Exhaled Nitric Oxide in the Management of Paediatric Asthma

8/13/2019 Exhaled Nitric Oxide in the Management of Paediatric Asthma

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Exhaled Nitric Oxide In The Management Of Paediatric Asthma

Ratnawati *,***, John Morton **,***, Richard L Henry *, Paul S Thomas *,***

* Faculty of Medicine, UNSW** Department of Respiratory Medicine, the Sydney Childrens Hospital, Randwick 2031 and

*** Department of Respiratory Medicine, the Prince of Wales Hospital, Randwick 2031

f exhaled nitric oxide (eNO) indicates airway inflammation and could be used to guide asthma management. eNO could assess the asthma control an

nd, randomised, parallel group design was selected and 23 asthmatic subjects taking GCS regularly were recruited.

h the intention of keeping eNO within the normal range (< 25 ppb), or: a control group who were treated by stan

etry). Thus, in the active group, GCS were increased to reduce eNO if elevated, and these drugs were reduced

s recruited, only 13 subjects completed the study which made it difficult to achieve the goals. The mean baselin

2 + 6.2 ppb and 37.6 + 9.8 ppb respectively. A significant decrease in bronchodilator usage, eNO levels (27.2 + 4d GCS (520+142.8 vs 183+44.1 g fluticasone) was found between active and control groups.

study has shown that eNO may be a tool for monitoring asthmatic control in children. Conducting a study with a la

eNO is a robust measurement to use in the community.

eNO, inhaled GCS, asthma control.

mation is part of the basic pathophysiology of asthma. For persistent asthma, inhaled glucocorticosteroids (GCS)

n recommended as first-line therapy for children with persistent symptoms1

, although concerns persist regarding tood growth.

2The degree of inflammation in asthma could logically be used to adjust the dose of anti-inflammat

in terms of airway obstruction at a single moment only and does not indicate the degree of inflammation, particu

dilators. Sputum induction showing eosinophils reflects the degree of inflammation, but this method is impractic

to be trained, is time consuming and difficult to apply to young children. It has been suggested that eNO is correlosinophils in sputum and bronchial hyper-responsiveness, and therefore may be a method by which airway inflam

f exhaled nitric oxide is a non-invasive investigation which indicates the degree of inflammation and could be us

ailable immediately. In chronic persistent asthma, anti-inflammatory drugs such as glucocorticosteroids (GCS) ar

acerbations and, in this study, the hypothesis that eNO can be used to adjust the dose of medication was tested. In

by bronchial mucosal biopsies4

and decrease allergen-induced airway eosinophilia.5,6

Thus, controlling asthma byage, reducing side effects of GCS and the cost of long-term treatments.

xide may be used as a surrogate marker to assess the response to GCS in asthmatic patients. Change in responshave eosinophilic or non-eosinophilic airway inflammation since an elevated eNO is more likely in those asthmatic(7)

The level of eNO is reduced in a dose-dependent manner in response to GCS, and conversely, the level


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ntended to answer whether eNO can be of use as a tool to aid the control of asthma in children and whether it can b

The study was implemented and conducted over a period of 24 months and eNO levels evaluated at each visit of th

thod to measure airway inflammation, this was compared with current methods of identifying of asthma control andoms, lung function testing, bronchial challenge, sputum induction, and exhaled breath condensate.

ed that eNO would reflect the degree of inflammation in chronic asthma, and indicate how anti-inflammatory medi.

s study were to monitor airway inflammation in asthmatic children who have been treated with anti-inflammatooxide (eNO), and to determine whether eNO could be used as a marker of asthma control.

randomised, parallel group design was selected for this study. To ensure an equal balance of subjects between activ

sed on gender and age was applied.

was chosen in this study since the study required a prolonged period of observation. The two groups were given diff

active group and the other group acted as a control. Assessment of both groups was applied at the end of the study

d between groups.

aries for recording symptom scores and peak expiratory flow every morning and evening,as well as asthma medica

or one week before the next clinic visit. Lung function testing, exhaled nitric oxide measurement and exhaled breathonths at each clinic visit for a total of twelve months. Bronchial challenge together with sputum induction was perf

months. Patients were evaluated with a 4 week run-in period followed by a 52 week study duration. Recruiting took. The trial was to be completed within 24 months.

ruited from the tertiary referral, Respiratory Clinic of Sydney Childrens Hospital (SCH) where they attended for rein this study were performed within 6 months at respiratory outpatients clinics SCH, twice a week during the asthm

udy were asked to participate by explaining the purpose of this study, advantages and disadvantages. They were giv

orm at that time, and returned it when they come to the following visit having signed the consent form sheet if theyas an incentive was tried.

