Childhood asthma management guided by repeated FeNO measurements: a meta-analysis

doi:10.1016/j.prrv.2011.11.002

Paediatric Respiratory Reviews

Volume 13, Issue 3, September 2012, Pages 178-183

https://doi.org/10.1016/j.prrv.2011.11.002 Get rights and content

Summary

The fraction of exhaled nitric oxide (FeNO) has gained interest as a non-invasive tool to measure airway inflammation in asthma since it reflects allergic inflammation. Recent controlled clinical studies have, however, questioned its role in the management of asthma in children. To assess the clinical value of FeNO in paediatric asthma management, a meta-analysis was performed on the controlled studies of childhood asthma management guided by repeated FeNO measurements, and relevant publications on the confounders of FeNO were reviewed. The data suggests that utilising FeNO to tailor the dose of inhaled corticosteroids in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes. Many disease and non-disease related factors (most importantly atopy, height/age and infection) affect FeNO levels which can easily confound the interpretation.

Introduction

The fraction of exhaled nitric oxide (FeNO) is thought to reflect the magnitude of allergic and/or eosinophilic airway inflammation.1, 2, 3, 4, 5 Since there are small portable, readily usable, patient-friendly measurement devices available, FeNO measurements have become increasingly popular in the diagnosis and management of asthma.1, 2, 3, 4

Recent clinical studies have, however, questioned the usefulness of FeNO in the diagnosis and management of asthma. The correlation between FeNO and markers of eosinophilic airway inflammation has been difficult to demonstrate.1, 2, 3, 4 Moreover, FeNO values have been elevated only in subjects with atopic asthma6, 7 and positively and strongly correlated with number of sensitizations in non-asthmatic children.8, 9, 10, 11, 12, 13 This important influence of atopy has not been known in many older clinical studies, which have demonstrated the specificity or sensitivity of FeNO in the diagnosis of asthma.14, 15, 16, 17, 18, 19, 20 Considering asthma treatment, corticosteroid treatment decreases FeNO, FeNO correlates with airway eosinophilia also in medicated children, and FeNO indicates failed inhaled corticosteroid (ICS) reduction.21, 22, 23 On the other hand, concerns have been raised whether FeNO reflects inflammation efficiently in medicated patients, or whether it even measures airway eosinophilia at all – instead just sensitization status.1, 3 Moreover, corticosteroids may decrease FeNO possibly faster than airway inflammation since they directly inhibit the expression of the inducible NO synthases.²

There is one meta-analysis available on the topic of the usefulness of titrating ICS dose based on repeated FeNO measurements versus clinical symptoms in patients with asthma.²⁴ It concluded that FeNO strategy has no additional benefit over guideline-based strategy. Importantly, FeNO strategy increased ICS doses in children with asthma.

We noticed two potential limitations in the earlier meta-analysis.²⁴ First, it did not have asthma exacerbations necessitating prednisolone course (a guideline-based marker for moderate-to-severe episodes) as an outcome.25, 26 This outcome could also influence ICS dose. Second, the outcome of FeNO level in the end of study period (one biological reasoning of FeNO is to measure eosinophilic airway inflammation) did not include all available studies.1, 2 Due to limitations of the earlier meta-analysis and its conclusion of increased ICS-doses by FeNO strategy in children, we considered that a new meta-analysis was warranted. Moreover, such a conclusion emphasizes the importance of knowing the confounders of FeNO.

Section snippets

Aims

Our primary aim was to perform a meta-analysis of controlled studies of childhood asthma management guided by repeated FeNO measurements to assess whether FeNO follow-up strategy has additional benefits over guideline based asthma management in children. We hypothesized that repeated FeNO measurements do not have additional benefit over guideline based asthma management in children. Our secondary aim was to review clinical factors affecting FeNO values to highlight important confounders.

