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Editorial

Indian Pediatr 2014;51: 101-102

Exhaled Nitric Oxide Measurement in Pediatric Asthma

PULMONOLOGIST’S PERSPECTIVE


Ranjan Suri

Pediatric Respiratory Consultant, Respiratory Unit, Great Ormond Street Hospital, and Portex Unit, UCL Institute of Child Health, London, United Kingdom.
Email: [email protected]


Nitric oxide (NO) is a biological mediator produced by NO synthase (NOS) in airway epithelial cells, which diffuses into the airway lumen. In the lungs, NO determines smooth muscle relaxation, affects ciliary beat frequency, mucus secretion and plasma exudation, and is involved in inflammation and cell-mediated immunity processes [1]. Measurement of fractional exhaled NO (FENO) requires a series of continuous expiratory manoeuvres using an incentive device. However, the role of measuring FENO as a non-invasive biomarker to optimize asthma management in children is hotly debated.

Chronic airway inflammation is an important feature of asthma. FENO levels are increased in patients with asthma as a result of induction of NOS-2 by pro-inflammatory cytokines. Elevated FENO levels have been shown to correlate with increased eosinophils in blood, bronchoalveolar lavage fluid and sputum, suggesting that FENO reflects eosinophilic inflammation [2]. However, asthma is not a single disease and at least three adult phenotypes of airway inflammation have been identified on the basis of predominant eosinophilic, neutrophilic, or pauci-granulocitic cellular pattern [3].

Even though FENO is increased in children with allergic asthma [4], the obtained levels cannot discriminate among school children with non-allergic asthma. Furthermore, FENO can be elevated in patients who are atopic and not asthmatic. Levels of FENO appear increased in asthmatics with pollen allergy during the season even though there may be an absence of symptoms and normal lung function [5].

It had been postulated that tracking FENO may be helpful in managing asthma, as it improves after steroid treatment and may predict exacerbations in pollen sensitive asthma. However, it has been shown not to correlate with symptoms, and a meta-analysis [6] of three pediatric studies showed that FENO-guided treatment did not improve asthma outcomes.

The goal of long-term asthma treatment is to reduce airway inflammation and control symptoms. In this month’s journal, Raj, et al. [7] studied children with asthma to investigate whether FENO could predict an acute exacerbation or its severity. This paper addresses a very important issue in current asthma management, as FENO has been proposed as a biomarker, correlating well with levels of eosinophilic airway inflammation. Some papers have suggested its use for guiding pharmacotherapy. In everyday practice, however, it seems to be very helpful for some patients, while it does not correlate with clinical symptoms and lung function in others.

The authors studied 243 asthmatic children (mean age 99 months), with an average duration of follow up of 434 days (range 84 to 825 days). Patients were reviewed every 3 months and underwent spirometry, FENO, pulmonary symptom scores, skin prick tests to aeroallergens and blood eosinophil counts were measured. Although FENO levels increased during an exacerbation, the authors were unable to find a particular cut-off which could help in either diagnosing an acute asthma exacerbation or predicting its severity in children.

So, should the results of this and other recently published studies [8,9] discourage the clinician from using FENO as a routine marker for guiding management in this age group? If asthma symptoms and inflammation were concordant, measuring FENO would not likely be useful. It is only when they are discordant – that is inflammation is disproportionately greater than symptoms, or vice-versa – measuring FENO may prove beneficial. Clearly, measuring FENO or other inflammatory biomarkers is no substitute for doing the basics of asthma management correctly; as often, simple measures can improve symptoms and avoid escalation of treatment. Adherence must be optimized, co-morbidities treated, allergen load reduced to a minimum and inhaler technique regularly checked.

Certainly more studies will need to be done in this area of pediatric asthma. FENO may remain a useful marker for assessing patients at the time of diagnosis and also to help monitor the level of asthma control of individual patients in clinical practice.

References

1. Kharatonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001;163:1693-1722.

2. Jouaville LF, Annesi-Maesano I, Nguyen LT, Bocage AS, Bedu M, Caillaud D. Interrelationship among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children. Clin Exp Allergy. 2003;33: 1506-11.

3. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368:804-13.

4. Frank TL, Adisesh A, Pickering AC, Morrison JF, Wright T, Francis H, et al. Relationship between exhaled nitric oxide and childhood asthma. Am J Respir Crit Care Med. 1998;158:1032-6.

5. Vahlkvist S, Sinding M, Skamstrup K, Bisgaard H. Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure. J Allergy Clin Immunol. 2006;117:1272-6.

6. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67:199-208.

7. Raj D, Lodha R, Mukherjee A, Sethi T, Agrawal A, Kabra SK. Fractional exhaled nitric oxide in children with acute exacerbation of asthma. Indian Pediatr. 2013;51:105-11.

8. de Jongste JC, Carraro S, Hop WC, the CHARISM Study Group, Baraldi E. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med. 2009;179:93-7.

9. Szefler SJ, Mitchell H, Sorkness CA, Gergen PT, O’Connor GT, Morgan WJ, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet. 2008;372:1065-72.

 

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