for the subjects in this study were; an asthmatic subject between ages of 6-16 whose asthma control could be iming due to asthma, rescue medication > 2 puffs per day of bronchodilator or diurnal PEF variation > 15%; FEV 1>7ility of >15%; ability to understand and comply with study requirements; usual adherence to a stable anti-asthmat

s who had other respiratory or systemic diseases; children who had taken oral GCS within the previous 3 months,

e previous 4 weeks; and subjects with a FEV1


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subjects were divided into two groups; one treated with the intention of keeping eNO within the normal range, as t

ed by criteria specifying the use of PEF and symptoms as per standard treatment in the National Asthma Council (A

creased if eNO was elevated above the values designated as the normal range, and likewise these drugs were reducemal range.

bjects were allocated at random to one of the above management strategies using a method of minimisation whiristics. The permuted block method of randomisation for a block size of four was performed, with A and B being

ndomisation codes were not revealed to the treating physician nor the study participants until after recruitment, trea

d.

tween the active and the control group was the definition of asthma control.

p, asthma control was defined as eNO being 25 ppb or less. (An eNO cut off point of 25 ppb was derived from our

ue for atopic non-asthmatic subjects was 27.6 + 3.0 ppb, and all subjects in this study were atopic asthmatic subjec

dies by Deykin et al and Smith et al).(13-15)

l group had eNO measured, but asthma control was defined by clinico-physiological readings, i.e., less than 3 episor need for rescue medication, and the FEV1and PEF being >80% of predicted or best with or < 4 episodes/week of either of nocturnal waking or need for rescue medication, and the FEV1 and PE

20% variability of PEF).


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Flow diagram 1. (Flow diagram study performed).

according their lung function and eNO level. The clinician opened 1 of 2 envelopes marked either Satisfactory con

nt was used to define whether GCS doses would change or not. The advice within the envelope was based on a) the

b) the eNO level if the subject was in the active group (Flow Diagram 2).


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Flow diagram 2. (Flow diagram clinical assessment)

ared between the two groups by the following outcomes:

superior control of asthma as judged by symptom scores including nocturnal waking, PEF and spirometry.

s: lower dose of inhaled glucocorticosteroid required for the same degree of asthma control.

med serial assessments according to the study protocol. In this study, subjects were assessed by completing the quesmeasurement of exhaled nitric oxide (eNO), bronchial challenge, sputum induction, diary of symptom and peak flo

h condensate (EBC). The methods of lung function testing, bronchial challenge, skin prick tests and eNO on-line m

publication7, while sputum induction, symptom monitoring and EBC collection are described below.


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on was performed together with hypertonic saline challenge as described.Sputum was collected by encouraging th

of hypertonic saline nebulised.

ere selected from saliva and was processed no more than 2 hours after induction. The sputum was processed by adputolysin 10%, Sigma, St Louis, USA), and mixed by rotation for 30 minutes at 37C, followed by the addition of

The suspension was filtered through a 60 mm nylon gauze (Millipore, North Ryde, NSW Australia) and the total ce

e solution staining (0.4% Sigma Aldrich, Irvine, UK) and determined by using a Neubauer haemocytometer (Websuspension was centrifuged at 200 xgfor 10 minutes, the supernatant was aspirated and stored at -70C. The cel

to a cell centrifuge for slide preparation.18

Differential count of nonsquamous cells were performed by Diff-Quick s

nduced sputum was assessed using three variables of slide quality including: adequate number of cells for enu

s on the slide and the proportion of squamous epithelial cells. Cell number was scored as 0 if there were fewer tha

400 or more cells were present. Pulmonary macrophages were scored as present (2) or absent (1). The proportion oas 2 if less than 20% and 1 if 20%

nd peak fl ow moni toring.

ency was used as a measure of asthma severity. All subjects were given a diary card to record peak expiratory

oms during the day and at night, as well as an early morning chest tightness, with a score ranging from 0 to 3 fo=severe). The use of short acting inhaled 2-adrenergic agonist (puff/day) for a rescue of breathlessness and time owas measured with a mini-Wright Respironics peak flow meter, full range 60-810L/min PEF (Personal Best, Respi

F manoeuvers three times and recorded the best value before using any inhaled bronchodilator therapy in the m

variability of PEF was calculated as

mum PEF X 100%

mum PEF /2

nsate coll ection (EBC)

rformed using a glass condensing chamber in wet ice. Children were instructed to breathe tidally by mouth through

ube for 5 minutes or until 250 ml of EBC was obtained. The samples were then immediately frozen and stored at -7

alysis.

