75 yrs46 pts (FeNO) groupFENO 15 ppb (cut-off)48 pts (GINA 2002) groupPhase 1: 3-13 moPhase 2: 12 moCSI (Fluticasone)

Mean daily dose:370 µg/day (FeNO)641 µg/day (GINA)

No significant differenceRate of exaerbationPulmoary functionUse of oral CSSputum Eos

Smith N Engl J Med 2005

FENO to Guide Management103 adults >18 yrs52 FENO group (atopy 62%, nasal polyps 11)51 BTS Gidelines (atopy 70%, nasal polyps 8)

Asthma Juniper score: 0-6 Score >1.57 double therapy Score<1.57 on 2 consecutive occasions therapy halved

FENO >26 ppb Increase ICSFENO<26 ppb on 2 consecutive occasions decrease ICSFENO<16 ppb decrease ICS

Shaw Am J Respir Crit Care Med 2007

FENO to Guide Management

FENO

Score

Total ICS 11% more in FENO

Shaw Am J Respir Crit Care Med 2007

FENO to Guide ManagementExaceb.freq/pat/yr0.09/0 FENO/Score

Exaceb.freq/pat/yr0.39/0.67FENO/Score

Score

FENO

FENO Score

Shaw Am J Respir Crit Care Med 2007

FENO + Symptoms in Titrating ICSsymptoms

46

39

n = 85Atopic asthma

6-18 yrs FENO & symptoms

1 yearVisit 0 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5FENO FENO FENO FENO FENO FENO

randomisation

FEV1 FEV1

PD20 PD20

diary card diary card diary card diary card diary card

Pijnenburg Am J Respir Crit Care Med 2005

FENO + Symptoms in Titrating ICSSymptoms

dyspnea, wheezing, cough; each day-night time, β2FENO & Symptoms

symptoms > 14FENO > 30 ppb

symptoms ≤ 14, first time

FENO ≤ 30 ppb &symptoms>14 =

symptoms ≤ 14, second timeFENO ≤ 30 ppb &

symptoms ≤ 14

Pijnenburg Am J Respir Crit Care Med 2005

FENO + Symptoms in Titrating ICSB

UD

or e

quiv

alen

tdos

e

FENO

Symptoms FENO

Symptoms

FENO every 3 monthsSymptoms group: decrease dose after 6 months of a stable conditionFENO group: decrease dose after a single low symptom score (more ICS?)

increase if FENO >30 even when symptoms were lowMore Inflammation in symptoms group

Pijnenburg Am J Respir Crit Care Med 2005

FENO + Symptoms in Titrating ICS

start 12 mo start 12 mo

Mea

n P

D20

Mch

(ug)

2.5 DD

1.1 DD

- similar cumulative ICS doses- similar clinical control- prendisone courses

8 in 7 pts FeNO+ symptoms (39)18 in 10 pts symptom (46)

- less bronchial hyperresponsive-ness in FENO +symptoms (58 pts)- more benefit in patients with low FENO 27* 31*

Pijnenburg Am J Respir Crit Care Med 2005

FENO to Reduce ICS40 children 10-14 yrsStable for 2 mo on ICS; Median ICS 400 (200-500 ug/day)Reduction 2 mo (dose halved)BHR, sputum Eos, FENO

Zacharasiewicz Am J Respir Crit Care Med 2005

FENO to Reduce ICS

PREDICTING LOSS OF CONTROL = EXACERBATION

Zacharasiewicz Am J Respir Crit Care Med 2005

FENO to Reduce ICSClinical Symptoms complete ICS withdrawal 30%

If used as indicator to prevent exacerbationExcluding children with FENO> 22would have prevented exacerbation in 11/14 (78%)

Excluding children with Sputum Eos > 3would have prevented exacerbation in 8/11 (72%)

If used as indicator not to reduce treatmentFENO > 22 could have prevented attempt to reduce ICS in 19/39 (39%)

Sputum Eos > 3 could have prevented attempt to reduce in 6/28 (21%)

Zacharasiewicz Am J Respir Crit Care Med 2005

31 children (6.2-14.8yrs)mild-moderate asthmaDesign:4 wks run-in (400µg x2 BUD) β2 on demand4 wks washout (no therapy)8 wks randomized treatment:

a) Low dose 200µg x2 BUD (n=15) b) No ICS (n=16)

β2 on demand all over the study

*

FENO to Monitor Adherence to ICS

Beck-Ripp Eur Respir J 2002

FENO to Predict Relapse37 asthmatic children; 29 atopic (RAST class>2)At discontinuation of ICS (100-400ug BUD/day)6 months stable because lack of symptomsNo leukotrienes antagonists

weeks

PEF

T-2 T0 T2 T4 T12 T24

FENO

Diary Card

SpirometryRelapsemore than one exacerbation/mo and/or exacerbations requiring oralor ICS use and/or need for rescue bonchodilators on 4 or more days/wk for at least 2 consecutive wks and/ormean diurnal PEF varaiability of >20%.

