Ronina A. Covar

Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children

BACKGROUNDnAsthma exacerbations are a common cause of critical illness in children.nnnOBJECTIVEnTo determine factors associated with exacerbations in children with persistent asthma.nnnMETHODSnRegression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study. Children age 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive either fluticasone propionate 100 microg twice daily (FP monotherapy), combination fluticasone 100 microg AM and salmeterol twice daily, or montelukast 5 mg once daily.nnnRESULTSnOf the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio [OR], 2.10; P < .001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast versus FP monotherapy (OR, 2.00; P = .005), season (spring, fall, or winter vs summer; P < or = .001), and average seasonal 5% reduction in AM peak expiratory flow (OR, 1.21; P = .01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low peak expiratory flow track together before an exacerbation, but have poor positive predictive value of exacerbation.nnnCONCLUSIONnChildren with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers and diary card tracking are not reliable predictors of asthma exacerbations.

Effect of montelukast on peripheral airflow obstruction in children with asthma

BACKGROUNDnMontelukast is a widely used controller agent in childhood asthma. It is modestly effective in reducing symptoms, decreasing the need for rescue albuterol, and improving forced expiratory volume in 1 second (FEV1).nnnOBJECTIVEnTo determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes, air trapping, airway resistance (Raw), and specific conductance (Sgaw).nnnMETHODSnTwenty-one children aged 9 to 18 years with mild-to-moderate asthma were randomized into a double-blind, placebo-controlled study to receive montelukast (5 or 10 mg) or matching placebo daily for 8 weeks. Symptoms and albuterol use were recorded twice daily, and exhaled nitric oxide measurement, forced oscillometry, spirometry, and body box plethysmography (before and after beta-agonist use) were performed at randomization and at 2, 4, 6, and 8 weeks. Circulating eosinophil counts and serum eosinophil cationic protein (ECP) levels were obtained at randomization and at 8 weeks.nnnRESULTSnMontelukast-treated patients had lower residual volume (P = .05), residual volume-total lung capacity ratio (P = .04), Raw (P = .02), Sgaw (P = .03), and serum ECP levels (P = .02) at 8 weeks compared with those treated with placebo. There was a trend toward reduced daytime and nighttime albuterol use, although the difference did not reach statistical significance. There were no significant differences in FEV1, FEV1-forced vital capacity ratio, exhaled nitric oxide levels, or daytime and nighttime symptom scores between the 2 groups.nnnCONCLUSIONSnMontelukast therapy was associated with less air trapping, hyperinflation, and Raw and better Sgaw compared with placebo. Lower serum ECP levels, a surrogate measure of airway inflammation, were associated with improvements in lung function.

Clinical assessment of asthma progression in children and adults

Asthma is a heterogeneous disorder with a variable course, characterized by episodes of cough, wheezing and shortness of breath, reversible airflow limitation, and bronchial hyperresponsiveness. It begins early in life in many subjects with intermittent symptoms occurring with viral respiratory tract infections. Over time, and in genetically susceptible children (those with an atopic predisposition), the disease becomes more persistent with symptoms occurring in the absence of respiratory tract infections. Children with persistent wheezing are eventually diagnosed with asthma, with those at greatest risk having developed allergic sensitization early in life. Among children with asthma, some will have lifelong asthma with active symptoms and progressive loss of lung function over time, whereas other children will undergo asthma remission in adolescence. Once in remission, the disease may remain quiescent, or it may relapse in midadult life. This review focuses on studies that have enhanced our understanding of the progression of asthma from infancy to adulthood. Studies evaluating progressive loss of lung function, the best-studied measure of asthma progression, are also reviewed, followed by a brief discussion of whether asthma progression can be modified by inhaled glucocorticoid therapy.

Identifying the components of asthma health status in children with mild to moderate asthma.

BACKGROUNDnWeak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of nonoverlapping components.nnnOBJECTIVEnFactor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children 5 to 12 years old. Results were compared across time (baseline and 48-month visit) and treatment arms.nnnMETHODSnAnalyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n = 1041). Measurements of lung function, symptoms, and health care utilization from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyperresponsiveness were included. Data on fractional exhaled nitric oxide and sputum eosinophil cationic protein were included in a subgroup of patients.nnnRESULTSnIn each of the study windows, factor analysis identified 5 factors that explained between 50% and 60% of the common variance. Factors identified included (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function, which subdivided into (4) FEV(1) and forced vital capacity, and (5) bronchodilator response and the FEV(1)/forced vital capacity ratio. Exploratory analyses suggest that fractional exhaled nitric oxide account for the atopy/inflammatory marker factor, and sputum measurements account for a sixth, separate factor.nnnCONCLUSIONnThe consistent identification of a 5-factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUNDnStudies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.nnnMETHODSnIn a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial.nnnRESULTSnParticipants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events.nnnCONCLUSIONSnAmong young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Glucocorticoid Therapy in Asthma

