Onset and persistence of childhood asthma: predictors from infancy.

OBJECTIVE: In a prospective study of children with a family history of asthma, asthma onset by 3 years of age was found previously to be positively associated with variables from the first year of life, including elevated total immunoglobulin E (IgE), frequent respiratory infections, and parenting difficulties. We followed this cohort of genetically at-risk children to investigate the relationship between factors assessed in infancy and asthma, allergy, and psychological status at school age. METHODS: A cohort of 150 children who were at risk for developing asthma were identified prenatally on the basis of the mothers' having asthma. For 28 children, the father had asthma as well, putting them at bilateral genetic risk. Families primarily were middle and upper middle class Caucasians. Parents came to the clinic during the third trimester of pregnancy for assessments of medical and psychosocial functioning. A home visit took place when the infant was 3 weeks old, when parenting risk was assessed before the onset of any asthma symptoms. Parenting difficulties included problems with infant caregiving as well as components of maternal functioning, such as postpartum depression and inadequate marital support. Blood was drawn for serum IgE at 6 months of age. Parents and offspring subsequently came to the clinic multiple times, with the last clinic visit during the child's sixth year. Follow-up at age 6 involved a clinic visit for allergy and psychosocial evaluations, consisting of interviews and a behavior questionnaire. Seventy-seven children received the allergy and psychosocial evaluation, 26 received the psychosocial evaluation in the clinic, and 30 families received telephone interviews and mailed in questionnaires. Additional monitoring of families by telephone and mail was maintained over the next 2 years, until the children were 8, to ensure accurate characterization of the course of illness. Comprehensive medical records were obtained and reviewed for all health care contacts. Children were designated as having asthma when there was documentation in medical records of physician-diagnosed asthma, observed wheezing, and/or prescription of asthma medications during the time period when the child was between 6 and 8 years of age. Parental reports of the occurrence of asthma corroborated the medical record data. RESULTS: Data regarding asthma status were available for 145 children through 8 years of age. Forty (28%) of the children manifested asthma between 6 and 8 years of age. Among variables previously reported to predict asthma onset by age 3, 3 proved to have significant univariate relationships with asthma between ages 6 and 8: elevated IgE levels measured when the children were 6 months of age, global ratings of parenting difficulties measured when infants were 3 weeks old, and higher numbers of respiratory infections in the first year of life. Among these offspring of mothers with asthma, paternal asthma showed a significant association with asthma between ages 6 and 8. Eczema in the first year was not significantly related to later asthma. Multiple logistic regression showed that the model that best predicted asthma at ages 6 to 8 from infancy variables included 2 main effects. The adjusted odds ratio for 6-month IgE was 2.15 (1.51, 3.05) and for parenting difficulties was 2.07 (1.15, 3.71). Although socioeconomic status (SES) was not associated with asthma at ages 6 to 8, families of lower SES were more likely to be rated as having parenting difficulties early in the child's life. The mothers of lower SES breastfed for a shorter period of time and were more likely to smoke during their infant's first year. There were more respiratory infections during the first year of life among infants whose mother was rated as having more parenting difficulties. Mothers who reported smoking breastfed their infants for a shorter length of time. Male gender was significantly associated with higher IgE levels when infants were 6 months of age. Laboratory testing was completed for 77 children at age 6. Total serum IgE levels were significantly higher for the children with asthma between ages 6 and 8. Skin-prick testing showed that the children with asthma had significantly more positive skin test reactions than did the children without asthma. Psychosocial interview data at 6 years of age were available for 103 families, and behavioral questionnaires were available for 133 families. On the basis of 6-year interviews, children with asthma were rated as being at greater psychological risk than were the children without asthma. Mothers' Child Behavior Checklist (CBCL) ratings of their children's behavior indicated higher internalizing scores for the children with asthma as compared with the children without asthma. Like the 6-month IgE, 6-year IgE was higher for boys. IgE levels measured at 6 months of age were significantly correlated with 6-year IgE levels. Parenting difficulties measured at 3 weeks were significantly correlated with 6-year measures of maternal depression, CBCL Internalizing score, and Child Psychological Risk (CPR) score. There also were significant correlations among the psychosocial variables assessed when the children were 6 years of age; maternal depression was significantly associated with child CBCL Internalizing score and CPR score, and the last 2 also were significantly correlated. Multiple logistic regression showed that 2 concurrently measured variables entered the model showing the strongest associations with asthma at ages 6 to 8. The adjusted odds ratio for CPR score was 3.21 (1.29-7.96) and for 6-year IgE was 1.71 (1.04-2.80). CONCLUSIONS: This study of the natural history of childhood asthma focused on the development of asthma into the school-age years in a genetically at-risk group of children. The relationships between biological and psychosocial variables in the first year and school-age asthma support the formulation of asthma as beginning early in life, with the developing immune system interacting with environmental influences. The data provide support for the possible contribution of psychosocial factors to asthma onset and persistence into childhood.

