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1.
N Engl J Med ; 362(11): 975-85, 2010 Mar 18.
Article in English | MEDLINE | ID: mdl-20197425

ABSTRACT

BACKGROUND: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking. METHODS: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%. RESULTS: A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005). CONCLUSIONS: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)


Subject(s)
Acetates/administration & dosage , Albuterol/analogs & derivatives , Androstadienes/administration & dosage , Asthma/drug therapy , Bronchodilator Agents/administration & dosage , Quinolines/administration & dosage , Administration, Inhalation , Administration, Oral , Adolescent , Adrenergic beta-Agonists/administration & dosage , Albuterol/administration & dosage , Asthma/complications , Asthma/ethnology , Asthma/physiopathology , Bronchodilator Agents/adverse effects , Child , Cross-Over Studies , Cyclopropanes , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Eczema/complications , Female , Fluticasone , Forced Expiratory Volume/drug effects , Glucocorticoids/administration & dosage , Humans , Leukotriene Antagonists/administration & dosage , Logistic Models , Male , Prednisone/administration & dosage , Salmeterol Xinafoate , Sulfides , Treatment Outcome
2.
J Allergy Clin Immunol ; 123(4): 861-7.e1, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19070356

ABSTRACT

BACKGROUND: Determination of the benefits and limitations of specific physiologic tests has not been well studied in long-term clinical pediatric trials. OBJECTIVE: We sought to determine the utility of impulse oscillometry in a long-term comparison of 3 controller regimens in children with persistent asthma. METHODS: Children 6 to 14 years of age with mild-to-moderate persistent asthma were characterized with oscillometry and spirometry before entry into a clinical trial and then serially during 48 weeks of therapy with either an inhaled corticosteroid, a combination inhaled corticosteroid with a long-acting beta-agonist, or a leukotriene receptor antagonist. RESULTS: The FEV(1)/forced vital capacity ratio, as well as the forced expiratory flow from 25% to 75% of forced vital capacity in terms of spirometric parameters and the reactance area (XA) from impulse oscillometry, appeared to complement information provided by FEV(1) when comparing the tests and factors that appeared to predict a response to treatment. XA was unique in that it, as distinct from spirometric variables, reflected ongoing improvement during the latter part of the trial. In general, improvements in XA during the latter part of the study occurred independently of indices of atopy and the level of airway responsiveness. CONCLUSION: Assessment of respiratory mechanics over time with oscillometry might offer additional insights into the response of asthmatic patients to therapy. In particular, the pattern of improvement seen in XA over the course of therapy suggests this test might detect alterations in airway mechanics not reflected by spirometry. The possibility that changes in XA reflect ongoing improvement in small airway function deserves additional study.


Subject(s)
Asthma/drug therapy , Acetates/administration & dosage , Adolescent , Albuterol/administration & dosage , Albuterol/analogs & derivatives , Androstadienes/administration & dosage , Asthma/physiopathology , Biomarkers , Child , Cyclopropanes , Double-Blind Method , Female , Fluticasone , Forced Expiratory Volume , Humans , Male , Oscillometry , Quinolines/administration & dosage , Salmeterol Xinafoate , Spirometry , Sulfides , Vital Capacity
3.
J Allergy Clin Immunol ; 122(6): 1127-1135.e8, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18973936

ABSTRACT

BACKGROUND: Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. OBJECTIVES: We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. METHODS: In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. RESULTS: The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. CONCLUSIONS: In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.


Subject(s)
Acetates/administration & dosage , Albuterol/administration & dosage , Bronchodilator Agents/administration & dosage , Budesonide/administration & dosage , Glucocorticoids/administration & dosage , Leukotriene Antagonists/administration & dosage , Quinolines/administration & dosage , Respiratory Sounds/drug effects , Respiratory Tract Diseases/drug therapy , Acetates/adverse effects , Administration, Inhalation , Albuterol/adverse effects , Bronchodilator Agents/adverse effects , Budesonide/adverse effects , Child, Preschool , Cyclopropanes , Double-Blind Method , Female , Glucocorticoids/adverse effects , Humans , Infant , Leukotriene Antagonists/adverse effects , Male , Quinolines/adverse effects , Respiratory Sounds/etiology , Respiratory Tract Diseases/complications , Sulfides
4.
J Allergy Clin Immunol ; 122(6): 1138-1144.e4, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18951618

ABSTRACT

BACKGROUND: Clinical trials in children with moderate-to-severe persistent asthma are limited. OBJECTIVE: We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. METHODS: The budesonide dose (with salmeterol [50 microg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 microg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. RESULTS: Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. CONCLUSION: Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma.


