Bronchodilator Response: Another Piece in the Asthma Mosaic

lack of spontaneous labor add to the risk of death in infants with congenital anomalies? Are late-preterm infants at higher risk of death if infants with congenital anomalies are excluded? To address the last issue, the authors performed additional analysis of their data after excluding infants with any congenital malformation, deformation, or chromosomal abnormality (ICD-10Q00-99) as the underlying cause of death. The differences in infant mortality between late-preterm and term infants were found to persist even with these exclusions, underscoring the inherent vulnerability of the latepreterm infant to serious morbidity and death. There are several limitations to the methodology used and, as such, to any conclusions drawn from data linked to death certificates.8 Death certificates lack information about contributing causes of death that could shed more light on diagnostic categories such as “atelectasis.” Autopsy findings were also not available to ascertain diagnoses such as sudden infant death syndrome (SIDS). Finally, data reported on gestational age may be subject to misclassification, although, as the authors argue, such errors should impact both subgroups included in the analysis. However, the hypothesis generated by these data that now needs further testing is straightforward: Are late-preterm infants at higher risk for death than their term counterparts, and, if so, why? Overall, it should come as no surprise that the higher morbidity reported in late-preterm infants may be associated with an increase in mortality as well. What is surprising is the magnitude of the difference in death rates between latepreterm and term infants, given the perception of mild and transient nature of these problems. The findings should also foster debate around the rationale for preterm delivery, particularly when the decision to do so is based on soft indications. Although the data provide no direct link to the widespread practice of induction of labor and/or elective cesarean

sections, it raises questions about the recent rise in such practices, particularly in the face of uncertainty in accurate estimation of gestational age. As such, future occurrences of serious morbidity/death in electively delivered late-preterm infants where a clear indication for early delivery is lacking should call for a thorough peer review of the circumstances around delivery and the subsequent care of the neonate. Finally, there is an urgent need to study the role of strategies to enhance maturity of the late-preterm fetus, such as the use of antenatal steroids. Given the large number of deliveries at late-preterm gestations, the public heath impact of such preventive strategies could be enormous. Lucky Jain, MD Department of Pediatrics and Physiology Emory University School of Medicine Atlanta, Georgia

REFERENCES 1. Dudell GG, Jain L. Hypoxic respiratory failure in the late preterm infant. Clin Perinatol 2006;33:803-30. 2. Jain L, Dudell GG. Respiratory transition in infants delivered by cesarean section. Semin Perinatol 2006;30:296-304. 3. Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 2006;118:1207-14. 4. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114:372-76. 5. Escobar GJ, Greene JD, Hulac P, Kincannon E, Bischoff K, Gardner MN, et al. Rehospitalisation after birth hospitalisation: patterns among infants of all gestations. Arch Dis Child 2005;90:125-31. 6. Davidoff MJ, Dias T, Damus K, Russell R, Bettegowda VR, Dolan S, et al. Changes in the gestational age distribution among U.S. singleton births: impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol 2006;30:8-15. 7. Clark RH. The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. J Perinatol 2005;25:251-7. 8. Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR. Differences in mortality between late-preterm and term singleton infants in the United States, 19952002. J Pediatr 2007;151:450-6.

Bronchodilator Response: Another Piece in the Asthma Mosaic

onsidering that it is such a common disease, the diagnosis and severity classification of asthma is extraordinarily difficult. Gross put it well: “It’s like love, we all know what it is, but who would trust anybody else’s definition?”1 The National Asthma Education and Prevention Program (NAEPP) guidelines suggest the diagnosis of asthma should be in large part based upon the medical history and physical examination.2 However, these guidelines rightly go on to point out that “patients with asthma are heterogeneous and present signs and symptoms that vary widely from patient to patient as

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well as within each patient over time.” Subtle variations in the interpretation of an individual patient’s signs and symptoms may greatly influence not only whether the diagSee related article, p 457 nosis of asthma is made, but also affect the agReprint requests: Howard Eigen, MD, Riley gressiveness of the ensuHospital for Children, 702 Barnhill Drive, ing treatment. Thus, we ROC 4270, Indianapolis, IN 46202. E-mail: [email protected]. can think of asthma as a J Pediatr 2007;151:446-8 complex mosaic, with 0022-3476/$ - see front matter the history and exam as Copyright © 2007 Mosby Inc. All rights only two tiles in a much reserved. larger diagnostic picture. 10.1016/j.jpeds.2007.07.016