A multimethod assessment of behavioral and emotional adjustment in children with asthma.

OBJECTIVE: Examine behavioral adjustment and emotion regulation among 6-year-old children with asthma and a group of healthy controls. METHOD: Subjects were 81 children with asthma and 22 healthy controls. Asthma and allergy statuses were confirmed by objective measures. Emotional and behavioral functioning were assessed through parent report, child interview, and child participation in an emotional regulation paradigm. RESULTS: Maternal report revealed more internalizing and total behavior problems for children with asthma compared to controls. Child interview and behavioral observations of emotion regulation yielded no differences between groups. Severity of asthma was related to increased emotional difficulties by clinician interview and observation but not by maternal report. CONCLUSIONS: Two groups of children with asthma who have psychological difficulties include those with increased anxiety and those with poor emotion regulation and more asthma symptoms. Different measures of child adjustment yield a complex picture of the behavioral difficulties associated with pediatric asthma.

Salmeterol compared with current therapies in chronic asthma.

BACKGROUND: Therapy with salmeterol, a long-acting, selective, inhaled beta 2-adrenergic agonist, is effective and safe for patients with persistent asthma; however, few long-term studies comparing salmeterol with current combination treatment regimens have been reported. METHODS: A multicenter, randomized, placebo-controlled, double-blind study was conducted in 386 patients over 41 to 46 weeks in 27 medical centers (two thirds of the investigators were primary care physicians). Patients were randomized to receive either salmeterol or placebo, and further randomized to weaning or nonweaning from current asthma therapies (except inhaled corticosteroids). Treatment groups were: salmeterol/weaning (S + W), placebo/weaning (P + W), salmeterol/no weaning (S + NW), and placebo/no weaning (P + NW). Attempts at active weaning were carried out at the discretion of the investigator for 2 to 6 weeks. Pulmonary function, albuterol use, and asthma symptoms were measured. RESULTS: The clinical benefits of salmeterol occurred despite weaning off existing nonsteroidal asthma medications. The mean morning peak expiratory flow rate was significantly increased in the S + W group (32.3 L/min) compared with both the P + W (4.9 L/min) and P + NW (6.8 L/min) groups (P < .001). Compared with the P + W and P + NW groups, the S + W group experienced significant (P < .05) improvements in overall mean asthma symptom scores, mean number of puffs of supplemental albuterol, the percentage of days with no supplemental albuterol use, and the mean number of awakenings caused by asthma (except for the P + NW comparison, P = .090). No significant differences were noted between treatment groups in any safety evaluation, including 12-lead electrocardiograms. CONCLUSIONS: The addition of salmeterol in the treatment of persistent asthma resulted in sustained improvement in pulmonary function and symptoms. The long-term use of salmeterol is safe and improves the clinical course and stability of asthma following reductions in nonsteroidal asthma therapy.

The appropriate use of skin testing and allergen immunotherapy in young children.

