PEDIATRICS Vol. 109 No. 2 February 2002, pp. 393-398
Outcome Measures in Childhood Asthma
David P. Skoner, MD
From the Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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ABSTRACT
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Although evidence suggests that asthma onset occurs early in
childhood, many standard asthma outcome measures are either
impractical or unreliable in preschool-aged children. In this
population, for instance, patient history and symptom reports
rely on the observations of caregivers, who tend to underreport
their child’s asthma symptoms. Furthermore, the use of
conventional measures of pulmonary function such as spirometry
may be impractical in very young children. Recent clinical studies
have used a variety of techniques to measure symptoms, pulmonary
function, and cellular mediators of inflammation. Outcomes such
as discontinuation and exacerbation rates, frequency of daytime
and nocturnal symptoms, and caregiver assessments of quality
of life can be useful measures in evaluating outcomes in young
children with asthma. Some measures, such as plethysmography
and inflammatory marker analysis, may be suitable options for
assessing pulmonary function and predicting asthma susceptibility
in preschool-aged children. Indeed, altered levels of inflammatory
markers, including immunoglobulin E, interleukin-10, and exhaled
nitric oxide, may be useful tools in diagnosing asthma, evaluating
interventions, and assessing future risks for asthma symptomatology
in very young children. Whether 1 or more of these outcome measures
will prove useful clinically in improving the diagnosis and
management of childhood asthma remains uncertain, although early
research results are encouraging.
Key Words: outcomes • asthma • pediatric • diagnosis • treatment
Abbreviations: ENO, exhaled nitric oxide • DWAS, days without asthma symptoms • FEV1, forced expiratory volume in 1 second • sRAW, specific airway resistance • LTRA, leukotriene receptor antagonist • IgE, immunoglobulin E • IL-10, interleukin-10 • RSV, respiratory syncytial virus • NO, nitric oxide
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INTRODUCTION
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Accumulating evidence indicates that asthma onset occurs early
in childhood, often before the age of 2 years.
1 It is critical
to identify children with asthma so that effective treatment
can be initiated early to prevent the irreversible airway remodeling
that can be characteristic of chronic disease. Identifying which
outcome measures are suitable in young children with asthma
can be a formidable task in clinical trials, however.
Generally, outcome measures in asthma are based on changes in symptoms, pulmonary function, quality of life, or the direct and indirect costs of this disease, but perspective often influences which outcome measure is most relevant. From a societal perspective, for example, the economic burden of asthma on the patient and on the health care system is a legitimate concern and thus an appropriate outcome measure. For children with asthma and their families, however, symptom severity and frequency, as well as quality-of-life measures, are outcomes with more immediate relevance because these measures assess the impact of asthma on day-to-day activities.
The choice of an outcome measure is also at least partially driven by the time scale of interest. A bronchodilator challenge test can reflect minute-to-minute changes in airway function, whereas measures of asthma symptomatology can indicate changes that occur over days, or, as in the case of the impact of environmental influences, even longer—weeks or months. In clinical trials, typical measures of symptomatology, especially in mild asthma, include an evaluation of nocturnal and breakthrough symptoms as well as an assessment of the frequency of wheezing after normal activities. Assessments of pulmonary function using plethysmography, and airway hyperresponsiveness using challenge testing, are beginning to be used to measure outcomes in mild asthma. Moreover, increases in certain markers of inflammation, such as the eosinophil level and exhaled nitric oxide (ENO), reflect poor disease control and may be useful outcome measures in these patients as well. Finally, evaluating the effects of early intervention on asthma progression in children will require years of outcome monitoring and evaluation. In clinical trials, these outcomes may include the frequency of acute exacerbations, often reflected by an increased need for corticosteroids, progressive changes in pulmonary function, and changes in the rates of asthma-related mortality, hospitalizations, and emergency department visits.