The Journal of Pediatrics • November 2007

In order to provide more objective diagnostic criteria, the NAEPP guidelines advise routine use of spirometry to aid in the diagnosis of asthma. Indeed, the three facets of history, exam and low baseline forced expiratory volume in 1 second (FEV1) remain the standard for diagnosing asthma in adults. However, in children there are convincing data showing that baseline FEV1 is not a good measure of the presence of asthma or its severity. In the Childhood Asthma Management Program study, which evaluated 1041 children with mild to moderate asthma, more than 50% of the patients had moderate persistent asthma as defined by frequency of symptoms.3 Asthma was well documented in these patients over the 5-year life of the study, yet the prebronchodilator FEV1 at the start of the study was clearly normal at 94% of predicted. A much quoted paper by Fuhlbrigge et al4 found those children with FEV1 values of ⬍60% predicted had a 70% likelihood of having an asthma exacerbation in the following year. In those with FEV1 values ⬎80%, the likelihood of experiencing an exacerbation was reduced to 25% to 30%. These data have been interpreted as showing that attacks can be predicted based on percent predicted FEV1. Yet it is perhaps more important to note that 94% of the FEV1 values in this population of asthmatic children were normal, meaning that 80% of asthma attacks occurred in children with a normal baseline FEV1. The limits of using FEV1 alone in the assessment of childhood asthma were also demonstrated by Bacharier et al,5 who found a lack of association among asthma symptom severity, intensity of medication therapy, and percent predicted FEV1 in asthmatic children. Bronchial lability may be a more useful measure in the diagnosis of childhood asthma. Proving the existence of airway hyperreactivity in the context of clinical symptoms begins to add more details to our asthma mosaic. This is not a new concept. Exaggerated bronchodilation followed by bronchoconstriction in response to exercise—the so-called “bronchial lability index”—was described in asthmatic children by Jones.6 This and other early studies observed that pediatric asthmatic airways are remarkably labile in both directions when appropriately stimulated. The study by Gallant et al7 published in this issue of The Journal shows that detecting broncholability by measuring the response to an inhaled bronchodilator can aid in the diagnosis of asthma in children. The authors demonstrate that using 9% as a distinct cutoff value for improvement in FEV1 after inhaled albuterol (either 180 ␮g by metered dose inhaler or 2.5 mg by nebulizer) can distinguish a group of known asthmatic children from those who are normal by history. The findings of Gallant et al support the earlier study by Dundas et al8 that determined that a 9% cutoff for the bronchodilator response (BDR) to 400 ␮g of salbutamol (albuterol) provided the greatest balance between sensitivity and specificity in separating wheezers from nonwheezers in a group of London schoolchildren (race not described). However as stated by Dundas et al, the diagnostic value of a 9% BDR cutoff will vary with the prevalence of wheezing in the study population. Gallant Editorials

et al studied a group of clinically diagnosed asthmatic children with a presumed incidence of wheezing of 100%. This exaggerated the difference between this study group and the comparator group to some degree. As a diagnostic test, BDR will be used in populations in which the incidence of wheezing may be much lower and the distinction between asthmatics and nonasthmatics is less clear. Without a prospective assessment of the 9% BDR cutoff value in an unselected cohort of subjects, the findings of Gallant et al still leave us several steps away from implementing BDR as a diagnostic test for asthma. Although the ethnic composition of Gallant et al’s population is described as primarily Hispanic, the racial composition is not fully described. As recognized by the authors, extrapolating the 9% BDR cutoff to similarly aged AfricanAmerican, Caucasian, or mixed populations is difficult, especially in light of the fact that different genetic groups respond to bronchodilator medications differently.9 The diagnostic BDR cutoff point certainly may be lower in children with less sensitivity to beta-agonist medications than the general population. The effect of baseline lung function on BDR measurement also must be considered, as Gallant et al acknowledge. This relationship was described by Sly,10 who noted that the greatest percent increase in peak expiratory flow rate (PEFR) with treadmill exercise was seen in those asthmatic children with the lowest baseline PEFR. Where a child stands in relation to his or her maximum lung function on the day of testing will contribute to his or her ability to respond. A child already at his or her personal maximum for FEV1 would not exhibit a response to a bronchodilator even if he or she were asthmatic. In a disease as variable as asthma, this may prove a difficult hurdle to cross to use BDR as a diagnostic criterion. The present study used 2 distinct methods of delivering the albuterol medication—some subjects used a metered dose inhaler, whereas others received the medication via wet nebulization. Although the quantitative difference in medication delivery between these 2 methods of medication administration may be small, the effect on BDR is not known. Using a single delivery method may have resulted in different outcomes. The dose and mode of delivery of beta-agonists are likely to play some role in the degree of observed bronchodilation and will need to be standardized to make this a clinically helpful test. Gallant et al have presented a very sound idea for helping pediatric clinicians diagnose asthma. They have shown that BDR distinguishes between asthmatics and nonasthmatics better than baseline FEV1 alone, and that a combination of a high BDR and a low FEV1 is best for discriminating asthmatics from nonasthmatics (although these characteristics may be linked). Finally, and perhaps most importantly, they have demonstrated another way in which lung function testing can be helpful in the difficult process of diagnosing and managing asthma in children. Spirometric evaluation is relatively simple to perform in many preschool-age and nearly all school-age children.11 We believe that with further study, BDR testing will prove to be an important tool in our efforts to complete the asthma mosaic. 447

