Antenatal risk factors, cytokines and the development of atopic disease in early childhood.

Atopic diseases are complex entities influenced by an array of risk factors, including genetic predisposition, environmental allergens, antenatal exposures, infections and psychosocial factors. One proposed mechanism by which these risk factors contribute to the development of atopic disease is through changes in the production of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) cytokines. The objectives of this review are to discuss antenatal exposures that are associated with paediatric atopic diseases, to discuss the influence of the intrauterine environment on neonatal immune responses, to provide an overview of the Th1 and Th2 pathways and how they relate to atopic disease, and to summarise our current understanding of the association between cytokine responses in cord blood and the development of atopic disease in early childhood.

Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization.

To better characterize infants presenting with diminished immunoglobulin levels and intact antibody formation, we present 49 such infants, correlating presenting characteristics with history and time to immunoglobulin normalization. Term infants with the following characteristics were included: 1) one or more immunoglobulin classes > 2SD below mean, 2) protective antibody titer to tetanus and diphtheria, 3) intact cellular immunity, 4) no features of other syndromes. The children were 69.4% male and had recurrent otitis media (77.6%), wheezing (61.2%), and atopy (26.5%). Diminished IgA (95.9%) was most common, but 65.3% had multiple isotypes diminished. During follow-up, 25/49 (51%) normalized immunoglobulins, of whom 80% were male; only 48% normalized in infancy. Female immunoglobulin normalization was significantly delayed (p < .001). No deaths or serious infections occurred. This phenotype is predominantly seen in male infants with otitis media and wheezing. Female infants have significantly delayed immunoglobulin normalization. Transient hypogammaglobulinemia of infancy can be diagnosed only retrospectively.

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Diagnosis and treatment of gastroesophageal reflux in children and adolescents with severe asthma.

BACKGROUND: The ability of gastroesophageal reflux disease to provoke asthma is controversial. Recent reports have suggested that reflux to the proximal esophagus may be especially likely to aggravate asthma, but the prevalence of proximal reflux in children and adolescents is poorly documented. It is also unclear how sensitive and specific the commonly used tests of reflux, barium swallow, and scintiscan are compared with pH probe studies in young patients. There is limited information on the effectiveness of the combination of H2 blockers and prokinetic agents in controlling reflux in children. OBJECTIVE: There were three objectives in this study: (1) to determine the prevalence of both proximal and distal gastroesophageal reflux in asthmatic children and adolescents; (2) to determine the sensitivity, specificity, positive and negative predictive values of barium swallow and scintiscan studies; and (3) to determine the effectiveness of standard antireflux pharmacotherapy. METHODS: A 24-hour, 2-channel pH probe study was carried out in 79 asthmatic children aged 2 to 17 years. The prevalence of abnormal proximal and distal gastroesophageal reflux was calculated from the findings. In 63 of these patients, barium swallow and Technetium99 scintiscan were carried out and the findings used to calculate the sensitivity, specificity, positive and negative predictive value of these studies relative to pH probe. In 11 subjects a follow-up, 24-hour pH probe was carried out after at least 3 weeks of therapy with an H2 blocker and prokinetic agent to determine the efficacy of therapy. RESULTS: There was abnormal proximal esophageal reflux in 64.5% of subjects and abnormal distal reflux in 73.4%. The sensitivity, specificity, positive and negative predictive values of barium swallow were 46.1%, 83.3%, 82% and 51%, respectively. Those of scintiscan were 15%, 72.7%, 50% and 32%, respectively. Of 11 subjects studied by repeat pH probe, 10 had persistent abnormal reflux. CONCLUSION: Abnormal reflux into the proximal esophagus occurs in the majority of asthmatic children with difficult-to-control disease. The barium swallow and scintiscan compare poorly with pH probe in diagnosing reflux. Treatment of reflux with recommended does of H2 blockers and prokinetic agents has a high failure rate, and follow-up studies are essential.