Despite the above array of outcome options, identifying outcome measures that are of value in making an accurate diagnosis or in evaluating the benefits of treatment in young children with asthma remains particularly difficult. All too often, standard symptom reports and the pulmonary function testing that are used successfully in adult asthma patients prove unreliable or impractical in very young children with asthma. Although the comprehensive battery of outcome measures used in the Childhood Asthma Management Program15 (children aged 5–12 years) should be used in long-term studies of controller medications in persistent asthma, not all of the measures would be possible in children 2 to 5 years old. This article will review some of the challenges and explore novel approaches to measuring outcomes and disease control in young children with asthma.
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CHALLENGES TO MEASURING ASTHMA OUTCOMES
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Among preschool-aged children, differentially diagnosing asthma
presents an ongoing challenge because its symptomatology often
mimics that of other respiratory disease. Additionally, a diagnosis
of asthma in young children is based often on only 1 or 2 patient
contacts with a caregiver, despite the fact that symptom presentation
and pulmonary function vary considerably in young children with
asthma. Thus, an accurate diagnosis requires an evaluation of
longitudinal information gleaned from repeated patient contacts.
Even with repeated patient contact, however, outcome measures
in young children must be chosen carefully.
Because of their complexity, standard methods for measuring pulmonary function, such as spirometry, are often impractical in very young children. Direct reports from young children with asthma are unreliable, and clinicians rely on information obtained from caregivers whose reports frequently miss symptoms of exercise-induced asthma and dyspnea. As a consequence, these hallmark symptoms of asthma frequently go unreported. Complicating matters even further, reports of nocturnal awakenings attributable to wheezing or cough, a common asthma outcome measure in clinical studies, depend largely on whether these symptoms are severe enough to awaken the caregiver; thus, these symptoms tend to be underreported as well. The extent of this problem was highlighted in one study during which a microphone that would automatically record episodes of coughing at night was placed on the necks of children with mild asthma.2 Eighty percent of the children were actually coughing at night, but the caregivers reported only about 15% of these episodes, leaving an alarming 85% of the nocturnal coughing episodes unreported.
Recent clinical studies in children with asthma have used a variety of traditional and nontraditional techniques to measure symptoms, pulmonary function, and cellular mediators of inflammation in asthma. Some of these techniques are expected to show promise as valid outcome measures in pediatric asthma.
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SYMPTOM AND QUALITY-OF-LIFE MEASURES
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The goal of a randomized, multicenter, open-label, long-term
(52 weeks) study of 2- to 6-year-old children was to examine
the effects of nebulized budesonide compared with nebulized
cromolyn in young children with mild-to-moderate asthma.
3 Several
measures proved useful for evaluating treatment outcomes. During
this study, the rate of discontinuations successfully differentiated
between treatment groups, with 8% and 20% of the children discontinuing
treatment in the budesonide and cromolyn groups, respectively.
Moreover, the asthma exacerbation rate differed significantly
(
P = .001) between groups, with a mean exacerbation rate of
1.23 per year and 4.65 per year for the budesonide and cromolyn
groups, respectively. Nighttime and daytime symptom rates also
differed significantly between groups, with clear improvements
seen in asthma symptom scores in the budesonide group
(Fig 1).
In addition, the caregiver’s quality-of-life score—measured
on study weeks 8, 28, and 52—revealed significant differences
between groups in terms of improvements in emotional status.
Significantly greater improvements in emotional status scores
were observed when the children received budesonide treatment.
These results suggest that in young children with asthma, outcomes
such as discontinuation and exacerbation rates, frequency of
daytime and nocturnal symptoms, and caregiver assessments of
quality of life can be useful measures.
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Fig 1.