Total nitrite/nitrate was measured by the fluorescent modification of the Greiss method. Briefly, 50 ml of breath cmM FAD and 250 IU nitrate reductase (Sigma, St Louis, USA). Samples were incubated for 1 hour at 37C and th

e). Samples were further incubated for 10 minutes in the dark and then 2.8M NaOH solution was added. Absorb

4000 plate reader (excitation 360/40, emission 395/25, gain 50). Standard curves were generated using sodium niton 2 mM, mean (SD) intra-assay coefficient of variation 3.11 (3.42%).

22


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oncentration was measured by a pH meter with a silicon chip sensor (Shindengen pH Boy-P2, Tokyo, Japan). Calibr

7.0 and 10.0 before measuring the samples.

the EBC pH was measured sequentially in 10 samples over 10 months and found to be stable with a coefficien

aken as the study was commenced prior to many of the publications suggesting that it may be beneficial.

pressed as mean and standard error or median and range. eNO levels and PC10data were log transformed to the Nor

morning PEF, total symptom scores, and rescue inhaler use (puff/day) were averaged from the last 7 days before eac

earman rank correlation due to the skewed distribution. Pearsons correlation (Students t-test) was applied to variaUnivariate linear regression analysis was used to determine correlation between continuous variables and eNO lev

re considered statistically significant. Sample size: if it is assumed that there is an 8 + 1 % difference in FEV1(from

oup, then a power calculation suggests that it would be possible to detect this difference if 80 patients were studied

% drop out rate (assuming Type I error, a = 0.05 and type II error, a= 0.1).as a two group comparison, however, due to the low rate of recruitment, within subject comparison had to be used for some of the variables. Between gro

ng the last available data point from each subject.

tients who were regularly taking inhaled (i)GCS agreed to participate in the study. Five patients withdrew before thtinely come for follow-up every two months, two subjects moved to another city, one subject stopped taking iGCS

Of the 13 subjects left, 6 subjects were allocated to the active group and 7 subjects were allocated to control group

t to achieve the goals of the study.

nd it difficult to follow the exact design which required regular visits every two months for one year. Two subjects

withdrew after the first visit, two subjects withdrew after the second visit, three subjects completed third visit only

until the fourth visit. Only two out of the thirteen subjects were able to finish the study as planned.

f the participants was 11.69 + 0.61 years (range, 8 to 15 years), and the majority of subjects were male (84.6%). Alg acting b2adrenergic agonist during the previous year. One subject (7.7%) was classified as a severe persistent asth

as moderate persistent asthma.(1)

The mean duration of asthma 7.4 + 0.7 years (range, 2 to 11 years). The characte

ed in Table 1.

s of study sample both from active and control groups

All subjects

(n = 13)

Active

(n = 6)

Control

(n = 7)


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E)

mean (year + SE)

ma:

usage, % (n)

cal ventilation

ersistent

sistent

s

ust, perfume, etc)

es

11.69 + 0.61

11/2

11/13 (84.6%)

147 + 2.9

46.1 + 2.8

7.39 + 0.7

9/13 (69.2%)

3/13 (23.1%)

1/13 (7.7%)

13/13 (100%)

3/13 (23.1%)

13 (100%)

4/13 (30.8%)

12/13 (92.3%)

1/13 (7.7%)

3/13 (23.1%)

3/13 (23.1%)

7/13 (53.8%)

4/13 (30.8%)

11/13 (84.6%)

3/13 (23.1%)

12 + 0.8

5/1

5/6

148 + 4.0

48 + 4.6

7.3 + 1.2

3/6

3/6

0/6

6/6

2/6

6/7

3/6

5/6

1/6

3/6

1/6

4/6

2/6

6/6

2/6

11.4 + 1.0

6/1

6/7

147.3 + 4.4

44.5 + 3.6

7.4 + 0.9

6/7

0/7

1/7

7/7

1/7

7/7

1/7

7/7

0/7

0/7

2/7

3/7

2/7

5/7

1/7


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2/13 (15.4%) 1/6 1/7

ng b2adrenergic agonists.

of eNO in active and control groups were 31.2 + 6.2 ppb and 37.6 + 9.8 ppb respectively.