Pijnenburg Thorax 2005

FENO to Predict Relapse

Who relapsed ?

wide variations in FENO

initial FENO (in therapy) not predictive

no correlations with symptoms for no-relapse Pijnenburg Thorax 2005

FENO to Predict Relapse

0,00

10,00

20,00

30,00

40,00

50,00

Basal 2 wks 4 wks

FENO in the relapse/no relapse group ROC curve for FENO 4 wks after discontinuation

Pijnenburg Thorax 2005

111 children 7-16 yrsMild-moderate asthma stable well controlledAllergy 71%ICS 56.8 %EIB treadmillFENO (Aerocrine No system)

FENO to Predict EIB

∆ FEV1> 15% < 15%

Reactive Nonreactive

Patients 30 81

Allergy / Steroid therapy 80% / 57% 68% / 57%

Median FENO 29.5* (21-55) 10.2 (8-15)

Mean Basaline FEV1 89.1*(84-94) 101.1 (99-104)

Buchvald Chest 2005

FENO to Predict EIB+ ive prediticve value 44% 53%- ive prediticve value 96% 88%

9371

59 76

on 100-1600ug BUD steroid naïve

Buchvald Chest 2005

FENO after Allergen Exposure21 children, 6-16 yrsseasonal allergic asthma8 on ICS during seasonFENO (CLD 700 Al-MED)Spirometry

Baraldi Am J Respir Crit Care Med 1999

FENO after Allergen Exposure

6 wks study11 asthmatic childrenAge (5-13 yrs)Allergy: Brich pollen + OtherSeasonal asthma

Therapy:2 on ICS2 on MontelukastAll β2-agonists on demand

*During study + 2 on ICS

FENO NIOX MINO (Aerocrine) daily at home

Vahlkvist J Allergy Clin Immunol 2006

FENO after Allergen Avoidance

Misurina Home

20 asthmatic children

Age 6-15 yrs

T0 admission

T1 15 days

T2 3 mo

13 on ICS between T0-T1

FENO (Logan LR 2149)

FEN

O p

pb

FEV1 2.006 2.007 2.112 ECPµg/L 16.2 16.01 16.02

Piacentini J Allergy Clin Immunol 1999

FENO after Allergen Avoidance/Exposure

Misurina Home M

22 Children6-15 yrs, allergy HDM12 in FLUT < 200µg/d19 days exposure to HDMβ -2 on demand

6 pts reported symptomsfor at least 3 days at home

<0.05 µg/gdust

30.9 µg/gdust

FENO NIOX MINO (Aerocrine) daily at homeBodini Chest 2007

FENO PHENOTYPE

Patients with asthma are clinically quite diverse, have variable levels of FENO, and are often difficult to distinguish phenotypically from one another

Nitrite Game

Shin J Appl Physiol 2007

FENO and pH Dysregulation

Decrease in H+ decreases peripheral but not alveolar NO

Nitrous acid

FENO Sources & Handling

2-compartment modelthe sum of 2 contributions, the alveolar region and the airwayregion, which depends on 3 flow-independent parameters:

George J Appl Physiol 2004

FENO and NOS1 Genotypes

Genotypes with a high trinucleotide identify a cohort of patients who have lower and less variable levels of exhaled NO, In an asthmatic cohort harboring two alleles with > 12 AAT repeats, the contribution of NOS1 to the total FENO level may be diminished

Wechsler Am J Respir Crit Care Med 2000

FENO TODAY

Kharitonov Chest 2006

Taylor Thorax 2006FENO Range Eos Infla Action

If asymptomatic and taking ICSGood complianceReduce /withdraw dose

If asymptomaticIf asymptomatic No change in ICS if patient is stable

intermediate Present but mild

If asymptomatic No change in ICS if patient is stable

significant

low unlikely If symptomaticReview diagnosis: Wheezy bronchitis; CF; Congential abnormalities (malacia); PCD; GER; Neutrophilic asthma, Rhinosinusitis; Hyperventation; Vocal cord dysfunction

If symptomatic considerInfection (worsening)Allergen exposureCheck compliancePoor inhalation technique (shift to PMDI + spacer if on powder device)Inadequate ICS doseAdd therapy or Increase ICS

High or rise of 60% more since previous visit

If symptomatic considerHigh allergen exposureCheck compliancePoor inhalation technique (shift to PMDI + spacer if on powder device)Inadequate ICS doseImminent exacerbation or relapse Monitor/Therapy – Review

45-h

ighe

r

30-4

0

5-25

Diagnostic Accuracy of Canine Scent Detection in Early- and Late-Stage Lung and Breast Cancer

Biological Breathmeterin standby

McCulloch Integrated Cancer Therapies 2005