Immunotherapy is clearly effective in the treatment of allergic rhinitis and Hymenoptera sensitivity and probably effective in the treatment of asthma. Few studies evaluate the risks and benefits of immunotherapy in young children. Current evidence suggests that young children are at increased risk for systemic reactions from immunotherapy. Furthermore, immunotherapy or adverse reactions resulting from immunotherapy may result in significant psychologic problems. The potential risks of immunotherapy would be justified if immunotherapy were demonstrated to be safe and additive to other therapies. Immunotherapy might be particularly effective in treating or helping to prevent house dust mite- or cockroach-associated asthma. Until the efficacy of immunotherapy is demonstrated in young children, we agree with the European Academy of Allergology and Clinical Immunology position that immunotherapy in young children is relatively contraindicated.

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.

Changes in bronchial responsiveness following nasal provocation with allergen.

The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV1, specific conductance, or lung volumes either 30 minutes or 4 1/2 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo (p = 0.011 at 30 minutes and p = 0.0009 at 4 1/2 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.

Immediate skin test reactivity to Food and Drug Administration-approved standardized extracts.

In an effort to determine whether recently introduced Food and Drug Administration-approved standardized extracts produce clinically appropriate responses in a population, 200 subjects were skin prick tested (SPT). Thirteen extracts (10 pollens, two house dust (HD) mites and cat) were tested in three groups of subjects, 50 with a history of asthma or allergic rhinitis (AL), 50 without asthma or perennial or seasonal allergic rhinitis but with a positive immediate family history for these conditions (FAL), and 100 subjects without a personal or family history for these conditions (NAL). An SPT mean wheal diameter greater than or equal to 3 mm was considered positive. Ninety percent (95% confidence interval [CI], 82% to 98%) of AL subjects had at least one positive SPT. Forty-six percent of FAL subjects (95% CI, 30% to 58%) and 29% of NAL subjects (95% CI, 20% to 38%) had at least one positive SPT. More FAL than NAL subjects had at least one SPT (p less than 0.05), and FAL subjects had more positive SPTs than NAL subjects (p less than 0.05), further supporting the genetic regulation of allergen-specific IgE production. Of the five AL subjects with no SPT wheal greater than or equal to 3 mm, three subjects were available for intradermal tests. Thirteen nonstandardized allergens similar to allergens used for SPT were applied intradermally in each of these three subjects and were all negative. Compared with history, an SPT wheal greater than or equal to 3 mm to cat produced a sensitivity of 0.90, a specificity of 0.90, and diagnostic accuracy of 0.90. Tenfold dilutions of pollens and cat reduced sensitivity without significantly improving specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between positive aeroallergen patch test reactions and aeroallergen exacerbations of atopic dermatitis.

Previously we have demonstrated that patient contact with specific aeroallergens can cause flares of atopic dermatitis. In this study we report six additional cases that further document the relationship between positive aeroallergen patch test reactions and aeroallergen exacerbation of atopic dermatitis. In total, we have seen 18 patients (8 male, 10 female; ages 1-54 years) who have noted marked improvement in their skin symptomatology when antigen elimination (or moderation) was instituted as part of their general management. Delineation of inciting allergen was accomplished by a combination of prick tests and patch tests to aeroallergens. On prick testing all patients had markedly positive immediate wheal and flare reactions to a variety of aeroallergen extracts (tree, grass, and weed pollen, house dust mite, animal protein, and mold spores). The same patients were subsequently patch tested on uninvolved, nonabraded skin with allergen extracts at the same concentrations that had given positive prick tests. Patch tests were applied for 48 hr, removed, and interpreted at 48 and 72 hr. Patients reacted to specific aeroallergens with an eczematous eruption at 48 or 72 hr or at both time points. Positive delayed cutaneous reactions correlated strongly with aeroallergens identified in the patient's environment and/or suspected by the patients as inducers of dermatitis. Delayed cutaneous reactions were negative to allergens not historically relevant. Avoidance of aeroallergens that elicited an eczematous reaction at patch test sites resulted in marked improvement or resolution of dermatitis in all patients. Environmental rechallenge with incriminated allergens resulted in flares of dermatitis. We conclude that aeroallergen contact plays an important role in select patients with atopic dermatitis and that the responsible allergens can be elucidated by a combination of prick and patch tests.

