Measuring Airway Eosinophils in Asthmatic Children
Measuring Airway Eosinophils in Asthmatic Children
Published: October 2008
It is clear that assessing asthma on the basis of history, physical examination and physiological testing – as recommended by most current national and international guidelines – is no longer state of the art.1 The inclusion of some measure of airway inflammation into the decision-making process improves control of asthma, usually – but not invariably – without the need for increased doses of inhaled corticosteroids, and may:2-5
• predict relapse when reducing or stopping asthma therapy;6,7
• predict impending asthma exacerbations;8 and
• improve the diagnosis of asthma.9
Surrogates used for inflammation in clinical practice include induced sputum,2,6 fractional exhaled nitric oxide (FeNO)3,4,6-8 and bronchial hyperreactivity (BHR).5 The following aspects characterise the perfect ‘inflammometer’:
• inexpensive;
• easy to maintain and calibrate;
• completely non-invasive;
• easy to use, no co-operation needed;
• direct measurement of all relevant aspects of inflammation;
• rapid availability of answers; and
• evidence of beneficial clinical outcomes.
In clinical practice, although direct invasive methods such as bronchoscopy, bronchoalveolar lavage (BAL) and endobronchial biopsy have been used on a ‘one-off’ basis to phenotype severe asthma and plan treatment,10,11 for most purposes non-invasive methods must be used. The most direct method is induced-sputum cytology, in particular eosinophil count. A randomised, double-blind, controlled study in adults demonstrated improved control of asthma if sputum eosinophil counts were normalised.2 In other words, increasing treatment in an asymptomatic patient if there was a raised sputum eosinophil count, and reducing treatment – irrespective of symptoms – if the sputum eosinophil count was <2.5%, leads to better outcomes with no increase in inhaled-corticosteroid dose than conventional guideline-driven management.12 Similarly, the absence of eosinophils from induced sputum predicted successful dose reduction in a group of asthmatic children.6 However, sputum induction is timeconsuming, may not be safe in severe airflow obstruction and is unsuccessful in around one-quarter of children.13 Hence, FeNO has been increasingly used as a surrogate for airway inflammation in clinical practice. This is not just because of ease of measurement in the clinic, but because it is becoming increasingly possible to monitor FeNO daily in the community.14-18 Guidelines for the measurement of exhaled nitric oxide have been published,19 and it is advised that the expiratory flow rate should be kept at 50ml/second (FeNO50).
- Zacharasiewicz A, Erin EM, Bush A, Noninvasive monitoring of airway inflammation and steroid reduction in children with asthma, Curr Opin Allergy Clin Immunol, 2006;6:155–60.
- Green RH, Brightling CE, McKenna S, et al., Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial, Lancet, 2002;360:1715–21.
- Pijnenburg MW, Bakker EM, Hop WC, de Jongste JC, Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial, Am J Respir Crit Care Med, 2005;172:831–6.
- Smith AD, Cowan JO, Brassett KP, et al., Use of exhaled nitric oxide measurements to guide treatment in chronic asthma, N Engl J Med, 2005;352:2163–73.
- Sont JK, Willems LN, Bel EH, et al., Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment, The AMPUL Study Group, Am J Respir Crit Care Med, 1999;159:1043–51.
- Zacharasiewicz A, Wilson N, Lex C, et al., Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children, Am J Respir Crit Care Med, 2005;177:1077–82.
- Pijnenburg MW, Hofhuis W, Hop WC, de Jongste JC, Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission, Thorax, 2005;60:215–18.
- Roberts G, Hurley C, Bush A, Lack G, Longitudinal study of grass pollen exposure, symptoms, and exhaled nitric oxide in childhood seasonal allergic asthma, Thorax, 2004;59:752–6.
- Smith AD, Cowan JO, Filsell S, et al., Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests, Am J Respir Crit Care Med, 2004;169:473–8.
- Payne DNR, Adcock IM, Wilson NM, et al., Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma after treatment with oral prednisolone, Am J Respir Crit Care Med, 2001, 164:1376–81.
- Payne D, Saglani S, Suri R, et al., Asthma: beyond the guidelines, Current Paediatrics, 2004,14:336–46.
- British Thoracic Society, Scottish Intercollegiate Guidelines Network, British guideline on the management of asthma, Thorax, 2003;58(Suppl.1):i1–94.
- Lex C, Payne DN, Zacharasiewicz A, et al., Sputum induction in children with difficult asthma: safety, feasibility, and inflammatory cell pattern, Pediatr Pulmonol, 2005;39:318–24.
- Pijnenburg MW, Floor SE, Hop WC, de Jongste JC, Daily ambulatory exhaled nitric oxide measurements in asthma, Pediatr Allergy Immunol, 2006;17:189–93.