ment

ment bronchodilator usage (BD) was significantly less in the active group, but spirometry and the measurements o

etween active and control groups. A significant difference was found in dose of iGCS and eNO levels between

es from runin period and final visits were compared, no significant differences were found between active and c

ators of asthma control (FEV1, bronchodilator usage, morning tightness, nocturnal asthma), iGCS and eNO between active and control groups at the fina

ht, BD usage and diurnal variability were recorded 1 week before the follow-up visit. (iGCS = inhaled glucocorticosteroids, BD = bronchodilator, eNO =

Active

(n=5)

Control

(n=6)

p-value

98.8 + 5.9 78.8 + 7.6 0.07 (unpaired t test)


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wk)

k)

%)

2 (0 -14)*

0 (0 - 5)*

0 (03)*

8.1 (5.213.5)

520 + 142.8

27.23 + 4.1

12 (4 - 40)*

3 (17)*

2.5 (0 -5)*

13.3(3.5 -

26.3)*

183 + 44.1

49.7 + 7.9

0.054 (Mann-

Whitney)

0.08 (Mann-Whitney)

0.1 (Mann-Whitney)

0.3 (Mann-Whitney)

0.04 (unpaired t test)

0.04 (unpaired t test)

st and the highest values (non-parametric data)

a points from either active or control group were separated into satisfactory control and unsatisfactory control simi

FEV1% predicted and bronchodilator usage in satisfactory control were significantly different when compared wpectively. In the control group, the indicators of asthma control including bronchodilator and diurnal variabil

actory control and unsatisfactory control p=0.01 and p=0.04 respectively. There were no significant differences in

etween satisfactory control and unsatisfactory control in the control group (Table 3).

es between satisfactory and unsatisfactory control in active and control groups. The mean levels of eNO, FEV1 (%), inhaled GCS, bronchodilator usasfactory and unsatisfactory control after adjusting the dose of iGCS based on the level of eNO for active group, and FEV 1 (%) predicted in control groury control was defined if eNO < 25 ppb in active group and FEV1>80% in control group. Unsatisfactory control was defined if eNO > 25 ppb in acti

Active Group P-

value

Control Group P-

valueatisfactoryontrol

n = 8)

Unsatisfac-tory

control

(n = 6)

Satisfactorycontrol

(n = 14)

Unsatisfac-tory

control

(n = 6)

9.7 + 1.4

01 + 3.3

50 + 97.7

+ 0.5

(03)*

.9 + 0.2

49.7 + 6.0

87.7 + 4.7

412 + 92.1

12 + 5.9

1 (05)*

1.5 (0 3)*

0.04

0.3

0.02

0.2

N/A

0.7

40.7 + 4.9

95 + 2.4

394 + 39.6

6.8 + 2.1

2 (0 - 6)*

1 (06)*

11 + 1.9

52.6 +11.2

68.3 + 4.4

216 + 24.7

18 + 4.8

4 (27)*

1 (04)*

0.2

0.03

0.01

0.06

0.4

0.04


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7.8 + 1.8 19 + 2.9

st and the highest values (Mann-Whitney)

ontrol data from both active and control groups show a significant difference in BD usage (p=0.04) and morning t

satisfactory control in the active group. The dose of inhaled GCS usage was higher in the active group compared

differences in diurnal variability between the two groups, and nocturnal asthma was not reported in the satisfa1, Table

el of eNO, FEV1(%), doses of iGCS and BD usage (puffs/week) in those with satisfactory control (SC) in both activ

n the active group and 11 in the control group. Satisfactory control was defined if eNO < 25 ppb in active group a

on of variables asthma control and doses of iGCS treatment derived from satisfactory control of active and control

ent based on eNO < 25 ppb for active group, and FEV1> 80% for control group).

Satisfactory control P-valueeNO < 25 ppb

(active group), n = 8

FEV1> 80%

(control group), n=11

19.7 + 1.4 40.7 + 4.9


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wk)

k)

%)

101 + 3.3

550 + 97.7

1 + 0.5

0 (03)*

0

6.9 + 0.2

95 + 2.4

393.9 + 39.6

6.8 + 2.1

2 (0 - 6)*

1 (06)*

11 + 1.9

0.05

0.04

0.04

N/A

0.2

st and the highest values.

m both the active and control groups were combined, and analysed based on the level of eNO, variables of asthma cness, asthma night time symptoms, bronchodilator usage and percentage of sputum eosinophils) were significantly l

ith the dose of iGCS usage being significantly higher in this group (Table 5).