Subject(s)
Acetates/administration & dosage , Anti-Bacterial Agents/administration & dosage , Asthma/drug therapy , Azithromycin/administration & dosage , Bronchodilator Agents/administration & dosage , Budesonide/administration & dosage , Glucocorticoids/administration & dosage , Quinolines/administration & dosage , Adolescent , Albuterol/administration & dosage , Albuterol/analogs & derivatives , Child , Cyclopropanes , Double-Blind Method , Female , Humans , Male , Medication Adherence , Salmeterol Xinafoate , Severity of Illness Index , Sulfides , Time Factors
6.
Am J Physiol Lung Cell Mol Physiol ; 293(1): L239-44, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17483193

ABSTRACT

Maturational changes have been noted in neurally mediated contractile and relaxant responses in airways from New Zealand White rabbits. In this study, we focused on prostaglandins with bronchoprotective properties as potential modulators of airway tone in maturing rabbits. Tracheal rings from 1-, 2-, and 13-wk-old rabbits were assessed for neurally mediated contractile and relaxant responses produced by electrical field stimulation (EFS) of nerves in the presence and absence of the prostaglandin inhibitor, indomethacin (Indo). We also measured EFS-induced release of prostaglandin E(2) (PGE(2)) and the stable metabolite of prostacyclin, 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In the presence of Indo, EFS produced significant increases in contractile responses in segments from 1- and 2-wk-old animals but not in segments from 13-wk adult rabbits. Tracheal rings from 1- and 2-wk-old animals precontracted with neurokinin A (NKA) relaxed 100% in response to EFS when Indo was not in the bath. In rings from 13-wk-old animals, relaxation was 40%. With Indo, relaxation was abolished in 1-wk-old animals and reduced to 30% in the 2- and 13-wk-old groups. Buffer from baths collected after EFS had significant increases in PGE(2) and 6-keto-PGF(1alpha) released from tissues from 1- vs. 2- and 13-wk-old animals. Dose response curves to PGE(2) using tissues precontracted to NKA showed significant increases in relaxant responses in 1- and 2- vs. 13-wk-old rabbits. In rabbit airways, this study demonstrates enhanced modulation of airway tone by PGE(2) and greater release of the bronchoprotective prostaglandins PGE(2) and prostacyclin early in life.


Subject(s)
Prostaglandins/pharmacology , Trachea/drug effects , 6-Ketoprostaglandin F1 alpha/metabolism , Animals , Dinoprostone/metabolism , Electric Stimulation , In Vitro Techniques , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Rabbits
7.
J Allergy Clin Immunol ; 119(1): 64-72, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17140647

ABSTRACT

BACKGROUND: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. OBJECTIVE: The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control. METHODS: A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) or= 80% predicted, confirming current guideline recommendations.


Subject(s)
Acetates/therapeutic use , Albuterol/analogs & derivatives , Androstadienes/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Quinolines/therapeutic use , Adolescent , Albuterol/therapeutic use , Body Height/drug effects , Child , Cyclopropanes , Drug Therapy, Combination , Female , Fluticasone , Forced Expiratory Volume/drug effects , Humans , Male , Salmeterol Xinafoate , Sulfides
8.
Am J Respir Crit Care Med ; 175(2): 126-35, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17095746

ABSTRACT

RATIONALE: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. OBJECTIVES: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice. METHODS: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure. MEASUREMENTS AND MAIN RESULTS: Estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge. CONCLUSIONS: These data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.