Selection of studies

For the meta-analysis, the randomized controlled trials concerning the adjustment (titration) of ICS dose using repeated FeNO measurements in children with asthma were systematically searched from PubMed database using “nitric oxide”, “asthma” and “management” as key words and English, clinical trial and human as limits for language, study type and subjects. Search was performed for the last 10 years (date of the last search was August 31^st 2011). In addition, we reviewed citations of the

Description of studies

Our data search resulted in 25 hits of which 6 controlled studies that have assessed the usefulness of repeated FeNO measurements in titrating inhaled corticosteroid doses compared to conventional follow-up in asthma.28, 29, 30, 31, 32, 33 Of these, 4 studies were paediatric trials and eligible for meta-analysis.28, 30, 32, 33

Of the 4 paediatric studies, randomization procedure was described in one study (see study details in Online Table E1).³² Two studies were double blind.28, 32 One study

Discussion

According to our meta-analysis of paediatric studies, FeNO monitoring lead to an increased dose of ICS while it did not have a meaningful influence on FEV1 compared to conventional asthma management. These findings were similar to the previous meta-analysis.²⁴ As new findings, FeNO monitoring decreased FeNO values itself, but did not influence the need for prednisolone courses.

Two paediatric studies have shown no difference in the dose of ICS when FeNO follow-up group has been compared to

Summary

Utilising FeNO to tailor the dose of ICS in children cannot be recommended for clinical routine, since there is a danger of excessive ICS doses without meaningful changes in clinical outcomes. Guideline-based asthma diagnostic and management strategies are essential. Clinicians should know confounders of FeNO. Future studies should focus on more appropriate patient groups (more severe illness?) and better FeNO cut-off values (higher?) for treatment decisions.

Disclosure Statement

The authors have no conflict of interest with this manuscript.

Educational Aims

•
To demonstrate the clinical value of the repeated fraction of exhaled nitric oxide (FeNO) measurements in paediatric asthma management
•
To review the confounders of FeNO
•
To help physicians to use and interpret FeNO critically

Practice Points

•
Utilising FeNO to tailor the dose of inhaled corticosteroids in children with mild-to-moderate asthma cannot be recommended for routine clinical practice
•
A clinician should know the confounders of FeNO, namely atopy, height, medications and infections, and use proper reference values
•
Clearly elevated FeNO in an atopic child (under school-aged children: >20-40 ppb; at school-age: >40-60 ppb) may suggest asthma, but as itself, it is not enough for the diagnosis of asthma
•
Normal FeNO does not exclude

