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.

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.

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.

Suppressor cell dysfunction and necrotizing lesions in a child.

A girl had opportunistic infections and was found to have T-cell dysfunction. During a period of months, recurrent staphylococcal infections, polyclonal hyperglobulinemia, eosinophilia, and peripheral, necrotizing, cutaneous lesions developed. Circulating immune complexes were demonstrated, and abnormal suppressor-cell function was found. At age 36 months, the child died of a staphylococcal pneumonia. At postmortem examination, the thymus gland was found to be histologically abnormal, lacking corticomedullary differentiation. We propose that this patient had a syndrome in which lymphocyte abnormalities and dysfunction of suppressor T cells permitted hyperresponsiveness of antibody-forming cells. Large amounts of circulating antibody and immune complexes were formed, and their deposition led to peripheral tissue injury.

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.

Management of the child with recurrent asthma.

A rational approach to the evaluation of the child with chronic asthma has been presented. The importance of careful historical, physical, and pulmonary assessment is stressed, especially since asthma may exist without overt wheezing. General allergic as well as sequential pharmacologic management of this disease is also discussed. A knowledge of the biochemical and pathophysiologic alterations in asthma should lead to rational and specific therapy that preserves normal function and decreases the long-term morbidity and mortality of the disease.

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.

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.

Depression of cell-mediated immunity in atopic eczema.

Prompted by recent observations that the thymus exerts an important regulatory influence over IgE antibody production in lower species, we conducted studies of immune function in 21 patients with atopic eczema to seek evidence for a similar relation in man. Skin tests for delayed hypersensitivity to Candida albicans and streptokinase-streptodornase (SK-SD) revealed a striking degree of anergy that correlated with the severity of the eczema. A correlation was also noted between the extent of the dermatitis and the magnitude of the serum IgE concentration. Other immunologic abnormalities did not appear related to the severity of eczema put pertained to the group as a whole. These included significantly (p = less than 0.0001) lower mean percentages of spontaneous sheep erythrocyte (E) or T cell rosettes and of rosettes with neuraminidase-treated sheep erythrocyte (En) rosettes, and significantly lower in vitro lymphocyte responsiveness of the mitogens concanavalin A (p = 0.0013) and poleweek mitogen (p = 0.0002) and to Candida antigen (p = 0.0017) than in normal subjects. Responses to phytohemagglutinin and tetanus toxoid were also depressed but differences were not statistically significant. An increased percentage (p = 0.0324) of peripheral blood B lymphocytes bearing the complement receptor was noted, but, except for a slight increase in lymphocytes bearing IgD, percentages of lymphocytes bearing other immunoglobulins (including IgE) were not elevated.

Cellular immunity and IgE levels in asthmatic children.

Several reports have suggested that asthmatic children may be particularly vulnerable to viral respiratory infections, in addition to this, abnormal cellular regulation has been suggested as an explanation for the increased IgE levels in atopy. Despite such evidence there have been few studies evaluating cellular immune function in asthmatic children. This study has examined in vivo and in vitro aspects of cellular immune function in twenty-six atopic asthmatic children and compared them with nineteen age-matched non-atopic control subjects. In vivo cellular immunity was assessed by quantitating the cutaneous delayed hypersensitivity (CDH) response to four ubiquitous antigens. Lymphocyte responsiveness to three polyclonal mitogens was measured in vitro. The serum IgE level was determined in all study subjects. The results indicate that CDH to Candida antigen is significantly diminished among the asthmatic subjects and lessened to streptokinase/streptodornase. Lymphocyte mitogen response did not differ significantly between the study groups. No correlation could be shown between in vitro lymphocyte responsiveness and IgE level. These studies suggest that a subtle cellular immune defect may exist in asthmatic children and support the need for further studies of this question.

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.

The effect of beta adrenergic blockade on bronchial sensitivity to acetyl-beta-methacholine in normal and allergic rhinitis subjects.

The effect of propranolol inhalation on sensitivity to methacholine inhalation was studied in normal and allergic rhinitis subjects to determine whether beta adrenergic blockade alters sensitivity to mediators in nonasthmatic atopic individuals. A partial beta adrenergic blockade is suggested as being instrumental in asthma. Hay fever patients studied showed similar effects and also developed asthma for the first time.

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.

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.

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.

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.

Lymphocyte subpopulations of atopic children and the effect of therapy upon them.

Recent reports note decreased T cell function in association with certain atopic conditions in man. This study was performed to determine whether numbers of circulating T cells are decreased in atopic children and adolescents in comparison with nonatopic age-matched control subjects. The subjects were not selected on the basis of a particular atopic diagnosis, but relatively more had allergic rhinitis and/or asthma (52) than had atopic eczema (7). Numbers of circulating T cells were not found to be significantly different in allergic children aged 2 to 10 yr than in control subjects. Atopic children and adolescents over age 10 yr had significantly fewer T cells in relative percentages (p less than 0.05), but when absolute numbers were considered significance was lost. Atopic children aged 2 to 10 years had significantly more B cells in both relative percentages and absolute numbers than did control subjects (p less than 0.02 and p less than 0.05, respectively). When those subjects treated with corticosteroids were separated from the total atopic group, there were no significant differences between the atopic and control subjects. The effects of corticosteroids, bronchodilators, antihistamines, and immunotherapy were considered and could be shown to produce no consistent effect on lymphocyte subpopulations.