Howard Eigen, MD Gregory S. Montgomery, MD Department of Pediatrics Section of Pediatric Pulmonology, Critical Care and Allergy Indiana University School of Medicine James Whitcomb Riley Hospital for Children Indianapolis, Indiana

REFERENCES 1. Gross NJ. What is this thing called love?, or defining asthma. Am Rev Respir Dis 1980;121:203-4. 2. National Asthma Education and Prevention Program. Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma. Publication 97-4051. Bethesda, MD: National Institutes of Health; 1997. 3. Spahn JD, Cherniack R, Paull K, Gelfand EW. Is forced expiratory volume in one second the best measure of severity in childhood asthma? Am J Respir Crit Care Med 2004;169:784-6. 4. Fuhlbrigge AL, Weiss ST, Kuntz KM, Paltiel AD. Forced expiratory volume in

1 second percentage improves the classification of severity among children with asthma. Pediatrics 2006;118:e347-55. 5. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF Jr, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med 2004;170:426-32. 6. Jones RS. Assessment of respiratory function in the asthmatic child. Br Med J 1966;2:972-5. 7. Galant SP, Morphew T, Amaro S, Liao O. The value of the bronchodilator response in assessing controller-naïve asthmatic children. J Pediatr 2007;151:457-62. 8. Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic accuracy of bronchodilator responsiveness in wheezy children. Thorax 2005;60:13-6. 9. Tsai HJ, Shaikh N, Kho JY, Battle N, Naqvi M, Navarro D, et al. Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African-American asthmatics. Hum Genet 2006;119:547-57. 10. Sly RM. Exercise-related changes in airway obstruction: frequency and clinical correlates in asthmatic children. Ann Allergy 1970;28:1-16. 11. Eigen H, Bieler H, Grant D, Christoph K, Terrill D, Heilman DK, et al. Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 2001;163:619-23.

Parenting Stress and Childhood Impairment

s neonatal intensive care has evolved, mortality and serious morbidity in survivors were the initial concerns and remain issues still today for those children born at borderline viability.1 It was also recognized that children who survive without major morbidities still have a wide variety of high frequency but less-severe impairments of cognitive, behavioral, and motor function.2 More recently, we have become equally concerned that simply measuring performance against normative data or comparison children born at term may give a fallacious view of outcome that is unnecessarily over-pessimistic. Recent studies have concerned outcomes for children and their families in functional terms that reflect the impact that these impairments have on day-to-day life. This in turn may affect our own perceptions of these conditions. There is little doubt that taking home a child who has been through the whole panoply of neonatal intensive care after very preterm delivery is a daunting task, even to welladapted mothers. The stress may be enhanced when there is evolving disability and will persist when there is serious childhood impairment. In this issue of The Journal, 2 groups report studies of parenting stress and wellbeing in children with or at high risk of childhood impairment and their families. Majnemer et al report a study of the factors that determine quality of life in school age children with cerebral palsy.3 The risk of this condition is often used to guide intensive care decisions, and thus it is valuable to detail what impact the associated disability has on the child or family and which factors determine the extent of this impact. This group of children was thought to be representative of a complete population of children with cerebral palsy from the case list of 1 pediatric neurologist (and comprised a high proportion of

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preterm children), but the associated motor deficit was classed as mild (GMFCS level 1) in nearly half the children, half were attending mainstream school, and only 28% had IQ scores ⬎2 SD below the mean. This is far from the commonly held outcome when a diagnosis of cerebral palsy is first broached with parents. The questionnaires used give a broad view of function in a wide range of dimensions for child and family. In particular, physical wellbeing might be easily predicted from the degree of limitation of activity (and is reassuringly well assessed with the simple gross motor function classification system), but psychosocial wellbeing was more dependent on associated behavioral problems, an area which might be amenable to modification and thus enhance quality of life. Notable among the measures that they report is the observation that parenting stress was high in nearly half of the families. Alongside this paper is a report from a longitudinal study of maternal stress and coping for families after very low birthweight (VLBW) infants are born from Singer et al.4 They observed 3 groups of children from birth: “high risk” VLBW children with chronic lung disease, “low risk” VLBW children, and term comparators. This is an important study because it charts the evolution of See related articles, family environment p 463 and p 470 from birth. It presents a mixed picture—mothers of VLBW children Reprint requests: Neil Marlow, DM, FRCPCH, FMedSci, Department of Child reported fewer family Health, Level E East Block, Queen’s Medstrains than the comical Centre, Nottingham NG7 2UH, UK. E-mail: [email protected]. parator group and less J Pediatr 2007;151:448-9 parent-child conflict, 0022-3476/$ - see front matter but perceived more conCopyright © 2007 Mosby Inc. All rights cern for their child’s reserved. health state and more 10.1016/j.jpeds.2007.08.020 The Journal of Pediatrics • November 2007