Aeroallergen contact can exacerbate atopic dermatitis: patch tests as a diagnostic tool.

Previous studies have documented that atopic dermatitis can worsen when patients ingest specific foods to which they are sensitive. In this article we demonstrate that patient contact with specific aeroallergens can cause flares of atopic dermatitis. Marked improvement in skin symptoms was noted when 12 patients (eight males and four females; ages, 1 to 54 years) were removed from their unusual environment. In response to prick tests, these patient had markedly positive, immediate wheel-and-flare reactions to a variety of aeroallergen extracts (tree, grass, and weed pollen; house dust mite; animal protein; and mold spores). The same patients were subsequently patch tested on uninvolved, nonabraded skin with the allergen extracts that had yielded positive prick tests. Patch tests were applied for 48 hours, removed, and interpreted 24 hours later. The patients reacted to specific aeroallergens with an eczematous eruption at 48 and 72 hours. Positive delayed cutaneous reactions correlated strongly with aeroallergens identified in the patient's environment or suspected by the patients as provocateurs of their atopic dermatitis. Delayed cutaneous reactions were negative to allergens not historically relevant. Continued avoidance of aeroallergens that elicited an eczematous reaction at patch test sites resulted in marked improvement or resolution of dermatitis in all patients. We conclude that aeroallergen contact plays an important role in select patients with atopic dermatitis.

A comparison of six epicutaneous devices in the performance of immediate hypersensitivity skin testing.

Six devices commonly used for immediate hypersensitivity epicutaneous skin testing were compared with regard to precision and diagnostic accuracy. Fifteen subjects were tested on the back to 10 mg/ml of histamine phosphate and 50% glycerosaline by prick technique with a smallpox needle (SN), bifurcated needle (BN), Greer "pen" (GP), and blood lancet, and by puncture with the Morrow-Brown needle (MB) and Multi-Test (MT). Five devices were tested in quintuplicate to histamine and once to glycerosaline in each subject; with MT, five histamine and three glycerosaline sites were used. Analysis of the wheal areas obtained with SN, BN, GP, and MB demonstrated comparable degrees of precision (coefficient of variation). The precision of MT was less than the other devices (p less than 0.05). The blood lancet demonstrated intermediate precision. Twenty-two of 45 (49%) of the glycerosaline skin tests performed with MT were falsely positive, significantly more than the other devices (p = 0.0001). We conclude that MB, BN, GP, and SP are comparable devices for use in immediate hypersensitivity skin testing. The low precision and reliability of MT used for testing on the back would appear to make this device less than adequate for diagnostic or research studies. Its high rate of false positive reactions requires caution in interpretation of results when it is used in the clinical diagnosis of allergy.

Methacholine inhalation challenge in young children: results of testing and follow-up.

The diagnosis of asthma is often difficult in young children because their symptoms may not be typical and pulmonary function testing cannot be performed by the patient. We therefore performed methacholine inhalation challenges (MIC) in 24 patients 1 to 5.8 years of age in whom the diagnosis of asthma was uncertain. These patients had histories of recurrent respiratory symptoms for a mean duration of 2.4 years (range = 0.5 to 5.1) in the absence of other systemic diseases. Testing was done by either the 5-breath technique or 1-min inhalation via face mask until wheezing or coughing and retractions developed or a maximum methacholine concentration of 5 to 25 mg/mL was reached. Eighteen MIC were positive and six negative. The mean provocative dose was 3.0 mg/mL (range = 0.6 to 10). No patients suffered serious or delayed reactions and all symptoms reversed with inhaled bronchodilators (BD). During the MIC, the progression of symptoms often mimicked progression of those observed in the past and was useful in teaching the parents. Patients were followed for 0.5 to 3.8 years (mean = 2.3). All patients with a positive MIC have continued to have recurrent respiratory symptoms and require regular or intermittent BD. Only one patient with a negative MIC at 5 mg/mL has recurrent respiratory symptoms and requires daily BD 3 years after the initial evaluation. We conclude that MIC can safely be performed in young children in whom the diagnosis of asthma is uncertain. A positive MIC in this context demonstrates increased bronchial reactivity and is supportive of a clinical diagnosis of asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Atopic dermatitis and aeroallergen contact sensitivity.

