piloted in the United States. These strategies seem destined tofail in a medical system such as ours, which does not reim-burse health care providers for the time devoted to dataanalysis without the patient being present.

Steven M. Willi, MDDirector, Diabetes Center for Children

Children’s Hospital of PhiladelphiaAssociate Professor of Pediatrics

University of PennsylvaniaPhiladelphia, PA

REFERENCES1. Bulsara MK, Holman CD, Davis EA, Jones TW. The impact of adecade of changing treatment on rates of severe hypoglycemia in a popula-tion-based cohort of children with type 1 diabetes. Diabetes Care2004;27:2293-8.2. Willi SM, Planton J, Egede L, Schwarz S. Benefits of continuoussubcutaneous insulin infusion in children with type 1 diabetes. J Pediatr2003;143:796-801.3. Alemzadeh R, Berhe T, Wyatt, DT. Flexible insulin therapy withglargine insulin improved glycemic control and reduced severe hypoglycemiaamong preschool-aged children with type 1 diabetes mellitus. Pediatrics2005;115:1320-4.4. Fox L, Buckloh LM, Smith SD, Wysocki T, Mauras N. A randomizedcontrolled trial of insulin pump therapy in young children with type 1diabetes. Diabetes Care 2005;28:1277-81.5. Diabetes Control and Complications Trial Research Group. Effect ofintensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus.J Pediatr 1994;125:177-88.

6. Tamborlane WV, Bonfig W, Boland E. Recent advances in treatmentof youth with type 1 diabetic: better care through technology. Diabetic Med2001;18:864-70.7. Springer D, Dzieura J, Tamborlane WV, Steffen AT, Ahearn J H,Vincent M, Weinzimer SA. Optimal control of type 1 diabetes in youthreceiving intensive treatment. J Pediatr 2006;149:227-32.8. Urbach SL, LaFranchi S, Lambert L, Lapidus JA, Daneman D, BeckerTM. Predictors of glucose control in children and adolescents with type 1diabetes mellitus. Pediatr Diabetes 2005;6:69-74.9. Kaufman FR, Halvorson M, Carpenter S. Association between diabetescontrol and visits to a multidisciplinary pediatric diabetes clinic. Pediatrics1999;103:948-51.10. Wysocki T, Harris MA, Wilkinson K, Sadler M, Mauras N, WhiteNH. Self-management competence as a predictor of outcomes of intensivetherapy or usual care in youth with type 1 diabetes. Diabetes Care2003;26:2043-7.11. Diabetes Control and Complications Trial Research Group. Resourceutilization and costs of care in the diabetes control and complications trial.Diabetes Care 1995;18:1468-78.12. Jeha GS, Karaviti LP, Anderson D, Smith EO, Donaldson S, McGirkTS, Haymond MW. Continuous glucose monitoring and the reality ofmetabolic control in preschool children with type 1 diabetes. Diabetes Care2004;27:2881-6.13. Beck JK, Logan KJ, Hamm RM, Sproat SM, Musser KM, EverhartPD, et al. Reimbursement for pediatric diabetes intensive case management:a model for chronic diseases? Pediatrics 2004;113:47-50.14. Montori VM, Helgemoe PK, Guyatt GH, Dean DS, Leung TW,Smith SA, Kudva TC. Telecare for patients with type 1 diabetes andinadequate glycemic control: a randomized controlled trial and meta-analysis.Diabetes Care 2004;27:1088-94.

NO THE EVIDENCE: WHAT HAVE MEASUREMENTS OF EXHALED NITRICOXIDE GOT TO OFFER?

The relationship between the measurement of exhalednitric oxide (FeNO) and pediatric investigators hasgone from the heady excitement of the early flirta-

tions to a more solid and permanent relationship, perhaps lesssuperficially exciting, requiring harder work, but ultimatelymore realistic. The initial nitric oxide studies were largelycross-sectional or, at best, very-short-term longitudinal,1,2 butwere sufficient to suggest that here was something that addeda new dimension to the management of asthma.

A sea change in asthma management was long overdue.The importance of asthma as an inflammatory disease (at leastin older children and adults, not necessarily in infants andpreschool children) has long been appreciated, but even recentconventional guidelines3 instruct us to treat airway inflamma-tion with potent and potentially toxic anti-inflammatoryagents,4 without ever measuring inflammation at all! It isunimaginable that a cardiologist would fail to measure bloodpressure while prescribing antihypertensives, but that is ex-actly the situation in which we now find ourselves.