Improvement of symptom scores (0–3 scale) with budesonide and cromolyn. In a study of children 2 to 6 years of age with mild-to-moderate asthma comparing the symptom score improvements with nebulized budesonide versus nebulized cromolyn, nighttime and daytime symptom improvements differed significantly between groups, with greater improvements of symptom scores in the budesonide group. BIS indicates budesonide inhalational suspension. P  .001 versus cromolyn sodium. A posteriori test, last value carried forward, mean changes adjusted for center effect. Error bars indicate 95% confidence interval. Adapted from Mendelson.3
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DAYS WITHOUT ASTHMA SYMPTOMS (DWAS)
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The use of a diary by caregivers of preschool children (2–5
years of age) included an assessment of DWAS as well as numerous
other behaviors and symptoms characteristic of asthma.
4 In the
Pediatric Asthma Caregiver Diary, a DWAS was defined as a day
free of daytime and nighttime asthma symptoms. In a group of
unstable asthma patients
(Fig 2), the percent of children experiencing
a DWAS was rare initially, between 3% and 13% (mean 11.0%) but,
with subsequent addition of (or increase in) antiinflammatory
therapy on days 8 to 21, the incidence of DWAS increased to
20% to 32%. In the group of stable asthma patients who were
taking sufficient antiinflammatory medication from the beginning
of the study, the percent of patients having a DWAS remained
between 33% and 45% (mean: 37.0%) throughout the 3-week study.
Figure 2 shows that the measurement of DWAS in preschoolers
significantly (
P = .0001) differentiated unstable from stable
patients. This parameter can be a valid outcome measure of the
control of asthma in preschool children.
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Fig 2.
DWAS. The percentage of children (2–5 years of age) with a DWAS over a 3-week study is presented. The solid line represents children with stable asthma (receiving adequate antiinflammatory therapy throughout the study) and the broken line represents children with unstable asthma who only started receiving adequate antiinflammatory therapy on day 8. Adapted from Santanello et al.4
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PULMONARY FUNCTION
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A discrete analysis of changes in forced expiratory volume in
1 second (FEV
1) evaluated the effects of beclomethasone and
montelukast in a randomized, double-blind study of 895 adults
with persistent asthma.
5 This analysis not only included the
mean percentage change from baseline in FEV
1 but also a histogram
of discrete intervals of 10% change in FEV
1 from baseline for
each drug. Both beclomethasone and montelukast produced significant
mean improvements in FEV
1 compared with placebo, and the mean
FEV
1 improvement was significantly greater with beclomethasone
(13.1%) than with montelukast (7.4%;
P < .05). The analysis
of the discrete changes, however, showed that both treatments
produced similar results. For both treatments, the distribution
of discrete FEV
1 responses resembled a bell-shaped curve and
not a bimodal distribution. With 50% of the beclomethasone patients
above the +11% median response, 42% of the montelukast patients
showed an improvement of 11% or greater in FEV
1 (Fig 3). This
study suggested that measuring discrete responses of FEV
1 may
be a more meaningful way to express changes of clinical importance
than just representing the changes as means. Although children
above 14 years of age were included in this study, it still
may prove to be useful in studies that are entirely pediatric.
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Fig 3.
Distribution of treatment responses for FEV1. In a study comparing the effects of beclomethasone with montelukast in 895 adults with persistent asthma, the distribution of discrete FEV1 responses for both groups were represented by a bell-shaped curve, with about 50% of the beclomethasone and 42% of the montelukast patients showing improvement of  11% in FEV1. Adapted from Malmstrom et al.5
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PLETHYSMOGRAPHY
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To examine the feasibility of using a whole-body plethysmograph
as a diagnostic tool for assessing the airway function in 38
asthmatic and 29 healthy children 2 to 5 years of age,
6 specific
airway resistance (sRAW) was measured from simultaneous airway
volume and flow measurements. The plethysmograph required these
young children to sit inside a clear acrylic chamber and breathe
normally through only a mouthpiece connected to a flow meter.