- Gill M, Graff GR, Adler AJ, Dweik RA, Validation study of fractional exhaled nitric oxide measurements using a handheld monitoring device, J Asthma, 2006;43:731–4.
- McGill C, Malik G, Turner SW, Validation of a hand-held exhaled nitric oxide analyzer for use in children, Pediatr Pulmonol, 2006;41:1053–7.
- Alving K, Janson C, Nordvall L, Performance of a new handheld device for exhaled nitric oxide measurement in adults and children, Respir Res, 2006;7:67.
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- Baraldi E, de Jongste JC, European Respiratory Society, American Thoracic Society, Measurement of exhaled nitric oxide in children, 2001, Eur Respir J, 2002;20:223–37.
- Piacentini GL, Bodini A, Costella S, et al., Exhaled nitric oxide and sputum eosinophil markers of inflammation in asthmatic children, Eur Respir J, 1999;13:1386–90.
- Pijnenburg MW, Bakker EM, Lever S et al, High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children, Clin Exp Allergy, 2005;35: 920–25.
- Proud D, Nitric oxide and the common cold, Curr Opin Allergy Clin Immunol, 2005;5:37–42.
- Fleming L, Wilson N, Bush A, NO the evidence: what have measurements of exhaled nitric oxide got to tell us?, J Pediatr, 2006;149:156–8.
- Nimmagadda SR, Szefler SJ, Spahn JD, et al., Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics, Am Rev Respir Crit Care Med, 1997;155:87–93.
- Torrego A, Pujols L, Roca-Ferrer J, et al., Glucocorticoid receptor isoforms alpha and beta in in vitro cytokine-induced glucocorticoid insensitivity, Am J Respir Crit Care Med, 2004;170:420–28.
- Spanier AJ, Hornung R, Lierl M, Lomphear BP, Environmental exposures and exhaled nitric oxide in children with asthma, J Pediatr, 2006;149:220–26.
- Almqvist C, Wickman M, Perfetti L, et al., Worsening of asthma in children allergic to cats, after indirect exposure to cat at school, Am J Respir Crit Care Med, 2001;163:694–8.
- Langley SJ, Goldthorpe S, Craven M, et al., Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects, Thorax, 2005;60:17–21.
- Byrnes C, Denarevic S, Busst C, et al., Is nitric oxide produced at airway or alveolar level?, Eur Respir J, 1997;10:1021–5.
- Tsoukias NM, George SC, A two-compartment model of pulmonary nitric oxide exchange dynamics, J Appl Physiol, 1998;85:653–66.
- Tsoukias NM, Shin HW, Wilson AF, George SC, A single-breath technique with variable flow rate to characterize nitric oxide exchange dynamics in the lungs, J Appl Physiol, 2001;91:477–87.
- Condorelli P, Shin HW, Aledia AS, et al., A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model, J Appl Physiol, 2007;102:417–25.
- Paraskakis E, Brindicci C, Fleming L, et al., Measurement of bronchial and alveolar nitric oxide production in normal and asthmatic children, Am J Respir Crit Care Med, 2006;174: 260–67.
- Kraft M, Djukanovic R, Wilson S, et al., Alveolar tissue inflammation in asthma, Am J Respir Crit Care Med, 1996;154:1505–10.
- Sutherland ER, Martin RJ, Bowler RP, et al., Physiologic correlates of distal lung inflammation in asthma, J Allergy Clin Immunol, 2004;113:1046–50.
- Kraft M, Martin RJ, Wilson S, et al., Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma, Am J Respir Crit Care Med, 1999;159:228–34.
- Lex C, Ferreira F, Zacharasiewicz A, et al., Airway eosinophilia in children with severe asthma: predictive values of noninvasive tests, Am J Respir Crit Care Med, 2006;174:1286–91.
- Leckie MJ, ten Brinke A, Khan J, et al., Effects of an interleukin- 5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response, Lancet, 2000;356:2144–8.
- Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS, Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway, Am J Respir Crit Care Med, 2003;167:199–204.
- van den Toorn LM, Overbeek SE, de Jongste JC, et al., Airway inflammation is present during clinical remission of atopic asthma, Am J Respir Crit Care Med, 2001;164:2107–13.
- NiOX MINO®, Aerocrine AB, Sweden.
- Reddel H, Ware S, Marks G, et al., Differences between asthma exacerbations and poor asthma control, Lancet, 1999;353: 364–9.
- Wensley D, Silverman M, Peak flow monitoring for guided selfmanagement in childhood asthma: a randomized controlled trial, Am J Respir Crit Care Med, 2004;170:606–12.
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