he mean variables of asthma control (FEV1, bronchodilator usage, morning tightness, nocturnal asthma, diurnal

nd EBC pH in subjects who have eNO concentrations < 25 ppb and who have eNO concentrations > 25 ppb (data

eNO < 25 ppb eNO > 25 ppb P - value

wk)

k)

%)

17

18.71 + 1.1

94.8 + 2.9

521.8 + 66.4

1.3 + 0.7

0 (04)

0 (04)

7.9 + 1.0

4.9 + 0.3

3.9 + 0.5

7.5 + 0.1

22

49.8 + 3.3

89.7 + 3.4

333.0 + 37.8

10 + 2.3

2 (07)

2 (06)

9.2 (2.626.3)

12.3 +1.7

3.0 + 0.7

7.2 + 0.2

0.3

0.003

0.0001*

0.003*

0.001*

0.2

0.003

0.4

0.3


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-Whitney test

tive and control groups, in those with a FEV1< 80 % predicted, diurnal variability was significantly higher (p

.04) when compared with those with a FEV1> 80% predicted.

ad an exacerbation after reducing the dose of iGCS, 2 subjects from the active group, and 3 subjects from

, the mean level of eNO in active group was not different compared with control group (48.6 + 17.9 ppb vs 51he active group compared with the control group (96 + 5.7 % vs 71.3 + 19.9 %), while the mean doses of iGCS 175

control group, and the mean of BD usage was lower in active group compared with control group (11 + 4.2 p

dy, during an exacerbation the active group showed better than control group in term of FEV1and BD usage.

haled nitric oxide and other variables.

ignificant negative correlation between eNO concentration and dose of iGCS treatment. eNO was lower in subje

ombining both active and control groups, p


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tween log eNO and bronchodilator usage (puffs/week) in both active and control groups (p= 0.02, Pearson r = 0.4).

ak flow readings

his study found that asthma symptoms (morning tightness, wheezing at night) and bronchodilator usage had a signi

urnal variability. FEV1 was correlated with morning tightness (p=0.001), diurnal variability (%) (p=0.02) and broncorrelation was detected between FEV1and asthma at night. There was a negative correlation found between FEV1a

visit.

enge and sputum eosinophilia.

r-responsiveness and sputum induction were performed in the run-in period and at the third visit. Using data fromD10in the active group (2.9 + 0.4 ml) was not significantly different when compared with the control group (3.4 + 0

up, adequate sputum samples were obtained from 5 of 6 subjects at run-in period and 4 subjects at third visit, and th2.5 % and 7.8 + 2% respectively. Two subjects did not produce an adequate sputum samples during hypertonic sali

ls in the control group was 9.6 + 2.3 in the first test and 13.8 + 4 in the second test. Data from all visits found that p

+ 0.4 %) was not significantly different when compared with control group (3.4 + 0.7 %), p=0.3.

sate pH and nitrite/nitrate (NOx)

of EBC pH in the active group (7.3 + 0.2) was not significantly different when compared with the control group (7

fference was found between the NOx concentration in the active group (17.6 + 4.5) and NOx in the control group (

gative correlation was found between EBC pH and eNO in the active and control groups, p=0.02, r=-0.3. EBC pH

ups, p=0.005, r=0.4. There was no correlation between EBC pH with FEV1(%) in both the active and control group

orrelation between NOx and eNO, pH, or iGCS or any other markers of inflammation in the active and contro

with eNO (p=0.02 in the active group and p=0.03 in the control group), and the dose of iGCS (p=0.03 both in activ

degree of bronchial hyper-responsiveness only in the active group (p=0.04), but not in the control group.


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et out to compare the value of eNO as a method for controlling asthma with conventional methods. The study had tment and a high drop out rate, with only two out of the initial 23 subjects recruited completing the study exactly as p

was difficult to apply to children since most of the parents did not want their children missing many school days. Ant rate was that parents who were working were unable to accompany their children to the hospital for the follow u

ate applied toadult subjects as they are more independent in aspects such as managing their time; and have authority

on, the salty taste and feeling unwell after hypertonic saline was one of the reason s why children reported that theydy.

ds were limited by the time and number of subjects that could be recruited for this study, causing difficulty in reachi

edical record files were not easily found except during the clinic attendance. The participants in this study did not h

difficulty especially when the subjects were unable to come at the time which had been scheduled, e.g. during scho

e the visits at times that suited the subjects the retention issues of this study might have been resolved.