Atopic dermatitis (AD) may be worsened by ingested foods or contact with irritants. We have identified 10 patients (six male and four female subjects, aged 1 to 54 years) with AD and contact sensitivity to a variety of aeroallergens. Marked improvement in skin symptomatology was noted when these patients were removed from their usual environment. The patients had markedly positive immediate wheal-and-flare reactions to a variety of aeroallergen extracts in response to prick tests and were subsequently patch tested on uninvolved skin with aeroallergen extracts (1:20 wt/vol, 50% glycerine) that elicited positive prick tests. Patch tests were applied for 48 hours, removed, and then were interpreted 24 hours later. Fifty percent glycerine was used as a negative control. Significant delayed cutaneous responses to a variety of aeroallergens were noted: house dust mite, tree, grass and weed pollens, animal danders, and various molds. Positive delayed cutaneous responses correlated strongly with aeroallergens identified in the patient's environment and/or suspected by the patients as provocateurs of their AD. Delayed cutaneous reactions were negative to aeroallergens not historically relevant to their AD. We conclude that aeroallergen contact may play an important role in selected patients with AD. The demonstration of immediate and delayed cutaneous responses in AD suggests both IgE and cell-mediated hypersensitivity as contributory mechanisms.

Kawasaki syndrome and house dust mite exposure.

We investigated exposure to house dust mites and freshly cleaned carpets in patients with Kawasaki syndrome (KS) who resided in Denver, CO. House dust samples were analyzed for mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae) and convalescent sera were assayed for immunoglobulin G antibody to mite antigen. House dust samples from case and neighborhood control homes showed no difference in the prevalence of mites. Fewer than 10% of dust samples from either group revealed evidence of live or dead mites. Nine of 18 (50%) children with KS had a prior history of exposure to freshly cleaned rugs within the 45 days of the onset of KS compared with 3 of 11 (27%) neighborhood controls. There was no difference in mean anti-mite antibody concentrations between convalescent sera from KS cases and sera from pediatric hospitalized controls. We conclude that in Denver KS can occur in the absence of significant mite exposure as defined by environmental studies or serologic means.

Steroid-induced fractures and bone loss in patients with asthma.

To study the association between bone disease and long-term steroid administration in asthmatics, we reviewed the hospital records of 128 patients over 40 years of age who had taken daily or alternate-day adrenal corticosteroids for at least a year and compared them with the records of 54 other asthmatics of similar age who had not required long-term administration of steroids. We found evidence in the records of a total of 58 fractures of the ribs or vertebrae in 14 of the patients who had received long-term steroid treatment (11 per cent) and no evidence of fractures in the patients who had not received long-term treatment. We also prospectively studied 30 hospitalized asthmatic patients between 20 and 70 years of age who had been screened for medications (other than steroids) or complicating diseases known to affect bone mineralization. Eight of 19 asthmatic patients receiving long-term steroid therapy had rib or vertebral fractures, whereas none of 11 matched patients not receiving such therapy had fractures. Furthermore, bone-density measurements of the distal and proximal radius by photon absorptiometry revealed that the trabecular, but not the cortical, bone mass was below normal in the former group of patients but not in the latter. Within the long-term steroid group, there was no significant correlation between bone density and dose or duration of steroid treatment. We conclude that long-term steroid therapy in asthmatic patients is associated with decreased trabecular bone density and an increased prevalence of rib and vertebral fractures.