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Recent Diagnosis Techniques in Pediatric Asthma: Impulse Oscillometry in Preschool Asthma and Use of Exhaled Nitric Oxide
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Citation Excerpt :
Larger studies are needed to determine normative values for healthy infant and preschoolers. There are numerous factors that influence FeNO values, including age, sex, height, atopy, smoking (active or passive exposure to tobacco smoke), consumption of nitrite-containing foods or caffeine,48,49 and prematurity.50,51 Thus, these factors must be taken into consideration when interpreting FeNO.
Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach
2016, Journal of Allergy and Clinical Immunology
There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response to steroids is unlikely to be uniform in all patients.
We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA.
Eighty-two children (median age, 12 years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4 weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV₁ ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24 ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains.
Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain).
A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving personalized medicine.
Use of exhaled nitric oxide in children with bronchial asthma
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Citation Excerpt :
Similar observations were made by Szefler et al who observed in 780 children that the addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids (ICS), without clinically important improvements in symptomatic asthma control.10 A meta-analysis performed by Jartti et al on the controlled studies of childhood asthma management guided by repeated FeNO measurements suggest that utilising FeNO to tailor the dose of ICS in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes.11 In a study by Malby et al on one hundred ninety-six, 6-year-old children with no asthma symptoms, intermittent asthma symptoms, and persistent asthma there was significant correlation between FeNO values and bronchial hyperresponsiveness whether the child had symptoms of asthma or not.12
Inflammation is an important aspect of the pathophysiology of bronchial asthma and measurement of inflammatory markers of airways can aid in management. Nitric oxide measurement in exhaled breath is a non-invasive method of determining airway inflammation which can be used in assessing severity and response to treatment in children with bronchial asthma.
Thirty children in the age group 6–14 years with previously or newly diagnosed bronchial asthma reporting for the first time to a tertiary care hospital constituted the study group. Assessment was done by history, clinical examination, spirometry and measurement of fractional excretion of nitric oxide (FeNO) before commencement of treatment as per standard guidelines and on follow up at 2 to 4 weeks intervals for a minimum of three times.
There was significant correlation between FeNO values, spirometry parameters and clinical profile in the first visit before the initiation of therapy. Children with higher FeNO in the first visit responded better to Inhaled Corticosteroids (ICS) with good clinical and spirometry responses and fall in FeNO on second visit. However, in subsequent visits no significant correlation was observed between clinical control, FeNO levels and spirometry.
High FeNO values at first presentation could give us a clue as to whether or not a child would respond to ICS but FeNO monitoring may not be helpful in long term follow up as various other factors can affect its value.
Use of inflammatory markers for monitoring paediatric asthma
2015, Revista Chilena de Pediatria
La evaluación del control del asma considera la medición de la sintomatología, la calidad de vida, la función pulmonar y los marcadores inflamatorios. En los últimos años se han multiplicado las publicaciones relacionadas con el estudio de biomarcadores en el manejo del asma pediátrica. A pesar de la gran variedad de marcadores inflamatorios descritos en estudios de investigación, solo un pequeño grupo ha demostrado ser útil en el control de la enfermedad. Los eosinófilos en esputo inducido tienen la evidencia más sólida en la medición del control de asma. El condensado de aire exhalado y los leucotrienos urinarios podrían tener utilidad en el futuro si se logran estandarizar sus procedimientos e interpretación de resultados. El óxido nítrico, la proteína catiónica básica del eosinófilo y la biopsia bronquial con lavado broncoalveolar parecieran tener utilidad solo en un grupo reducido de pacientes.
The assessment of asthma control takes into account the symptoms, quality of life, lung function, and inflammatory markers. In the last few years, there has been a large increase in the number of publications related to the study of biomarkers in the management of paediatric asthma. Despite the large variety of inflammatory markers described in research studies, only a small group has shown to be useful in monitoring the disease. Induced sputum eosinophils offer the most solid evidence in assessing asthma control. Exhaled breath condensate and urinary leucotrienes could be useful in the future if there is standardisation in their procedures and interpretation of the results. Nitric oxide, basic eosinophil cationic protein, and bronchial biopsy with bronchoalveolar lavage, only appeared to be useful in a reduced group of patients.
Exhaled nitric oxide and the management of childhood asthma - yet another promising biomarker "has been" or a misunderstood gem
2015, Paediatric Respiratory Reviews
Citation Excerpt :
In contrast, at least one expert group argues that FENO has an important role in the management of asthma [38]. Between evidence synthesis [35–37] and expert opinion [38], a recent report from the National Institute for Clinical Efficacy in the UK [39] has suggested that “it could be argued that the available evidence does point towards some benefit to the technology [FENO measurement]” and cites limitations in the current literature as including “cut off values [which] are highly variable and largely based on derivation studies” and “unclear step-up/step-down protocols”. Although this is not a systematic review, the eight papers identified in section 2.1 are likely to represent most papers published in this area and a meta-analysis was undertaken using standard software (Review manager 5.2).
Childhood asthma is a common chronic condition. Approximately five percent of all children in western countries are prescribed treatment with inhaled corticosteroids (ICS) to prevent asthma symptoms. Current guidelines advocate titrating ICS dose to symptoms but this approach is not without problem, e.g. how to discern asthmatic from non-asthmatic symptoms? And when to reduce ICS dose? This review describes the strengths and weaknesses of fractional exhaled nitric oxide (FE_NO) as an objective index for individualising asthma control in children. Epidemiological and mechanistic evidence suggest that FE_NO should be a promising biomarker for eosinophilic airway inflammation (a hall mark for asthma) but somewhat surprisingly, clinical trials in children have not consistently found benefit from adding FE_NO to a symptom-based approach to ICS treatment in children. There are a number of reasons why FE_NO has apparently failed to translate from promising biomarker to clinically useful tool, and one reason may be a lack of understanding of what merits a significant intrasubject change in FE_NO. This review describes the rise and apparent fall of FE_NO as biomarker for asthma and then focuses on more recent evidence which suggest that FE_NO may prove to have a role in the management of childhood asthma, and in particular preventing exacerbations.
Childhood asthma biomarkers: Present knowledge and future steps
2015, Paediatric Respiratory Reviews
Citation Excerpt :
Findings suggest that using FENO to tailor the dose of inhaled corticosteroids in children is not to be recommended in routine clinical practice because this carries a danger of excessive inhaled corticosteroid doses being used without any corresponding significant improvement in clinical outcomes [36]. What is more, the meta-analyses both found no relevant variation in asthma exacerbations in the FENO group [35,36]. A more recent review [29] updated the results of these meta-analyses, however, using the asthma exacerbation rate and/or time to first asthma exacerbation as the primary outcome, instead of the number of exacerbations: taking this approach, the FENO-based asthma management strategy was associated with significantly lower exacerbation rates [29].
Asthma represents the most common chronic respiratory disease of childhood. Its current standard diagnosis relies on patient history of symptoms and confirmed expiratory airflow limitation. Nevertheless, the spectrum of asthma in clinical presentation is broad, and both symptoms and lung function may not always reflect the underlying airway inflammation, which can be determined by different pathogenetic mechanisms. For these reasons, the identification of objective biomarkers of asthma, which may guide diagnosis, phenotyping, management and treatment is of great clinical utility and might have a role in the development of personalized therapy. The availability of non-invasive methods to study and monitor disease inflammation is of relevance especially in childhood asthma. In this sense, a promising role might be played by the measurement of exhaled biomarkers, such as exhaled nitric oxide (FE_NO) and molecules in exhaled breath condensate (EBC). Furthermore, recent studies have shown encouraging results with the application of the novel metabolomic approach to the study of exhaled biomarkers. In this paper the existing knowledge in the field of asthma biomarkers, with a special focus on exhaled biomarkers, will be highlighted.