Glucocorticoids (GCs) are the most effective therapy we have for the treatment of asthma. Systemically administered GCs are first-line agents for acute severe asthma, whereas topical (i.e., inhaled) GCs are first line agents for the long-term management of all patients with persistent asthma. In the treatment of acute asthma exacerbations, early institution of systemic GCs can prevent further worsening of symptoms, reduce emergency room visits, and hospitalizations. Inhaled GCs are the recommended controller class of medications for all patients with persistent asthma, including children. They are the most effective class of agents in reducing symptoms, improving lung function, and decreasing bronchial hyperresponsiveness, in addition to reducing asthma morbidity and mortality. Long-term administration of oral GCs is associated with multiple adverse effects including adrenal insufficiency, weight gain, increased skin fragility, myopathy, osteoporosis, cataracts, and mood changes. Thus, in patients with chronic severe asthma who require regular systemic GC therapy, all other treatments should be maximized, and the lowest dose sufficient for control should be established through regular monitoring visits. As with oral GC therapy, high-dose inhaled GC therapy can result in systemic adverse effects. Several studies have shown that low-dose inhaled GC therapy, even when administered long term, is unlikely to result in any clinically meaningful adverse effects. By using the lowest possible effective GC dose, as well as maximizing other therapeutic modalities, adverse systemic effects from GCs can be greatly minimized.

32 – Special Considerations for Infants and Young Children

Key Points • The care of infants and small children with suspected asthma deserves special consideration because of the potential to modulate the disease process early on and alleviate the increased morbidity associated with uncontrolled asthma in this age group.• After confounders and masqueraders of asthma have been excluded in the evaluation of children with suspected asthma, recurrent wheezing in infants and young children still comprises a heterogeneous group of conditions with different risk factors and prognoses.• The diagnosis of asthma in infants and small children is often based on clinical grounds and complicated by the lack of clinically available tools that meet the criteria for the definition of asthma used in older children and adults such as airway inflammation, bronchial hyperresponsiveness and airflow limitation.• Difficulties in the management of asthma include limited effective and convenient delivery devices, complete dependence on the caregivers to carry out the treatment regimen, and an inadequate selection of medications completely devoid of adverse effects.• A partnership approach with emphasis on education, monitoring and training is key in the effective management of chronic cough or recurrent wheezing illnesses in very young children.• Clinical trials using as needed treatment interventions have shown favorable efficacy outcomes, aimed at preventing severe exacerbations in young children with recurrent wheezing; however, trials aimed at primary prevention are still lacking.

Use of an asthma risk questionnaire to identify young children likely to benefit from controller therapy

Abstract Rationale To date, no validated scoring system is available to assess young children with suspected asthma who may benefit from asthma controller therapy. Methods As part of a larger study evaluating the utility of an asthma risk questionnaire (ARQ), clinical data for preschool children with ≥1 episode of wheeze and not on controller agents were analyzed. Children were enrolled during their pediatric office visit in the summer months. The ARQ assigns points to the following categories: asthma symptoms (56), history of acute episodes (36), family/personal atopic history (30), triggers (8). A score of >45 was chosen to indicate a potential need for controller therapy. Results 173 were enrolled (mean age: 31.5 ± 19.4 months; 55% male). The mean ARQ score was 40.2 ± 19.2; 40% scored >45. Those who scored >45 had the following scores: asthma symptoms 14.5 ± 12.3; history of acute episodes 14.9 ± 8.2; atopy 27.1 ± 7.8; triggers 2.3 ± 1.9. Although only 5% of parents listed wheezing as the primary reason for the office visit, many children had active asthma symptoms: 21% had >2 daytime symptoms/week; 56% had nighttime symptoms at least once a week; 20% had activity limitation. Bronchodilators were previously prescribed in 66%, but only 11% used albuterol in the previous week. Conclusion The ARQ identified a number of young children with a history of wheezing as potential candidates for controller therapy. The ARQ provides a systematic way of gathering information to assist primary care physicians in decision-making regarding the need for controller therapy in children at risk for asthma.