Subject(s)
Bronchial Hyperreactivity/etiology , Estrogen Receptor alpha/physiology , Lung/physiopathology , Receptor, Muscarinic M2/metabolism , Respiratory Hypersensitivity/etiology , Acetylcholine/metabolism , Allergens/immunology , Animals , Bronchial Hyperreactivity/blood , Bronchial Hyperreactivity/physiopathology , Cytokines/metabolism , Electrophysiology , Estrogen Receptor alpha/genetics , Estrogens/blood , Female , Inflammation/immunology , Lung/drug effects , Lung/innervation , Methacholine Chloride/pharmacology , Mice , Mice, Knockout , Ovalbumin/immunology , Peripheral Nerves/physiology , Plethysmography , Receptor, Muscarinic M2/analysis , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/physiopathology , Serotonin/pharmacology , Trachea/drug effects , Trachea/innervation , Trachea/physiopathology
9.
Pediatr Pulmonol ; 41(12): 1242-9, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17068826

ABSTRACT

Nerve growth factor (NGF), a neurotrophin that regulates neuronal development, enhances production of neuropeptides that control airway caliber including substance P (SP). Little is known about the developmental interplay between neurotrophins and neuropeptides. Our goal was to assess release of NGF, SP, and vasoactive intestinal peptide (VIP) from tracheal segments of young (2-week-old) and fully-grown (13-week-old) rabbits, and ascertain location of neuropeptides in airways with mechanical denudation of epithelium and immunohistochemistry. After electrical field stimulation of nerves, bath solutions were collected and immunoassays performed to quantify NGF, SP, and VIP release. There were significant decreases in NGF, SP, and VIP release from airways in 13- versus 2-week-old rabbits. There were also significant decreases in SP and VIP release from denuded versus normal tissues at 2 weeks of age. A similar pattern for SP was seen in 13-week-old rabbits. Immunohistochemistry demonstrated increased neuropeptides in airways from younger rabbits. Although SP was seen in the epithelium and submucosal nerves in the younger group, it was localized to the latter location in fully-grown rabbits. VIP was seen in only submucosal nerves at both ages. Thus, release of NGF, SP, and VIP with neural stimulation decreases in rabbit tracheal segments with age. Decreases in SP with maturation and epithelial denudation appear related in part to decreases in epithelial SP with growth. However, decreases in VIP that occur normally and with epithelial denudation are not explained by location of VIP within the epithelium. The epithelium may be a source of factors that inhibit release of neuropeptides.


Subject(s)
Aging/metabolism , Neuropeptides/metabolism , Trachea , Animals , Follow-Up Studies , Immunohistochemistry , Muscle, Smooth/growth & development , Muscle, Smooth/innervation , Muscle, Smooth/metabolism , Nerve Growth Factor/metabolism , Neurons/cytology , Neurons/metabolism , Photomicrography , Physical Stimulation , Rabbits , Substance P/metabolism , Trachea/growth & development , Trachea/innervation , Trachea/metabolism , Vasoactive Intestinal Peptide/metabolism
10.
N Engl J Med ; 354(19): 1985-97, 2006 May 11.
Article in English | MEDLINE | ID: mdl-16687711

ABSTRACT

BACKGROUND: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. METHODS: We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. RESULTS: During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. CONCLUSIONS: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).


Subject(s)
Androstadienes/administration & dosage , Asthma/prevention & control , Bronchodilator Agents/administration & dosage , Respiratory Sounds/drug effects , Administration, Inhalation , Analysis of Variance , Asthma/drug therapy , Child, Preschool , Disease Progression , Disease-Free Survival , Female , Fluticasone , Growth/drug effects , Humans , Male , Regression Analysis , Respiratory Physiological Phenomena/drug effects , Risk Factors , Treatment Outcome
11.
J Allergy Clin Immunol ; 117(1): 45-52, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16387583