View all citing articles on Scopus

^☆: The study was supported by the Academy of Finland (grant number 132595), the Finnish Medical Foundation, Sigrid Juselius Foundation and Foundation for Paediatric Research, all in Helsinki, Finland.

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ReviewChildhood asthma management guided by repeated FeNO measurements: a meta-analysis☆

Summary

Introduction

Section snippets

Aims

Selection of studies

Description of studies

Discussion

Summary

Disclosure Statement

Educational Aims

Practice Points

Paediatr Respir Rev

Paediatr Respir Rev

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

Lancet

Chest

Respir Med

J Allergy Clin Immunol

J Pediatr

J Pediatr

J Allergy Clin Immunol

Basic aspects of exhaled nitric oxide

European Respiratory Monograph

Exhaled Nitric oxide in asthma

European Respiratory Monograph

Airway inflammation is present during clinical remission of atopic asthma

Am J Respir Crit Care Med

Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children

Clin Exp Allergy

A community study of exhaled nitric oxide in healthy children

Am J Respir Crit Care Med

Exhaled nitric oxide in healthy nonatopic school-age children: determinants and height-adjusted reference values

Pediatr Pulmonol

Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children

Thorax

Exhaled monoxides in asymptomatic atopic subjects

Clin Exp Allergy

Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate

Am J Respir Crit Care Med

Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests

Am J Respir Crit Care Med

Exhaled nitric oxide and asthma in young children

Pediatr Pulmonol

Review
Childhood asthma management guided by repeated FeNO measurements: a meta-analysis☆