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Towards Improved Diagnostics and Monitoring in Childhood Asthma: Methodological and Clinical Aspects of Exhaled NO and Forced Oscillation Technique
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Asthma is a heterogeneous disease. Diagnosis relies on symptom evaluation and lung function tests using spirometry. Symptoms can be vague. Spirometry is effort-dependent and does not reliably evaluate small airways. Allergic asthma in preschool children is not easily separated from episodic wheeze.

Exhaled NO (FeNO) is a marker of allergic Th2-cytokine-driven airway inflammation. However, FeNO is not feasible in preschoolers with current devices and algorithms. Alveolar NO is an estimate of small airway involvement. Forced oscillometry (FOT) is an effort-independent lung function test assessing both large and small airways.

Aims: To study clinical and methodological aspects of FeNO, alveolar NO and lung function indices by FOT.

Methods: Asthmatic children and young adults and healthy controls, were included in the studies. FeNO at 50 mL/s was performed in all studies (in study III with an adapted single-breath method with age-adjusted exhalation times). FeNO at multiple exhalation flow rates were performed in studies I, II and IV to calculate alveolar NO, as was spirometry. FOT indices were assessed in study IV.

Results: The exhalation time needed to reach steady-state NO was < 4 s in subjects aged 3-4 years, and was related to subject height. FeNO was higher in ICS-naïve asthmatic children than in controls. ICS-naïve asthmatic preschool children had FeNO < 20 ppb. The oral contribution to FeNO was similar in asthmatic and healthy youths. Multiple flow rates and modelling of alveolar NO were feasible in children aged 10-18 years. Alveolar NO correlated to asthma characteristics, though not when axial diffusion correction was applied. FOT resistance measures were associated with asthma diagnosis, and small airway FOT measures were associated with asthma control, in adolescents.

Conclusion: An adapted FeNO method is feasible from 4 years, and exhalation time is related to child height. Our findings emphasise the need to refine clinical cut-offs for FeNO in younger children. FOT variables discriminate between asthmatics and controls, much like spirometry. The information provided by FOT is additive to that from spirometry. Further studies of exhaled NO dynamics and FOT indices of small airways are warranted to evaluate new treatment options and possibly improve asthma control.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1262
Keyword [en]
asthma, children, exhaled NO, forced oscillation technique, airway inflammation, small airways, asthma diagnostics
National Category
Clinical Medicine
Research subject
Pediatrics; Lung Medicine
Identifiers
URN: urn:nbn:se:uu:diva-304264ISBN: 978-91-554-9710-1OAI: oai:DiVA.org:uu-304264DiVA: diva2:1033170
Public defence
2016-11-25, Robergsalen, Akademiska sjukhuset, Ingång 40, 4tr, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2016-11-03 Created: 2016-10-03 Last updated: 2016-11-21
List of papers
1. The fraction of NO in exhaled air and estimates of alveolar NO in adolescents with asthma: methodological aspects
Open this publication in new window or tab >>The fraction of NO in exhaled air and estimates of alveolar NO in adolescents with asthma: methodological aspects
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2012 (English)In: Pediatric Pulmonology, ISSN 8755-6863, E-ISSN 1099-0496, Vol. 47, no 10, 941-949 p.Article in journal (Refereed) Published
Abstract [en]

Rationale

This study investigated the oral contribution to exhaled NO in young people with asthma and its potential effects on estimated alveolar NO (CalvNO), a proposed marker of inflammation in peripheral airways. Secondary aims were to investigate the effects of various exhalation flow-rates and the feasibility of different proposed adjustments of (CalvNO) for trumpet model and axial diffusion (TMAD).

Methods

Exhaled NO at flow rates of 50–300 ml/sec, and salivary nitrite was measured before and after antibacterial mouthwash in 29 healthy young people (10–20 years) and 29 with asthma (10–19 years). CalvNO was calculated using the slope–intercept model with and without TMAD adjustment.

Results

Exhaled NO at 50 ml/sec decreased significantly after mouthwash, to a similar degree in asthmatic and healthy subjects (8.8% vs. 9.8%, P = 0.49). The two groups had similar salivary nitrite levels (56.4 vs. 78.4 µM, P = 0.25). CalvNO was not significantly decreased by mouthwash. CalvNO levels were similar when flow-rates between 50–200 or 100–300 ml/sec were used (P = 0.34 in asthmatics and P = 0.90 in healthy subjects). A positive association was found between bronchial and alveolar NO in asthmatic subjects and this disappeared after the TMAD-adjustment. Negative TMAD-adjusted CalvNO values were found in a minority of the subjects.

Conclusions

Young people with and without asthma have similar salivary nitrite levels and oral contributions to exhaled NO and therefore no antibacterial mouthwash is necessary in routine use. TMAD corrections of alveolar NO could be successfully applied in young people with asthma and yielded negative results only in a minority of subjects.