Respiratory health, lung function, and airway responsiveness in school-age survivors of very-low-birth-weight.

The purpose of this study was to determine the respiratory symptoms, pulmonary function, and airway reactivity in school-age survivors of very-low-birth-weight and to describe the influence of birth weight and perinatal illness on their pulmonary function. Thirty (of 39) 10- to 11-year-old survivors of very-low-birth-weight (VLBW) recruited at birth into a prospective longitudinal study of development; 30 (of 32) normal-birth-weight peers recruited from the same school or census tract as the VLBW group at age 5; and 15 normal-birth-weight siblings of the VLBW group participated in the study. Outcome measures were mother's reports of respiratory health; forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1); FEV1/FVC; forced expiratory flow, midexpiratory phase (FEF25-75); peak expiratory flow rate (PEFR); and tolerance to methacholine. There were no differences between groups in mothers' reports of current respiratory health. Pulmonary function values were lower for the VLBW survivors but significant only for FEF25-75 (F = 4.13; P = 0.02). Number of days in the intensive care nursery correlated significantly with decreased FEV1 (r = -.40, df = 28, P = 0.03), FEV1/FVC (r = -.37, df = 28, P = 0.04, and FEF25-75 (r = -.39, df = 28, P = 0.03). Only the relationship between length of nursery stay and FEV1/FVC was independent of birth weight. Number of days on mechanical ventilation was significantly correlated with decreased FEV1 (-.44, df = 28, P = 0.01), FEV1/FVC (r = -.38, df = 28, P = 0.04), FEF25-75 (r = -.44, df = 28, P = 0.01, and PEFR (r = -.40, df = 28, P = 0.03). All of these relationships were independent of birth weight. There were no significant associations between perinatal risk factors and methacholine responsiveness. Differences between VLBW children and normal-birth-weight children in pulmonary function are modest even when statistically significant. Severity of perinatal illness influences pulmonary function parameters into late childhood.

An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.

Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.

Treatment of severe respiratory failure during status asthmaticus in children and adolescents using high flow oxygen and sodium bicarbonate.

OBJECTIVE: Status asthmaticus with respiratory failure is a potentially fatal complication of bronchial asthma. To prevent a fatality in status asthmaticus with respiratory failure, treatment with intravenous isoproterenol or mechanical ventilation has been advocated. These interventions also have serious potential complications, however, and while continuous inhalation of beta agonists has shown promise, the optimal therapy of severe status asthmaticus remains unclear. This paper describes our experience with a treatment protocol used in status asthmaticus with respiratory failure that seeks to avoid intravenous isoproterenol or assisted ventilation. STUDY DESIGN: Case series of pediatric intensive care patients with severe respiratory failure due to status asthmaticus. Six children and adolescents experienced a total of nine episodes of severe respiratory failure due to status asthmaticus. RESULTS: In seven of the nine episodes the patients were managed without either intravenous isoproterenol or mechanical ventilation. Hypercarbia persisted for an average of 25 hours (range 17 to 40 hours) in these seven episodes. All subjects recovered without notable sequelae. In two episodes, clinical and blood gas deterioration led to mechanical ventilation. Ventilation was required for 112 and 42 hours, respectively, in these episodes and the patients developed either pneumothorax or pneumomediastinum during ventilation. CONCLUSION: Using a protocol initiated in 1978 for correction of hypoxia and acidemia, many patients with severe respiratory failure from status asthmaticus can be treated without isoproterenol or mechanical ventilation. Since those treatments have significant risks, consideration should be given to this intervention before resorting to them.

Beta 2-agonist metered dose inhaler overuse: psychological and demographic profiles.