Most children felt comfortable going into the chamber without
their parents. The results demonstrated the value of sRAW as
a diagnostic measure: it had a high sensitivity (68%) and specificity
(93%–100%) for distinguishing asthmatic individuals from
healthy control subjects
(Table 1). Additionally, sRAW demonstrated
excellent repeat reliability, with a correlation coefficient
of 0.96 between the original and repeat measures. Therefore,
sRAW may be a useful measure of airway function to use with
young children.
In a separate study, a plethysmograph was used to assess changes
in pulmonary function following specific asthma therapy.
7 In
this crossover study, 16 children 2 to 5 years of age were treated
with either the leukotriene receptor antagonist (LTRA) montelukast
or placebo. The sRAW after cold air and placebo increased 46%,
whereas montelukast only permitted an increase of sRAW by 17%
(
P < .05;
Fig 4).
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Fig 4.
Plethysmography as a diagnostic test for asthma. In a study of 16 children 2 to 5 years of age treated with montelukast or placebo, a significant reduction in the bronchoconstrictive response to cold air challenge was detected in the LTRA (montelukast) group, with sRAW increasing by only 17% compared with a 46% increase after placebo treatment. Adapted from Bisgaard and Nielsen.7
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These studies indicate that sRAW obtained using plethysmography
may be useful both in establishing a diagnosis and in evaluating
treatment outcomes in young children with asthma.
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INFLAMMATORY MARKERS
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Sensitization and Immunoglobulin E (IgE)
In a study of 817 infants 1 to 2 years of age with atopic dermatitis
and a family history of atopic disease, the children were randomized
to receive either cetirizine or placebo treatment for 18 months
to determine if the prophylactic value of an antihistamine therapy
prevented the subsequent development of asthma (as defined by
3 episodes of nocturnal cough with sleep disturbances or wheezing,
separated by at least 7 days, in a clinical setting where asthma
is likely and conditions other than allergy have been excluded).
8 When analyzing whether asthma occurred, no significant difference
was detected between the fraction of children in each group
who developed asthma.
A subgroup analysis, however, revealed important differences when a group of children were categorized using a preselected indicator. When children were followed who, at baseline were sensitized to grass pollen or house dust mite, there were significant differences in the probability of their developing asthma when they received cetirizine versus placebo (Fig 5). The data in Fig 5 represent the progressive onset of asthma and the consequent probability of developing asthma in each group and are not represented by a single endpoint but presented graphically as a Kaplan-Meier estimate of the cumulative probability. The onset of asthma in each group clearly diverges in occurrence attributable to the intervention.
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Fig 5.
Occurrence of asthma in patients sensitized to house dust mite. A subgroup analysis of children 1 to 2 years of age with atopic dermatitis and a family history of atopic disease were randomized to either cetirizine or placebo. There was a significant reduction of the risk of developing asthma in cetirizine-treated children with IgE antibodies for grass pollen and house dust mite. Adapted from the ETAC Study Group.8
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Whereas this study showed that atopic infants responded with
less asthma when receiving cetirizine, it also presented a novel
way in which to present an outcome, especially in infants who
are very difficult to diagnose for asthma. This approach requires
a clearly defined distinction or definition for inclusion in
the analysis; in this case, it was a specific sensitization.
But such an analysis could also use another indicator for inclusion
such as the frequency of wheezing, nocturnal awakenings, or
of needed emergency medical rescue. A specific randomized, placebo-controlled
study with an unstudied therapy could determine if the therapy
reduces the probability of subsequently developing asthma or
another disease.