uitment of subjects is always a critical issue especially when the study needs a certain target group size. In this studendent subjects needed to be recruited in order to achieve the sample size calculation for the aims. Collaboration wiaediatricians to refer patients to participate in this study might have helped to increase the number of the study subje

or disease advocacy groups also has been suggested by Society of Clinical Research Associates. (23) This study wa

nity and area, which was close to the study centre, but altering the follow-up to coincidewith the school holidays mi

of this pilot study are useful as it has shown that eNO provides more information relating to asthma disease activity

of this study was achievement of asthma control as judged by symptom scores, PEF and spirometry. At the last visit

g FEV 1, BD usage, morning tightness, nocturnal asthma and diurnal variability in the active group, were lower in tce was shown,probably due to the small sample size of these groups. If analysing data from all visits, this study fou

urnal variability were significantly lower in the active group compared with the control group. Adjusting the dose o

ontrol than if using conventional guidelines, if asthma control was used as the outcome.

of iGCS required for controlling asthma was the secondary end point of this study. During the study period, adjust

t in the active group, thus increasing the dose of iGCS to reduce the eNO level. This approach was shown to consisneeded per week. The data show that the mean dose of iGCS to control asthma symptoms in moderate persistent a

which is categorised as a high dose by the NAC guidelines.

S dose may have been due to a number of factors. Therapy adjustment in the control group based on FEV 1 resulted

lator needed per week, suggesting that FEV 1 was inferior compared with eNO to control inflammation in asthmati

tient compliance in taking the correct dose of iGCS as suggested plus not stratifying for baseline dose of iGCS alsotive and control groups at the final visit in this study. The study by Pijnenburg at al titrating iGCS doses based on e

nly, demonstrated that airway inflammation was improved with lower doses of iGCS in the group using eNO and s

e active group was significantly higher than the control group and this was associated with an improvement in meas


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uced to the levels seen in normal non-atopic individuals, but did almost achieve the target level of 25 ppb. These da

by using higher doses of iGCS. This is in contrast to the study by Smith et al, which demonstrated that adults were

GCS, and lower doses were achieved using eNO as an indicator of control and to modify treatment. 14

suggested that high dose fluticasone propionate (5001000 g/day) should only be prescribed in exceptions, e.g. in

duction in growth velocity, bone turnover and adrenal cortical function, but conventional doses ( < 200 g/day) appildhood asthma. (25) Studies in asthmatic adults with poorly controlled asthma suggest that optimal control is achie

riables of asthma control. In this study eNO was correlated with several indicators of asthma control including mor

ght and bronchodilator needed per week.

NO has a significant correlation with BD usage, suggesting that eNO does have relationship with asthma control. Olation between eNO and diurnal variability of PEF or FEV 1. A study of patients with difficult asthma by Stirling e

with frequency of symptoms and rescue b 2 agonist use but did not correlate with FEV 1. 27 The recent use of b 2 achanges in peak flow but can cause large errors in monitoring diurnal variability. 20

NO and GCS

at the eNO concentration has a negative correlation with dose of iGCS. 28 According to the NHLBI guidelines inh

matic patients who have symptoms more than twice a week or require an inhaled 2 adrenergic agonist more than ongnificant negative correlation with the dose of iGCS. A study in asthmatic children conducted by Beck-Ripp et al r

nitor compliance with iGCS as it was found that there was an inverse correlation between the level of eNO and the

ng doses of iGCS. They suggested that eNO has an ability to differentiate between children treated with or without

ated that eNO has a linear dose relationship with iGCS and may be used to assess the anti-inflammatory effect of thed that after discontinuing iGCS, eNO may be used as a predictor of asthma relapse 2 and 4 weeks after discontinu

s after discontinuation of GCS had the best combination of sensitivity (71%) and specificity (93%) for an asthma reth et al demonstrated that eNO measurement could be used to titrate doses of iGCS in asthmatic adults and this met

y based on conventional guidelines. 14

NO and sputum eosinophilia

ear to be useful as an indirect method of quantitating sputum eosinophilia to assess airway inflammation, (10) and b

mation during iGCS therapy in children with asthma. eNO and percentage of eosinophils in sputum can be used as a

onstrated that airway hyper-responsiveness 32 and eosinophils in sputum 33 can be used to adjust doses of iGCS to

e not easy to perform in clinical practice as they are time consuming and difficult to apply in children. On the other

oducible, and non-invasive, hence suitable tool for either adults or children. 34

