The Journal of Pediatrics
Volume 149, Issue 2 , Pages 156-158, August 2006

No the evidence: What have measurements of exhaled nitric oxide got to offer?

  • Louise Fleming, MRCPCH
    • ,
  • Nicola Wilson, MD, FRCPCH
    • ,
  • Andrew Bush, MB, BS (Hons), MA, MD, FRCP, FRCPCH

      Affiliations

    • Corresponding Author InformationReprint requests: Professor Andrew Bush, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom

Article Outline

Abbreviations:  FeNO, Exhaled nitric oxide

 

The relationship between the measurement of exhaled nitric oxide (FeNO) and pediatric investigators has gone from the heady excitement of the early flirtations to a more solid and permanent relationship, perhaps less superficially exciting, requiring harder work, but ultimately more realistic. The initial nitric oxide studies were largely cross-sectional or, at best, very-short-term longitudinal,1, 2 but were sufficient to suggest that here was something that added a new dimension to the management of asthma.

See related article, p 220

A sea change in asthma management was long overdue. The importance of asthma as an inflammatory disease (at least in older children and adults, not necessarily in infants and preschool children) has long been appreciated, but even recent conventional guidelines3 instruct us to treat airway inflammation with potent and potentially toxic anti-inflammatory agents,4 without ever measuring inflammation at all! It is unimaginable that a cardiologist would fail to measure blood pressure while prescribing antihypertensives, but that is exactly the situation in which we now find ourselves.

Initial studies in adults clearly demonstrated that asthma could be better managed if a measure of inflammation was used. Perhaps the best study showed that using induced sputum eosinophils to titrate the dose of inhaled corticosteroids resulted in fewer exacerbations without any increase in the dose of inhaled medication when compared with a group managed conventionally.5 A number of pediatric studies have shown that FeNO can be used to titrate the dose of inhaled steroids, leading to a better outcome,6 and to predict relapse after cessation of inhaled corticosteroids.7 A low FeNO value predicted successful steroid reduction (but not vice versa),8 so these measurements must be interpreted with caution.9 Nonetheless, proof of concept has unequivocally established that state-of-the-art asthma management no longer comprises simply history, physical examination, and lung function studies. However, a number of questions arise: What do we actually want to treat? What is FeNO actually measuring? Is measuring FeNO the best way to assess inflammation in asthma? And, finally, what does an elevation in FeNO actually mean for clinical practice today?

The first question seems to have an obvious answer: eosinophilic airway inflammation. However, recent literature sounds a note of caution. There is a poor relationship between eosinophilia seen on endobronchial biopsy and eosinophil counts in induced sputum or bronchoalveolar lavage, whereas sputum and lavage eosinophils show a good correlation.10 What are we trying to treat? What is the significance of the large numbers of eosinophils seen in endobronchial biopsy specimens of young adults who have outgrown asthma?11 The answer will come only from longitudinal studies, and then only if we can find a noninvasive marker of airway wall eosinophils.

In broad terms, there is a correlation between FeNO and induced sputum eosinophil count,12 which is usually seen only in those not taking inhaled corticosteroids.13 In our hands, FeNO is commonly elevated when sputum eosinophil count is normal, at least in severe asthmatics, and a normal FeNO with elevated sputum eosinophils is very unusual.10, 14 So it is likely that the finding of elevated FeNO overestimates eosinophilic inflammation in the airway in some children.

The characteristics of an ideal “inflammometer” would be as follows: cheap; easy to maintain and calibrate; completely noninvasive; easy to use, requires no patient cooperation; directly measures all relevant aspects of inflammation; and provides rapid availability of answers and evidence of beneficial clinical outcomes. Of course, no such device exists, but FeNO has many desirable characteristics, particularly the easy and noninvasive nature of the measurements and the rapid availability of answers. But we need to be aware that the search for a better inflammometer should go on.

Finally, what does a pediatrician do when confronted with a child with an elevated FeNO in the clinic? One should be aware that this may be a false-positive finding, and that no action may be needed. We are not yet at the point of treating elevated FeNO in an asymptomatic child outside the context of a controlled trial. However, particularly if the child is symptomatic, a raised FeNO is strongly suggestive of uncontrolled eosinophilic inflammation, except in the presence of a viral respiratory infection.15 There are a number of possible causes, including an inadequate prescribed dose of inhaled corticosteroids, failure to take the prescribed dose, inadequate drug delivery due to an inappropriate choice of device or poor education, and relative steroid resistance. A FeNO measurement by itself cannot distinguish between these possibilities. How should the clinician respond? Obviously with a full review of the child, not just with an increase in the medication dose without due thought.

In this issue of The Journal, Spanier et al16 valuably remind us that environmental influences may be an important cause of a raised FeNO, and that these should be tackled before escalating pharmacotherapy. There is good evidence that low-dose allergen exposure insufficient to cause deterioration in lung function can possibly cause asymptomatic deterioration in terms of bronchial hyperreactivity and airway inflammation.17 In addition, the presence of allergens to which the patient is sensitized can cause relative steroid resistance, probably mediated through an interleukin-2– and -4–driven mechanism.18, 19 Although these authors could not determine an effect of exposure without sensitization, another group has shown that adult asthmatics exposed to high levels of Der p1 and Can f1, but not Fel d1, have higher levels of FeNO independent of sensitization.20 The emphasis on reducing allergen exposure in the home is particularly important, given the mounting evidence of synergy between allergens and viral infections in causing acute exacerbations of asthma.21, 22 Because all of the children in the study of Spanier et al were passively exposed to cigarette smoke, the study was not optimal for detecting whether passive smoking had a relationship with FeNO. It is noteworthy that adult asthmatics who smoke have a relative resistance to the effect of inhaled and oral corticosteroids, albeit without sputum eosinophilia.23, 24

In summary, although there is perhaps more evidence of the usefulness of FeNO measurements than Spanier et al acknowledge,6, 7, 8 these authors’ reminder of the importance of the environment in the control of asthma in children is timely. So, NO what to do now? If your child with asthma has an elevated FeNO, consider whether the environment could be driving it up, as well as about increasing the dose of the medication and changing the drug delivery device. Finally, place a call to the local pharmacy; inhaled steroids never work if they remain uncollected!

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References 

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PII: S0022-3476(06)00484-7

doi:10.1016/j.jpeds.2006.05.035

Refers to article:

  • Environmental exposures and exhaled nitric oxide in children with asthma

    Adam J. Spanier, Richard Hornung, Michelle Lierl, Bruce P. Lanphear
    The Journal of Pediatrics August 2006 (Vol. 149, Issue 2, Pages 220-226)

The Journal of Pediatrics
Volume 149, Issue 2 , Pages 156-158, August 2006

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