In infants receiving placebo who had an elevated level of total IgE, or specific IgE for grass pollen, house dust mite, or cat dander, an elevated risk for asthma was measured. For cetirizine-treated infants, the risk of developing asthma was reduced in those who began the study sensitive to grass pollen and house dust mite, but not to cat dander. Moreover, elevated total and allergen-specific IgE levels may be a predictor for asthma in some infants and may be a meaningful outcome measure when assessing the value of an intervention to prevent or delay the onset of asthma.8
Interleukin-10 (IL-10)
In young children, changes in the level of certain inflammatory mediators have been shown to be useful not only in diagnosing asthma but also in evaluating the antiinflammatory effects of asthma treatments. In one study, in vitro cytokine responses, particularly IL-10, were measured in whole blood cultures stimulated with lipopolysaccharide (100 ng/mL) and interferon-
(20 ng/mL).9 This study included 50 children younger than 13 months of age hospitalized for respiratory syncytial virus (RSV), bronchiolitis, and associated recurrent wheezing, as well as 27 control children free of atopy or infection. Because the episodic wheezing associated with the RSV virus can occur months or even years after the infection,10 follow-up data were collected for 1 year after hospital discharge to evaluate the relationship between the presence of recurrent wheezing and a cytokine response, in vitro.
During the acute RSV phase, 24 hours after admission, IL-10 levels were comparable to those observed in controls (Fig 6)9; however, during the convalescent phase, 3 to 4 weeks later, IL-10 responses were significantly elevated in the RSV-infected group. All of the 27 RSV-infected children who developed wheezing during follow-up also had elevated IL-10 levels during the convalescent phase compared with those RSV-infected children who did not develop wheezing. The IL-10 responses during the convalescent phase correlated significantly with the frequency of subsequent wheezing episodes, implying that certain cytokine responses in vitro, such as elevated IL-10, may predict recurrent nonasthmatic wheezing in young children. Recent studies have shown that IL-10 levels actually are suppressed, when compared with healthy controls, in patients with atopic asthma and other conditions characterized by chronic inflammation of the airways.11,12 Reduced levels of IL-10 may play a role in the pathogenesis of chronic airway inflammation, and, as an outcome measure, the levels of this antiinflammatory cytokine may distinguish atopic asthma from other nonatopic wheezing conditions common in young children, such as wheeze secondary to RSV infection.
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Fig 6.
IL-10 production in whole blood culture during the acute and convalescent phase of RSV bronchiolitis. In vitro IL-10 production in whole blood obtained during the acute phase and during the convalescent phase of RSV bronchiolitis. Whole-blood cultures were stimulated to produce IL-10 for 48 hours with lipopolysaccharide and interferon-. Adapted from Bont et al.9
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ENO
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ENO, a marker of inflammation, can be used as an aid in the
diagnosis of asthma and as an outcome measure in young asthmatic
children. In a study that included children 6 to 11 years of
age with mild-to-moderate asthma, baseline nitric oxide (NO)
levels were significantly elevated in the children with asthma
when compared with nonasthmatic children
(Fig 7).
13 During treatment
with the LTRA montelukast, ENO levels significantly decreased.
Two weeks after montelukast treatment ceased, however, NO levels
returned toward baseline.
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Fig 7.
ENO. When children 6 to 11 years of age with mild-to-moderate asthma were compared with nonasthmatic participants during treatment with montelukast, ENO levels significantly decreased. Two weeks after treatment ceased, NO levels returned toward those measured at baseline. Adapted from Bratton et al.13
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A separate, double-blind, 2-week crossover study examined the
effects of montelukast treatment on NO levels in children 6
to 15 years of age also receiving inhaled corticosteroid or
ß-agonist therapy.
14 When compared with placebo treatment,
montelukast reduced NO levels by 20%—but did not normalize
them. These results show that the addition of montelukast further
reduces the inflammatory response in children receiving either
ß-agonist alone or combined with inhaled corticosteroid
therapy. The level of ENO appears to be a sensitive marker of
inflammation in these young patients and, therefore, ENO measurements
may be a noninvasive objective outcome measure, not only in
identifying the presence of inflammatory diseases like asthma,
but also in assessing responses to treatment.