NO and bronchial hyper-responsiveness

relation between bronchial hyper-responsiveness and eNO concentration. This result was in line with the study by L


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eNO and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge in patients with well-c

bronchial hyper-responsiveness since BHR may be a marker for underlying asthma severity which reflects some in

remodelling, while eNO is a marker of inflammatory changes related to current control of asthma. 36

Pijnenburg et al 24 demonstrated that eNO based titration of iGCS improved PD 20 methacholine in paediatric ast

een eNO and BHR in this study, probably as daily administration of iGCS caused a reduction in sensitivity to hype-2000 u g have been taken daily for 2 to 8 weeks. 37-39 Methacholine is more sensitive challenge than hypertonic s

ferences.

ate nitrite/nitrate and EBC pH

e the oxidised metabolites of nitric oxide and have been proposed as markers of airway inflammation. 40 The data f

NOx and eNO or any other indicators of asthma control. EBC NOx levels may be influenced by several factors inc

pharyngeal tract in healthy subjects and production of nitrite from the oropharyngeal tract during EBC collection an

rway inflammation. 41,42

n between EBC NOx and EBC pH in this study, although pH has a significant correlation with eNO in both the actipH had no correlation with asthma symptoms in terms of either asthma at night or morning tightness, EBC pH was FEV 1 > 80%, suggesting that EBC pH may be used as an additional tool to indicate severity.

uitment of subjects is always a critical issue especially when the study needs a certain target group size. In this studendent subjects needed to be recruited in order to achieve the sample size calculation for the aims. Collaboration wi

aediatricians to refer patients to participate in this study might have helped to increase the number of the study subje

or disease advocacy groups also has been suggested by Society of Clinical Research Associates. 23 This study was

a, which was close to the study centre, but altering the follow-up to coincide with the school holidays might have d

s that the level of eNO may reflect the inflammation of the asthmatic airway, thus it may help to identify whether p

also provides information regarding the usefulness eNO in monitoring asthma control compared with spirometry. T

detect and adequate of anti-inflammatory treatment can be defined by measuring the eNO level. It was hypothesiseO level might help more rapid reduction of GCS therapy, thereby minimise GCS side effects in chronic asthma part

sing that using eNO as a marker of inflammation was associated with a higher dose of iGCS, but improved asthma c

GCS was inadequate, or that compliance was an issue that only improved in the active group. This latter explanatio

hould have been also in the control group. This indicates a significant difference between the paediatric subjects in t

ment, while the adult subjects in the study by Smith et al appear to have been initially over-treated with GCS and b4

n eNO and indicators of asthma control suggest that eNO could be used as a marker of asthma control. In addition, Eay be used with spirometry to define airway obstruction. A larger sample size however is needed to clarify the resul

NTS


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arents and children for participating, Barbara ODonovan of the Respiratory Laboratory and the staff of the Outpati

udy. NiOx equipment was supported by Aerocrine, Sweden and Ratnawati was assisted by a grant from the School

and Blood Institute. GINA workshop report (updated 2004) on Global strategy for asthma management and prevention 200559. Available at: http://www.ginasthma.org

J, Welch M, Walton-Bowen K, Cruz-Rivera M, Smith JA. Longitudinal growth in infants and young children treated with budestent asthma. J Allergy Clin Immunol 2000; 105:259-68.

Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine respoorax 1998; 53:91-5.

hn M, Gilbey T, O'Connor BJ, Chung KF, et al. Effect of inhaled budesonide on lung function and airway inflammation: assessment by v

. Am J Respir Crit Care Med 1999;159:22-30.

aathof KCM, Vaselic-Charvat MA, Zwinderman AH, Bel EH, Sterk PJ. Effect of inhaled steroids on airway hyperresponsivenesde levels in patients with asthma. Thorax 1999; 54:403-8.

, Chung KF, Barnes PJ. An inhaled steroid improves markers of airway inflammation in patients with mild asthma. Eur Respir

J, Henry RL, Thomas PS. Measurement of exhaled nitric oxide in asthmatic children. J Respir Indo 2005; 25:110-6.elly LE. Montuschi P, Corradi M, Collins JV, Barnes PJ. Dose-dependent onset and cessation of action of inhaled budesonided asthma. Thorax 2002; 57:889-96.

P, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, et al. Exhaled NO and assessment of anti-inflammatory effects of inh. Eur Respir J 2002; 20:601-8.