Keyword
exhaled nitric oxide, alveolar nitric oxide, nitrite, TMAD-adjustment, pediatric asthma
National Category
Pediatrics Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-172352 (URN)10.1002/ppul.22556 (DOI)000308714100002 ()22467536 (PubMedID)
Available from: 2012-04-05 Created: 2012-04-05 Last updated: 2016-10-05Bibliographically approved
2. Alveolar and exhaled NO in relation to asthma characteristics: effects of correction for axial diffusion
Open this publication in new window or tab >>Alveolar and exhaled NO in relation to asthma characteristics: effects of correction for axial diffusion
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2014 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, no 8, 1102-1111 p.Article in journal (Refereed) Published
Abstract [en]

Background: Inflammation in the small airways might contribute to incomplete asthma disease control despite intensive treatment in some subgroups of patients. Exhaled NO (FeNO) is a marker of inflammation in asthma and the estimated NO contribution from small airways (Calv(NO)) is believed to reflect distal inflammation. Recent studies recommend adjustments of Calv(NO) for trumpet model and axial diffusion (TMAD-adj). This study aimed to investigate the clinical correlates of Calv(NO), both TMAD-adjusted and unadjusted. Methods: Asthma symptoms, asthma control, lung function, bronchial responsiveness, blood eosinophils, atopy and treatment level were assessed in 410 subjects, aged 10-35 years. Exhaled NO was measured at different flow-rates and Calv(NO) calculated, with TMAD-adjustment according to Condorelli. Results: Trumpet model and axial diffusion-adjusted Calv(NO) was not related to daytime wheeze (P = 0.27), FEF50 (P = 0.23) or bronchial responsiveness (P = 0.52). On the other hand, unadjusted Calv(NO) was increased in subjects with daytime wheeze (P < 0.001), decreased FEF50 (P = 0.02) and with moderate-to-severe compared to normal bronchial responsiveness (P < 0.001). All these characteristics correlated with increased FeNO (all P < 0.05). Unadjusted Calv(NO) was positively related to bronchial NO flux (J'aw(NO)) (r = 0.22, P < 0.001) while TMAD-adjCalv(NO) was negatively related to J'awNO (r = -0.38, P < 0.001). Conclusions: Adjusted Calv(NO) was not associated with any asthma characteristics studied in this large asthma cohort. However, both FeNO and unadjusted Calv(NO) related to asthma symptoms, lung function and bronchial responsiveness. We suggest a potential overadjustment by current TMAD-corrections, validated in healthy or unobstructed asthmatics. Further studies assessing axial diffusion in asthmatics with different degrees of airway obstruction and the validity of proposed TMAD-corrections are warranted.

Keyword
alveolar nitric oxide, asthma, axial diffusion, exhaled nitric oxide, peripheral inflammation
National Category
Pediatrics Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-231109 (URN)10.1111/all.12430 (DOI)000339436200013 ()24894594 (PubMedID)
Available from: 2014-09-07 Created: 2014-09-04 Last updated: 2016-10-05Bibliographically approved
3. New method for single-breath fraction of exhaled nitric oxide measurement with improved feasibility in preschool children with asthma
Open this publication in new window or tab >>New method for single-breath fraction of exhaled nitric oxide measurement with improved feasibility in preschool children with asthma
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2015 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 7, 662-667 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Respiratory societies recommend use of standardized methodologies for fraction of exhaled nitric oxide (FeNO) measurements in adults and children, but in preschoolers, feasibility remains a problem. The exhalation time needed to obtain steady-state FeNO is unclear. Our primary aim was to study the feasibility of an adapted single-breath FeNO method with age-adjusted exhalation times. We also studied the association between time to steady-state NO level and height, as well as FeNO in relation to asthma and current treatment with inhaled corticosteroids (ICS).

METHODS: Sixty-three children aged 3-10 years performed FeNO measurements with a hand-held electrochemical device with a newly developed flow-control unit. Exhalation times were pre-adapted to age. Exhaled air was simultaneously sampled to a chemiluminescence analyzer to measure time to steady-state NO level.

RESULTS: Eighty-one percent of the children achieved at least one approved measurement. From 4 years upwards, success rate was high (96%). Time to steady-state [NO] (median and interquartile range) was 2.5 s (2.4-3.5) at the age of 3-4 years and 3.5 s (2.7-3.8) at the age of 5-6 years. Height was associated with time to steady state (r(2)  = 0.13, p = 0.02). FeNO (geometric mean [95% CI]) was higher in ICS-naïve asthmatic children (n = 19): 15.9 p.p.b. (12.2-20.9), than in both healthy controls (n = 8) 9.1 p.p.b. (6.6-12.4) and asthmatic subjects on treatment (n = 24) 11.5 p.p.b. (9.7-13.6).

CONCLUSION: We found this adapted single-breath method with age-adjusted exhalation times highly feasible for children aged 4-10 years. ICS-naïve asthmatic children had FeNO levels under the current guideline cutoff level (20 p.p.b.), highlighting the importance of taking age into account when setting reference values.

Keyword
airway inflammation; asthma; biomarker; children; feasibility; fraction of exhaled nitric oxide; preschool
National Category
Respiratory Medicine and Allergy Pediatrics
Identifiers
urn:nbn:se:uu:diva-270371 (URN)10.1111/pai.12447 (DOI)000365410900013 ()26184580 (PubMedID)
Available from: 2015-12-27 Created: 2015-12-27 Last updated: 2016-10-05Bibliographically approved
4. Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control
Open this publication in new window or tab >>Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control
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(English)Article in journal (Refereed) Submitted
Keyword
asthma, lung function, small airways
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-304031 (URN)
Available from: 2016-09-29 Created: 2016-09-29 Last updated: 2016-10-07Bibliographically approved

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