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CONCLUSION
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Until the pathophysiology of childhood asthma is more completely
understood, asthma symptomatology such as coughing and wheezing
is likely to continue as a primary outcome measure in young
children with asthma. Because the symptom profile of other respiratory
ailments can mimic asthma in young children, and treatment can
mask the presence of asthma symptoms, symptom assessment alone
is not a sufficient outcome measure. Indeed, no single outcome
measure is likely to provide an accurate diagnosis or evaluation
of asthma interventions. The results of recent, controlled clinical
studies in asthma suggest that certain nontraditional measures
such as sRAW and alterations in the levels of certain markers
of inflammation, including IgE, NO, and IL-10, are inflammation-sensitive
measures and can be used successfully in asthma diagnosis, assessment
of asthma therapy, and in evaluating the risk for the eventual
development of asthma in very young children.
Although these findings are certainly encouraging, whether one or a combination of these outcome measures ultimately will be of routine clinical value remains uncertain. As our understanding of the pathophysiology and cellular mechanisms of asthma in children continues to improve steadily, the likelihood of identifying reliable, valid, and practical outcome measures in young children with asthma improves as well.
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FOOTNOTES
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Received for publication May 4, 2001; Accepted Oct 22, 2001.
Reprint requests to (D.P.S.) Sections of Allergy and Immunology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Room 4B320, Pittsburgh, PA 15213. E-mail: skonerd{at}chplink.chp.edu
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REFERENCES
|
|---|
1.
Wainwright C, Isles AF, Francis PW. Asthma in children.
Med J Aust. 1997; 167:218–223
[Medline]
2.
Skoner DP, Seroky J, Doyle W. Use of home-based telemetry to objectively determine cough characteristics in children with asthma [abstract]. Pediatr Res. 1991; 29:378A
3.
Mendelson LM. Greater efficacy of budesonide inhalation suspension compared to cromolyn sodium over 52 weeks in young children with persistent asthma [abstract]. Am J Respir Crit Care Med. 2000; 161:A36
4.
Santanello NC, DeMuer-Mercon C, Davies O, et al. Validation of a pediatric asthma caregiver diary. J Allergy Clin Immunol. 2000; 106(5, pt 1):861–866
5.
Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthm. Ann Intern Med. 1999; 130:487–495[Medline]
6.
Nielsen KG, Bisgaard H. Lung function response to cold air challenge in asthmatic and healthy children of 2–5 years of age. Am J Respir Crit Care Med. 2000; 161:1805–1809[Abstract/Full Text]
7.
Bisgaard H, Nielsen K. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children. Am J Respir Crit Care Med. 2000; 162:187–190[Abstract/Full Text]
8.
ETAC Study Group. Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Pediatr Allergy Immunol. 1998; 9:116–124[Medline]
9.
Bont L, Heijnen CJ, Kavelaars A, et al. Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study. Am J Respir Crit Care Med. 2000; 161:1518–1523[Abstract/Full Text]
10.
Sims DG, Downham MA, Gardner PS. Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy. BMJ. 1978; 1:11–17[Medline]
11.
Takanashi S, Hasegawa Y, Kanehira Y, et al. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur Respir J. 1999; 14:309–314[Medline]
12.
Kenyon NJ, Kelly EA, Jarjour NN. Enhanced cytokine generation by peripheral blood mononuclear cells in allergic and asthma subjects. Ann Allergy Asthma Immunol. 2000; 85:115–120[Medline]
13.
Bratton DL, Lanz MJ, Miyazawa N, White CW, Silkoff PE. Exhaled nitric oxide before and after montelukast sodium therapy in school-age children with chronic asthma: preliminary study. Pediatr Pulmonol. 1999; 28:402–407[Medline]
14.
Bisgaard H, Loland L, Anhoj J. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukas. Am J Respir Crit Care Med. 1999; 160:1227–1231[Abstract/Full Text]
15.
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide on nedocromil in children with asthma. N Engl J Med. 2000; 343:1054–1063[Abstract/Full Text]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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ABSTRACT
INTRODUCTION