OBJECTIVE: To identify psychological and demographic correlates of children and adolescents known to overuse beta 2-agonist metered dose inhalers (beta-MDIs). DESIGN: During residential care for severe asthma, demographic and psychological characteristics of 17 children and adolescents known to be beta-MDI overusers were compared with 38 asthmatic subjects of similar age without such history. RESULTS: beta-MDI overuse occurred among all groups; however, males, minorities, and those from lower socioeconomic groups were overrepresented. Overusers scored significantly lower on standardized IQ tests. Subtests of arithmetic for numeric reasoning, comprehension for understanding of social values, and picture completion for visual attention to detail were also significantly lower in beta-MDI overusers, as were reading achievement tests. Testing also revealed tendencies toward dominant, shrewd, and undisciplined personality traits in the overusers. CONCLUSION: Recognition of these characteristics of children prone to beta-MDI overuse will raise the clinician's awareness of this potential. Greater efforts and alternative approaches toward education and treatment of the at-risk patient and family are indicated.

Theophylline effects on cognition, behavior, and learning.

OBJECTIVE: To compare a group of hospitalized asthmatic children taking theophylline with a similar group of hospitalized nonasthmatic children on standardized measures of distractibility, attention, hyperactivity, and academic achievement. DESIGN: Standardized psychological tests were used to measure cognition, attention, and learning, and results for the two groups were compared. SETTING: All subjects were hospitalized in an intermediate care facility. PATIENTS: Up to 63 asthmatic children taking theophylline were compared with a group of 46 nonasthmatic children matched for age, sex, socioeconomic status, and full-scale IQ. Children with head injuries, mental retardation, or known learning disabilities were not included. INTERVENTIONS: All asthmatic children and none of the nonasthmatic children maintained therapeutic levels of theophylline during the evaluation period. MAIN OUTCOME MEASURES: Independent t tests were used to examine differences between groups on psychological tests of cognition, attention, and learning. RESULTS: No significant differences were found between groups on any variables at the 95% level of confidence. CONCLUSIONS: While idiosyncratic side effects of theophylline are possible, most children are not more hyperactive, distractible, short of memory, different in academic achievement, or more impulsive than other children with chronic illness.

Objective indicators of severity of asthma.

Subjects with asthma who are intensively treated in residential care facilities frequently demonstrate marked clinical improvement in their disease, with fewer attacks and improved well being. Despite their improved status, it is known that pulmonary function test results often remain abnormal in patients with asthma. This prospective study on children with asthma receiving residential care was carried out to determine which pulmonary function parameter best reflected clinical improvement through correlation with the duration of complete freedom from wheezing. Evaluated in 42 children were spirometry values including forced vital capacity, forced expiratory volume in 1 second, peak expiratory flow rate, forced expiratory flow (between 25% and 75% of forced vital capacity), and lung volumes as reflected by residual volume/total lung capacity. Bronchial hyperreactivity as reflected by bimonthly provocative concentration causing a 20% fall in FEV1 in response to methacholine inhalation was evaluated in 18 patients. All pulmonary function test results were correlated with days since last wheezing episode. Results indicate that only peak expiratory flow rate (r = 0.91; p < 0.001), forced expiratory volume in 1 second (r = 0.69; p < 0.01), and forced expiratory flow (r = 0.62; p < 0.05) demonstrated significant correlation with the number of days since last wheezing episode. Of particular interest was the failure of bronchial hyperreactivity to improve despite intensive therapy with bronchodilators and corticosteroids. Persistence of bronchial hyperreactivity despite intensive therapy with corticosteroids suggests that in at least some children with severe asthma, bronchial hyperreactivity may be especially long-lived, may be perpetuated by inhaled beta 2 agonists, or may exist independently of airway inflammation.

Hyposmia in allergic rhinitis.