Cowan JO, Flannery EM, Hancox RJ, Mclachlan CR, et al. The predictive value of exhaled nitric oxide measurements in assRespir Crit Care Med 2001; 164: 738-43.

ization and stratification of patients to clinical trials. J Chron Dis 1974; 27:365-75.

Keech AC. Randomisation in clinical trials. MJA 2002; 177:565-7.

F, Drazen JM, Israel E. Exhaled nitric oxide as a diagnostic test for asthma. Online verus offline techniques and effect of flow 1597-1601.

, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N En

PG, Wang H, Shah S, Henry RL. The relationship of exhaled nitric oxide to airway inflammation and responsiveness in childre

ncil Australia. Asthma Management Handbook 2002. Melbourne, Australia. Available at: http://www.NationalAsthma.org.au

ety. The British Guidelines in Asthma Management. Thorax 1997; 52 (Suppl 1):1-21.

JL, Hankin R, Powell H, Henry RL. Relationship between induced sputum eosinophils and the clinical pattern of childhood as

zyk JW, Hensley MJ, Hensley MJ, Gleeson M, Henry RL, et al. Epidemiological association of airway inflammation with asthms in childhood. Am J Respir Crit Care Med 1998; 158:36-41.

Woolcock A. Diurnal variability-time to change asthma guidelines? BMJ 1999; 319:45-7.

, Robbins RA, Danziger LH, Rubinstein I. Collection and analysis of exhaled breath condensate in humans. Am J Respir Crit

J, Salvemini D, Moore WM, Currie MG. A fluorometric assay for the measurement of nitrite in biological samples. Anal Bioche

t of research subjects. Issue 27, Februari 2001. Available at :Http://www.temple.edu/oupr/oct/doc/recruit1.pdf

ker EM, Hop WP, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma. Am J Respir Crit Care Med

eer E, Postma DS, Arends LR, de Vries TW, Brand PLP, et al. Side-effects of fluticasone in asthmatic children: no effects afte0 -5.

R, Mark GB, Ware SI, Xuan W, Salome CM, et al. Optimal asthma control, starting with high doses of inhaled budesonide. Eur
http://www.temple.edu/oupr/oct/doc/recruit1.pdfhttp://www.temple.edu/oupr/oct/doc/recruit1.pdfhttp://www.temple.edu/oupr/oct/doc/recruit1.pdfhttp://www.temple.edu/oupr/oct/doc/recruit1.pdf


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ov SA, Campbell D, Robbinson DS, Durham SR, Chung KF, et al. Increase in exhaled nitric oxide levels in patients with difficusease severity despite treatment with oral and inhaled corticosteroids. Thorax 1998; 53:1030-4.

nov S, Lim S, Barnes PJ. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with m

M, Arenz S, Koring C, Pasqualoni B, Bufler P. Changes of exhaled nitric oxide during steroid treatment of childhood asthma. E

uis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thora

lson N, Lex C, Erin EM, Li AM, Hansel T, et al. Clinical use of noninvasive measurements of airway inflammation in steroid re2005; 171:1077-82.

A, Bel EH, van Krieken JHJM, Vandenbroucke JP, Sterk PJ, et al. Clinical control and histopathologic outcome of asthma whn additional guide to long-term treatment. Am J Respir Crit Care Med 1999; 159:1043-51.

CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbation and eosinophil counts: a randomised control

F, Kelly C, Meah S, Barnes PJ. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and ch

M, Jenkins CR, Koskela H, Brannan JD, Anderson SD, et al. Markers of airway inflammation and airway hyperresponsivenesur Respir J 2001; 18:444-50.

E, Tilles SA, O'Hollaren M, Cook J, Thukkani N, et al. Exhaled nitric oxide levels correlate with measures of disease control in45-50.

se-induced asthma and the use of hypertonic saline aerosol as a bronchial challenge. Respirology 1996; 3:175-81.

JL, Rodwell LT, Jenkins CR. Acute effect of sodium cromoglycate on airway narrowing induced by 4.5 percent saline aerosoaerosol corticosteroids in patients with asthma. Chest 1994; 105:673-80.

Quanjer PH, Cockcroft DW, O'Byrne PM, Anderson SD, et al. Standardized challenge testing with pharmacological, physical 993; 6 Suppl.16:53-83.

, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149:538-51.

DC, Weitzberg E, Schedin U, Alving K. Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitr- 25.

d biomarker puzzle: bacteria play their card in the exhaled nitric oxideexhaled breath condensate nitrite game. Thorax 2005

Exhaled Nitric Oxide in the Management of Paediatric Asthma

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