Initial studies in adults clearly demonstrated thatasthma could be better managed if a measure of inflammationwas used. Perhaps the best study showed that using inducedsputum eosinophils to titrate the dose of inhaled corticoste-roids resulted in fewer exacerbations without any increase inthe dose of inhaledmedication when com-pared with a groupmanaged convention-ally.5 A number of pe-diatric studies haveshown that FeNO canbe used to titrate thedose of inhaled ste-roids, leading to a bet-ter outcome,6 and topredict relapse aftercessation of inhaledcorticosteroids.7 A low

See related article, p 220

Reprint requests: Professor AndrewBush, Department of Paediatric Respira-tory Medicine, Royal Brompton Hospital,Sydney Street, London SW3 6NP,UK. E-mail: a.bush@rbh.nthames.nhs.uk.

J Pediatr 2006;149:156-8

0022-3476/$ - see front matter

Copyright © 2006 Mosby Inc. All rightsreserved.

10.1016/j.jpeds.2006.05.035

156 Editorials The Journal of Pediatrics • August 2006

FeNO value predicted successful steroid reduction (but notvice versa),8 so these measurements must be interpreted withcaution.9 Nonetheless, proof of concept has unequivocallyestablished that state-of-the-art asthma management nolonger comprises simply history, physical examination, andlung function studies. However, a number of questions arise:What do we actually want to treat? What is FeNO actuallymeasuring? Is measuring FeNO the best way to assess inflam-mation in asthma? And, finally, what does an elevation inFeNO actually mean for clinical practice today?

The first question seems to have an obvious answer:eosinophilic airway inflammation. However, recent literaturesounds a note of caution. There is a poor relationship betweeneosinophilia seen on endobronchial biopsy and eosinophilcounts in induced sputum or bronchoalveolar lavage, whereassputum and lavage eosinophils show a good correlation.10

What are we trying to treat? What is the significance of thelarge numbers of eosinophils seen in endobronchial biopsyspecimens of young adults who have outgrown asthma?11 Theanswer will come only from longitudinal studies, and thenonly if we can find a noninvasive marker of airway walleosinophils.

In broad terms, there is a correlation between FeNOand induced sputum eosinophil count,12 which is usually seenonly in those not taking inhaled corticosteroids.13 In ourhands, FeNO is commonly elevated when sputum eosinophilcount is normal, at least in severe asthmatics, and a normalFeNO with elevated sputum eosinophils is very unusual.10,14

So it is likely that the finding of elevated FeNO overestimateseosinophilic 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 patientcooperation; directly measures all relevant aspects of in-flammation; and provides rapid availability of answers andevidence of beneficial clinical outcomes. Of course, no suchdevice exists, but FeNO has many desirable characteristics,particularly the easy and noninvasive nature of the mea-surements and the rapid availability of answers. But weneed to be aware that the search for a better inflammom-eter should go on.

Finally, what does a pediatrician do when confrontedwith a child with an elevated FeNO in the clinic? One shouldbe aware that this may be a false-positive finding, and that noaction may be needed. We are not yet at the point of treatingelevated FeNO in an asymptomatic child outside the contextof a controlled trial. However, particularly if the child issymptomatic, a raised FeNO is strongly suggestive of uncon-trolled eosinophilic inflammation, except in the presence of aviral respiratory infection.15 There are a number of possiblecauses, including an inadequate prescribed dose of inhaledcorticosteroids, failure to take the prescribed dose, inadequatedrug delivery due to an inappropriate choice of device or pooreducation, and relative steroid resistance. A FeNO measure-ment 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 medicationdose without due thought.

In this issue of The Journal, Spanier et al16 valuablyremind us that environmental influences may be an importantcause of a raised FeNO, and that these should be tackledbefore escalating pharmacotherapy. There is good evidencethat low-dose allergen exposure insufficient to cause deterio-ration in lung function can possibly cause asymptomatic de-terioration in terms of bronchial hyperreactivity and airwayinflammation.17 In addition, the presence of allergens towhich the patient is sensitized can cause relative steroid re-sistance, probably mediated through an interleukin-2– and-4–driven mechanism.18,19 Although these authors could notdetermine an effect of exposure without sensitization, anothergroup has shown that adult asthmatics exposed to high levelsof Der p1 and Can f1, but not Fel d1, have higher levels ofFeNO independent of sensitization.20 The emphasis on re-ducing allergen exposure in the home is particularly impor-tant, given the mounting evidence of synergy between aller-gens and viral infections in causing acute exacerbations ofasthma.21,22 Because all of the children in the study of Spanieret al were passively exposed to cigarette smoke, the study wasnot optimal for detecting whether passive smoking had arelationship with FeNO. It is noteworthy that adult asthmat-ics who smoke have a relative resistance to the effect ofinhaled and oral corticosteroids, albeit without sputumeosinophilia.23,24

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

Louise Fleming, MRCPCHNicola Wilson, MD, FRCPCH

Andrew Bush, MB, BS (Hons), MA, MD, FRCP, FRCPCHDepartment of Paediatric Respiratory Medicine