BACKGROUND: The association between nasal allergy and loss or diminution of smell is frequently alluded to in the literature; however, neither the true prevalence of hyposmia in individuals with allergic rhinitis nor its bases have been established. METHODS: We assessed olfactory threshold for phenylethyl alcohol in 91 patients with symptoms of allergic rhinitis and 80 nonatopic control subjects. To determine the degree to which nasal congestion contributes to hyposmia in allergic rhinitis, total nasal resistance was measured in 64 of the patients and 72 of the control subjects. RESULTS: Olfactory thresholds were significantly higher in allergic patients than in control subjects (p < 0.001), with 23.1% of the patients demonstrating a clinically significant smell loss (defined as threshold at or above the 2.5th percentile of control values). Although nasal resistance was significantly higher among patients than among controls (p < 0.001), it was not related to olfactory threshold in either group. Clinical or radiographic evidence of sinusitis or nasal polyps or both in allergy patients was found to be significantly associated with hyposmia (p < 0.006). CONCLUSIONS: The observed prevalence of hyposmia among patients with allergic rhinitis suggests that this is a major etiologic factor contributing to smell disorders. Sinusitis or nasal polyps or both may underlie many cases of allergy-related hyposmia.

SCH 434: a new antihistamine/decongestant for seasonal allergic rhinitis.

In a double-blind, multicenter study, we compared the effects of SCH 434 (Claritin-D; Schering Corp., Kenilworth, N.J.), a new sustained-release, combination antihistamine/decongestant medication, with the effects of its individual components and placebo in 435 patients with seasonal allergic rhinitis. SCH 434 contains 5 mg of loratadine, a nonsedating antihistamine, and 120 mg of pseudoephedrine as the decongestant component. Administered twice daily in this study, SCH 434 effected a 50% decrease in total symptom scores at day 4 and was significantly (p less than or equal to 0.03) more effective than the components alone or the placebo. Loratadine or pseudoephedrine alone, with 43% and 33% decline in symptom scores, respectively, also was more effective than placebo (p less than 0.05). As expected, pseudoephedrine alone was more effective than loratadine (p less than 0.01) in relieving nasal stuffiness; SCH 434 was more effective (p less than or equal to 0.01) than placebo and loratadine in relieving nasal stuffiness. All treatments were safe and well tolerated, although insomnia and dry mouth were noted in a significant number of patients who received either SCH 434 or pseudoephedrine. No serious side effects were noted. The incidence of sedation did not differ significantly among the four treatment groups. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis. The combination drug (SCH 434) was better than its components for some, but not all, symptoms.

Transient hypogammaglobulinemia of infancy: need to reconsider name and definition.

Twenty-three infants with diminished levels of one or more immunoglobulin isotypes, intact antibody producing capacity, and a generally benign clinical course were initially diagnosed as having transient hypogammaglobulinemia of infancy. Prospective evaluation of these infants, including seven to age 60 months, revealed that acquisition of normal immunoglobulin levels was often delayed beyond infancy. In some cases the diminished immunoglobulin levels were a prodrome of selective lgA deficiency. These children seemed to experience frequent sinopulmonary infections early in life, but fewer with age. None of these children received exogenous gammaglobulin. The designation of transient hypogammaglobulinemia of infancy is a misnomer, and the diagnosis, even if accepted, can be made only in retrospect. The alternative designation hypogammaglobulinemia of early childhood is suggested, to which can be added "with recovery" or "with development of other dysgammaglobulinemia," depending on the eventual phenotype observed.

The relationship of cerebrospinal fluid and plasma theophylline concentrations in children and adolescents taking theophylline.

Ten ambulatory subjects with asthma experienced a seizure while they were receiving oral theophylline preparations and were evaluated prospectively according to a set protocol. The protocol included a lumbar puncture that permitted the simultaneous determination of plasma and cerebrospinal fluid (CSF) theophylline concentrations. A constant relationship was observed between the plasma theophylline concentration and that of the CSF. It was found that the theophylline concentrations in these two biologic fluids could be characterized by the regression equation y = 0.41 X + 0.7 where y is the CSF theophylline concentration and X is the plasma theophylline concentration. Two infants with hydrocephalus treated by ventriculoperitoneal shunt were also simultaneously evaluated for plasma and CSF theophylline concentrations. These infants demonstrated greater than expected entry of theophylline into the CSF. Some central nervous system abnormalities may be characterized by increased theophylline entry into the CSF.