ABSTRACT

BACKGROUND: Outcome data are needed to base recommendations for controller asthma medication use in school-aged children. OBJECTIVE: We sought to determine intraindividual and interindividual response profiles and predictors of response to an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LTRA). METHODS: An ICS, fluticasone propionate (100 mug twice daily), and an LTRA, montelukast (5-10 mg nightly, age dependent), were administered to children ages 6 to 17 years with mild-to-moderate persistent asthma using only as-needed bronchodilators in a multicenter, double-masked, 2-sequence, 16-week crossover trial. Clinical, pulmonary, and inflammatory responses to these controllers were evaluated. RESULTS: Improvements in most clinical asthma control measures occurred with both controllers. However, clinical outcomes (asthma control days [ACDs], the validated Asthma Control Questionnaire, and albuterol use), pulmonary responses (FEV(1)/forced vital capacity, peak expiratory flow variability, morning peak expiratory flow, and measures of impedance), and inflammatory biomarkers (exhaled nitric oxide [eNO]) improved significantly more with fluticasone than with montelukast treatment. eNO was both a predictor of ACDs (P = .011) and a response indicator (P = .003) in discriminating the difference in ACD response between fluticasone and montelukast. CONCLUSIONS: The more favorable clinical, pulmonary, and inflammatory responses to an ICS than to an LTRA provide pediatric-based group evidence to support ICSs as the preferred first-line therapy for mild-to-moderate persistent asthma in children. eNO, as a predictor of response, might help to identify individual children not receiving controller medication who achieve a greater improvement in ACDs with an ICS compared with an LTRA.


Subject(s)
Acetates/therapeutic use , Androstadienes/therapeutic use , Asthma/drug therapy , Leukotriene Antagonists/therapeutic use , Quinolines/therapeutic use , Adolescent , Asthma/physiopathology , Child , Cross-Over Studies , Cyclopropanes , Double-Blind Method , Female , Fluticasone , Forced Expiratory Volume/drug effects , Humans , Male , Nitric Oxide/analysis , Sulfides
12.
Pulm Pharmacol Ther ; 19(5): 335-42, 2006.
Article in English | MEDLINE | ID: mdl-16242981

ABSTRACT

Phosphodiesterase IV (PDE IV) and neutral endopeptidase (NEP) may modulate the neurally mediated nonadrenergic noncholinergic inhibitory (NANCi) response. This response is not present in normal rabbits until 2 weeks of age. Allergen sensitization and challenge of fully grown 13-week old rabbits decreases the NANCi response. Our goal was to assess NANCi as a function of age and allergen sensitization. Tracheal smooth muscle (TSM) rings from normal 1-, 2-, and 13-week old rabbits plus ragweed immune as well as ragweed immune/challenged (I/C) 13-week old rabbits were assessed. Colorimetric assays of PDE IV and NEP activity were conducted on TSM from each group. NANCi responses were obtained in the presence and absence of Ro 20-1724 (PDE IV inhibitor) and/or phosphoramidon (Phos; NEP inhibitor) after contraction of TSM with neurokinin A. In normal TSM, there was no difference in PDE IV as a function of age. Conversely, NEP decreased significantly from 1 to 13 weeks of age. The immune and I/C groups had decreases in NEP and increases in PDE IV that were significant. Neither Ro 20-1724 nor Phos alone or together increased NANCi responses in TSM from 1- or 2-week old rabbits. However, both enhanced relaxation in TSM from normal, immune, and I/C 13-week old rabbits with an additive effect when drugs were combined. This work demonstrates (1) normal maturational changes in NEP but not PDE IV within TSM of this species; (2) modulation of the NANCi response by inhibitors of PDE IV and NEP in 13- but not 2-week old rabbits; (3) increased PDE IV and decreased NEP levels in the immune and I/C groups with reconstitution of NANCi responses by the combination of inhibitors. We conclude that mediation of the NANCi response is different in normal 2- and 13-week old rabbits. Both PDE IV and NEP modulated relaxation in fully grown rabbits, but had no effect at the younger age. Furthermore, both ragweed sensitization alone and ragweed challenge of immune rabbits altered NANCi via increases in PDE IV and decreases in NEP.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Allergens/immunology , Muscle, Smooth/enzymology , Neprilysin/metabolism , Trachea/enzymology , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone/pharmacology , Age Factors , Allergens/administration & dosage , Ambrosia/immunology , Animals , Animals, Newborn , Cyclic Nucleotide Phosphodiesterases, Type 4 , Drug Synergism , Electric Stimulation , Glycopeptides/pharmacology , Humans , Immunization/methods , Muscle Relaxation/drug effects , Muscle Relaxation/physiology , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Neprilysin/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Rabbits , Receptors, Adrenergic/metabolism , Receptors, Cholinergic/metabolism , Time Factors , Trachea/drug effects , Trachea/immunology
13.
J Allergy Clin Immunol ; 115(4): 657-66; quiz 667, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15805980