Royal Brompton HospitalLondon, United Kingdom

REFERENCES1. Kharitonov S, Yates D, Robbins RA, Logan Sinclair R, ShinebourneEA, Barnes PJ, et al. Increased nitric oxide in exhaled air of asthmaticpatients. Lancet 1994;343:133-5.2. Byrnes CA, Denarevic S, Shinebourne EA, Barnes PJ, Bush A. Ex-haled nitric oxide measurements in normal and asthmatic children. PediatrPulmonol 1997;24:312-8.3. British guideline on the management of asthma. Thorax 2003;58(Suppl1):S1-94.4. Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCanceD. Survey of adrenal crisis associated with inhaled corticosteroids in theUnited Kingdom. Arch Dis Child 2002;87:457-61.5. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D,Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: arandomised controlled trial. Lancet 2002;360:1715-21.

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6. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titratingsteroids on exhaled nitric oxide in children with asthma: a randomizedcontrolled trial. Am J Respir Crit Care Med 2005;172:831-6.7. Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitricoxide predicts asthma relapse in children with clinical asthma remission.Thorax 2005;60:215-8.8. Zacharasiewicz A, Wilson N, Lex C, Erin EM, Li AM, Hansel T,et al. Clinical use of noninvasive measurements of airway inflammation insteroid reduction in children. Am J Respir Crit Care Med2005;171:1077-82.9. Pijnenburg MW, Bakker EM, Lever S, Hop WC, De Jongste JC. Highfractional concentration of nitric oxide in exhaled air despite steroid treat-ment in asthmatic children. Clin Exp Allergy 2005;35:920-5.10. Lex C, Ferreira F, Payne DNR, Zacharasiewicz A, Nicholson A,Haslam P, et al. Comparison of noninvasive and invasive methods forassessment of airway inflammation in children with asthma. Thorax2003;58,SIII:iii61.11. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogst-eden HC, Prins JB. Airway inflammation is present during clinical remissionof atopic asthma. Am J Respir Crit Care Med 2001;164:2107-13.12. Baraldi E, de Jongste JC, European Respiratory Society, AmericanThoracic Society. ERS/ATS Statement. Measurement of exhaled nitric oxidein children. Eur Respir J 2002;20:223-37.13. Piacentini GL, Bodini A, Costella S, Vincentini I, Mazzi P, SperadisS, et al. Exhaled nitric oxide and sputum eosinophil markers of inflammationin asthmatic children. Eur Respir J 1999;13:1386-90.14. Lex C, Payne DN, Zacharasiewicz A, Li AM, Wilson NM, HanselTT, et al. Sputum induction in children with difficult asthma: safety, feasi-bility, and inflammatory cell pattern. Pediatr Pulmonol 2005;39:318-24.15. Proud D. Nitric oxide and the common cold. Curr Opin Allergy ClinImmunol 2005;5:37-42.16. Spanier AJ, Horung R, Lierl M. Lanphear BP. Environmental

exposure and exhaled nitric oxide in children with asthma. J Pediatr2006;149:220-6.17. Sulakvelidze I, Inman MD, Rerecich T, O’Byrne PM. Increases inairway eosinophils and interleukin-5 with minimal bronchoconstriction dur-ing repeated low-dose allergen challenge in atopic asthmatics. Eur Respir J1998;11:821-7.18. Nimmagadda SR, Szefler SJ, Spahn JD, Surs W, Leung DYM. Aller-gen exposure decreases glucocorticoid receptor binding affinity and steroidresponsiveness in atopic asthmatics. Am Rev Respir Crit Care Med1997;155:87-93.19. Torrego A, Pujols L, Roca-Ferrer J, Mullol J, Xaubet A, Picado C.Glucocorticoid receptor isoforms alpha and beta in in vitro cytokine-induced glucocorticoid insensitivity. Am J Respir Crit Care Med2004;170:420-8.20. Langley SJ, Goldthorpe S, Craven M, Woodcock A, Custovic A.Relationship between exposure to domestic allergens and bronchial hyperre-sponsiveness in non-sensitised, atopic asthmatic subjects. Thorax 2005;60:17-21.21. Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL,Woodcock A. Synergism between allergens and viruses and risk of hos-pital admission with asthma: case-control study. Br Med J 2002;324:763-6.22. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston S,et al. A study of modifiable risk factors for asthma exacerbations: virusinfection and allergen exposure increase the risk of asthma hospitalization inchildren. Thorax 2006;61:376-82.23. Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP,Thomson NC. Influence of cigarette smoking on inhaled corticosteroidtreatment in mild asthma. Thorax 2002;57:226-30.24. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W,Thomson NC. Cigarette smoking impairs the therapeutic response to oralcorticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308-11.

158 Editorials The Journal of Pediatrics • August 2006