ABSTRACT

The purpose of this review is to provide practitioners and clinical investigators with an update on methods of assessing respiratory function in young children. The importance of this topic is presented in light of the natural history of asthma, as well as maturational changes that occur early in life in terms of airway development. Models of disease are cited to support the concept that injury of the mammalian airway early in postnatal life might have far-reaching consequences in terms of control of airway caliber and responsiveness. The methods currently available to measure respiratory function in our younger patients are outlined. The ability of children to perform the maneuvers necessary for this testing is considered as a function of age. Areas in which research and development are needed are highlighted.


Subject(s)
Asthma/diagnosis , Lung/growth & development , Respiratory Function Tests , Animals , Child, Preschool , Humans , Respiratory Function Tests/methods , Respiratory Physiological Phenomena
14.
J Allergy Clin Immunol ; 115(2): 233-42, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15696076

ABSTRACT

BACKGROUND: Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. OBJECTIVE: We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. METHODS: Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 microg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. RESULTS: Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC(20) and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC(20) and pulmonary function values. CONCLUSIONS: Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.


Subject(s)
Acetates/therapeutic use , Androstadienes/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Quinolines/therapeutic use , Acetates/administration & dosage , Administration, Inhalation , Adolescent , Androstadienes/administration & dosage , Anti-Asthmatic Agents/administration & dosage , Asthma/blood , Asthma/physiopathology , Bronchodilator Agents/administration & dosage , Child , Cross-Over Studies , Cyclopropanes , Double-Blind Method , Eosinophil Cationic Protein/blood , Eosinophils/pathology , Exhalation , Female , Fluticasone , Forced Expiratory Volume , Humans , Immunoglobulin E/metabolism , Leukocyte Count , Male , Nitric Oxide , Predictive Value of Tests , Quinolines/administration & dosage , Sulfides , Vital Capacity
15.
Am J Physiol Lung Cell Mol Physiol ; 288(4): L761-70, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15608150

ABSTRACT

The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of airway sensory neuropeptides, thereby contributing to the development of altered airway function. BALB/c mice were infected with RSV followed by assessment of airway function, inflammation, and sensory neuropeptide expression. After RSV infection, mice developed significant airway inflammation associated with increased airway resistance to inhaled methacholine and increased tracheal smooth muscle responsiveness to electrical field stimulation. In these animals, substance P expression was markedly increased, whereas calcitonin gene-related peptide (CGRP) expression was decreased in airway tissue. Prophylactic treatment with Sendide, a highly selective antagonist of the neurokinin-1 receptor, or CGRP, but not the CGRP antagonist CGRP(8-37), inhibited the development of airway inflammation and AHR in RSV-infected animals. Therapeutic treatment with CGRP, but not CGRP(8-37) or Sendide, abolished AHR in RSV-infected animals despite increased substance P levels and previously established airway inflammation. These data suggest that RSV-induced airway dysfunction is, at least in part, due to an imbalance in sensory neuropeptide expression in the airways. Restoration of this balance may be beneficial for the treatment of RSV-mediated airway dysfunction.


Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Lung/metabolism , Pyrrolidonecarboxylic Acid/analogs & derivatives , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/virology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/pathogenicity , Animals , Antiemetics/pharmacology , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Calcitonin Gene-Related Peptide/genetics , Humans , Inflammation/etiology , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Neurokinin-1 Receptor Antagonists , Peptide Fragments/pharmacology , Pyrrolidonecarboxylic Acid/pharmacology , Substance P/pharmacology
16.
Arch Pediatr Adolesc Med ; 158(12): 1170-6, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15583103

ABSTRACT

BACKGROUND: Pulmonary hypertension has not been described as a predisposing risk factor for high-altitude pulmonary edema (HAPE) in children. Previous studies have shown an association of HAPE with abnormally increased pulmonary vasoreactivity to hypoxia but generally normal pulmonary artery pressure (PAP) after recovery. OBJECTIVE: To describe HAPE of relatively rapid onset and its management in a series of children residing at moderate to high altitudes, all of whom had underlying pulmonary hypertension. METHODS AND RESULTS: From 1997 to 2003, 30 children came to our center with high-altitude illness. Of these, 10 children (aged 4-18 years; male-female ratio, 8:2) living at moderate to high altitudes (1610-3050 m) underwent cardiac catheterization after recovery from HAPE, and all were found to have chronic pulmonary hypertension (mean PAP, 38 +/- 9 mm Hg; pulmonary vascular resistance, 8.6 +/- 2.8 U x m2). Increases in PAP and pulmonary vascular resistance to hypoxia (16% oxygen) suggest that these children have a reactive pulmonary pressor response and hence are susceptible to HAPE. Six of the 10 patients had predisposing cardiopulmonary abnormalities, and 5 of these 6 patients did not receive a diagnosis prior to the onset of HAPE. Long-term treatment with calcium channel blockers, bosentan, sildenafil citrate, and/or oxygen lowered PAP, improved symptoms, and prevented the recurrence of HAPE. CONCLUSION: Children living at altitude who develop HAPE should undergo screening for diagnosis of underlying cardiopulmonary abnormalities including pulmonary hypertension.


Subject(s)
Altitude Sickness/complications , Hypertension, Pulmonary/complications , Oxygen/therapeutic use , Pulmonary Edema/etiology , Adolescent , Adult , Altitude Sickness/drug therapy , Altitude Sickness/physiopathology , Cardiac Catheterization , Child , Child, Preschool , Female , Humans , Male , Oxygen/administration & dosage , Pulmonary Edema/drug therapy
17.
J Allergy Clin Immunol ; 114(6): 1282-7, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15577824

ABSTRACT

BACKGROUND: Few studies have characterized the atopic profile of toddler-aged children with recurrent wheezing at high risk of the development of persistent asthma. Objective We sought to determine the atopic profile of toddler-aged children with frequent wheeze at high risk for the development of persistent asthma who either had a parental history of asthma, a personal history of atopic dermatitis, or both. METHODS: Participants enrolled in the Prevention of Early Asthma in Kids study (n = 285) on the basis of a modified Asthma Predictive Index were characterized on the basis of allergy and asthma questionnaire responses and allergy skin puncture test results. RESULTS: The majority of the children (60.7%, n = 148) were sensitized to either food or aeroallergens. Male children were significantly more likely to be sensitized to aeroallergens ( P = .03) and to have a blood eosinophil level of 4% or greater ( P = .03) and a total serum IgE level of greater than 100 IU/mL ( P = .0004). Additionally, eosinophilia and total serum IgE level had the strongest correlation with aeroallergen sensitization. CONCLUSION: The high prevalence of aeroallergen sensitization in this high-risk cohort suggests that aeroallergens might have an important role in the early development of asthma. As such, the Prevention of Early Asthma in Kids cohort appears to be an appropriate cohort in which to test whether early intervention with an inhaled corticosteroid can significantly attenuate, or perhaps even prevent, the allergic march from the initial stages of allergic sensitization to the subsequent development of asthma in toddlers with episodic wheezing.


Subject(s)
Allergens/immunology , Asthma/etiology , Respiratory Sounds/immunology , Age Factors , Animals , Animals, Domestic , Asthma/ethnology , Asthma/prevention & control , Child, Preschool , Cohort Studies , Double-Blind Method , Female , Humans , Infant , Male , Recurrence , Sex Factors
18.
Pediatr Pulmonol ; 38(2): 97-106, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15211691

ABSTRACT

Neural pathways help control airway caliber and responsiveness. Yet little is known of how neural control changes as a function of development. In rabbits, we found electrical field stimulation (EFS) of airway nerves led to more marked contractile responses in 2- vs. 13-week-old animals. This enhanced response to EFS may be due to prejunctional, junctional, and/or postjunctional neural mechanisms. We assessed these mechanisms in airways of 2- and 13-week-old rabbits. The contractile responses to methacholine did not differ in the groups, suggesting postjunctional neural events are not primarily responsible for differing responses to EFS. To address junctional events, acetylcholinesterase (AChE) was measured (spectrophotometry). AChE was elevated in 2-week-olds. However, this should lead to less and not greater responses. Prejunctionally, EFS-induced acetylcholine (ACh) release was assessed by HPLC. Airways of 2-week-old rabbits released significantly more ACh than airways from mature rabbits. Choline acetyltransferase, a marker of cholinergic nerves, was not different between groups, suggesting that more ACh release in young rabbits was not due to increased nerve density. ACh release in the presence of polyarginine increased significantly in both groups, supporting the presence of functional muscarinic autoreceptors (M2) at both ages. Because substance P (SP) increases release of ACh, SP was measured by ELISA. This neuropeptide was significantly elevated in airways of younger rabbits. Nerve growth factor (NGF) increased SP and was also significantly increased in airways from younger rabbits. This work suggests that increases in EFS-induced responsiveness in young rabbits are likely due to prejunctional events with enhanced release of ACh. Increases in NGF and SP early in life may contribute to this increased responsiveness.


Subject(s)
Aging/physiology , Autonomic Nervous System/physiology , Muscle, Smooth/physiology , Respiratory Mechanics/physiology , Acetylcholine/metabolism , Acetylcholinesterase/analysis , Animals , Autonomic Nervous System/drug effects , Bronchoconstrictor Agents/pharmacology , Choline O-Acetyltransferase/analysis , Electric Stimulation , Methacholine Chloride/pharmacology , Muscle Contraction/drug effects , Muscle Contraction/physiology , Muscle, Smooth/drug effects , Muscle, Smooth/innervation , Nerve Growth Factors/analysis , Rabbits , Receptor, Muscarinic M2/physiology , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/physiology , Respiratory Mechanics/drug effects , Substance P/analysis , Trachea/drug effects , Trachea/innervation , Trachea/physiology
19.
Curr Opin Pharmacol ; 4(3): 215-20, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15140411

ABSTRACT

The lung is an important source of sensory neuropeptides that modulate airway function in health and disease. Among these neuropeptides, calcitonin gene-related peptide (CGRP) plays a prominent role. CGRP is constitutively expressed in normal lungs where it localizes to a specialized subset of epithelial cells (neuroendocrine cells) and sensory C fibers distributed to pulmonary airways, blood vessels and lymphoid tissue. CGRP can mediate multiple effects, some of which have potential implications in airway homeostasis. These include vasoregulation, bronchoprotection, anti-inflammatory actions and tissue repair. Targeting these effects of CGRP could be a future avenue for modulation of certain aspects of airway diseases.


Subject(s)
Calcitonin Gene-Related Peptide , Homeostasis/physiology , Lung , Receptors, Calcitonin Gene-Related Peptide , Animals , Calcitonin Gene-Related Peptide/biosynthesis , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/physiology , Humans , Lung/metabolism , Lung/physiology , Receptors, Calcitonin Gene-Related Peptide/metabolism , Receptors, Calcitonin Gene-Related Peptide/physiology
20.
Control Clin Trials ; 25(3): 286-310, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15157730

ABSTRACT

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.


Subject(s)
Androstadienes/therapeutic use , Asthma/prevention & control , Bronchodilator Agents/therapeutic use , Patient Education as Topic , Randomized Controlled Trials as Topic/methods , Administration, Inhalation , Age Factors , Androstadienes/administration & dosage , Asthma/diagnosis , Bronchodilator Agents/administration & dosage , Child, Preschool , Cohort Studies , Double-Blind Method , Female , Fluticasone , Galvanic Skin Response , Humans , Male , Patient Selection , Predictive Value of Tests , Preventive Health Services , Prospective Studies , Respiratory Function Tests , Spirometry/methods
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