Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that causes damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. Although COPD shares some clinical features with asthma, another prevalent airway inflammatory disease, there are distinct differences in the phenotypic characteristics of airway inflammation between COPD and asthma. The eosinophil is the most prominent inflammatory cell in asthma, with mast cells, lymphocytes, and macrophages playing important but less prominent roles. In COPD the cellular composition of the airway inflammatory infiltrate differs, with neutrophils, macrophages, and lymphocytes assuming prominence and the eosinophil playing a minor role, except in the setting of exacerbations. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy.     

Terbutaline elixir in preschool children with chronic asthma

In a double-blind, single-dose trial asthmatic children, ages two to six years, received 25, 50 or 100 ug/kg terbutaline and placebo on four consecutive days. After ingestion of all doses and placebo mean pulmonary index score and mean total respiratory resistance (Rrs), measured by forced oscillation decreased significantly at 0.5, 1, 2, 3 and 4 hours, with maximal decrease at two hours. A dose response was apparent but was significant only between doses of 25 ug/kg and 50 ug/kg at four hours. Adverse effects included elevation of heart rate two hours after the 100 ug/kg dose and tremor. In a subsequent nine-week, single-blind trial clinical wheezing was completely prevented by terbutaline 50 ug/kg tid in five of eight patients and by 75 or 100 ug/kg tid in two patients. Baseline Rrs did not decrease. No adverse ophthalmologic, hematologic or biochemical changes were observed.     

Theophylline: Potential antiinflammatory effects in nocturnal asthma

BACKGROUND: Recent information suggests that one of the therapeutic properties of theophylline is an antiinflammatory effect. OBJECTIVE: We evaluated this potential effect of theophylline in eight patients with nocturnal asthma. METHODS: The study design was a randomized, double-blind, placebo-controlled crossover of 2-week treatment periods, separated by a 1-week washout period. Spirometry and bronchoscopy were performed. RESULTS: Theophylline, compared with placebo, significantly improved the overnight decrement in lung function. The higher the nocturnal theophylline level, the greater the improvement in lung function. Theophylline also significantly decreased the percentage of neutrophils in the 4:00 AM bronchoalveolar lavage fluid and stimulated leukotriene B₄ levels from macrophages obtained at 4:00 AM. The greater change in neutrophils correlated with increasing serum theophylline concentration. Also, the change in leukotriene B₄ production was significantly correlated with the theophylline-induced decrement in lavage granulocytes (neutrophils and eosinophils). CONCLUSION: This study suggests that one action of theophylline is to alter inflammatory cell number and function in nocturnal asthma and that it may do this through an leukotriene B₄–mediated mechanism. (J ALLERGY CLIN IMMUNOL 1996;97:1242-6.)     

Antibiotic administration to treat possible occult bacteremia in febrile children

We performed a prospective, randomized, placebo-controlled, double-blind clinical trial of antibiotic administration to treat possible occult bacteremia in febrile children. A total of 955 children aged 3 to 36 months with temperatures greater than or equal to 39.0 degrees C and no focal bacterial infection were enrolled at the emergency departments of two children's hospitals from January 1982 until July 1984. Blood samples for culture were obtained, and the children were randomly assigned to receive either oral amoxicillin or placebo and were restudied approximately 48 hours after enrollment. Data were also collected on 228 children who could not be randomly assigned. Twenty-seven of the randomly assigned children (2.8 percent) had bacteremic infections with pathogenic organisms (Streptococcus pneumoniae, Haemophilus influenzae, and salmonella). There were no differences in the incidence of major infectious morbidity associated with bacteremia between the antibiotic and placebo groups--2 of 19 patients (10.5 percent) in the antibiotic group and 1 of 8 (12.5 percent) in the placebo group--although the power for this comparison was low. Antibiotics reduced fever (P less than 0.005) and improved the clinical appearance (P = 0.07) in the children with bacteremia but not in those without bacteremia. Although there were no statistically significant differences in the incidence of side effects, diarrhea tended to occur more often in the patients treated with amoxicillin (15 vs. 11 percent, P less than 0.10). We conclude that our data do not support the routine use of standard oral doses of amoxicillin in febrile children who do not have evidence of focal bacterial disease.     

Outpatient treatment of chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that cause damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy. The outpatient treatment of COPD differs from the approach used in asthma and can be divided into 3 subgroups: health care maintenance, drug therapy, and nondrug therapy. Smoking cessation, regular spirometry, and immunization are important components of health care maintenance. Drug therapy consists of optimal bronchodilator therapy supplemented, when necessary, with either inhaled corticosteroids or theophylline. Nondrug therapies include pulmonary rehabilitation, supplemental oxygen, and surgery.     

Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma.

Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.     

Treatment with inhaled corticosteroids improves pulmonary function in children under 2 years old with risk factors for asthma

PURPOSE OF REVIEW: To report on recent studies on the effect of inhaled corticosteroids on pulmonary function in young children with asthma. RECENT FINDINGS: Inhaled corticosteroids are considered the most effective treatment for persistent asthma in children. Appropriate control of childhood asthma may prevent more serious disease or irreversible obstruction in later years. While some authors have described an improvement with the use of inhaled corticosteroids in young children, others found no clinical or functional benefit. Various studies have shown that inhaled corticosteroids ameliorate clinical outcomes, and recently a study demonstrated improvement in pulmonary function in young children with asthma. The use of different study designs may explain the lack of consistent results and disagreement regarding the efficacy of inhaled corticosteroids in these patients. SUMMARY: Based on the preponderance of evidence, treatment with inhaled corticosteroids in infants and young children with recurrent wheeze and risk factors of developing asthma appears to allow better control of the illness and improve the pulmonary function.     

Panic-fear in asthma: Requests for as-needed medications in relation to pulmonary function measurements

Requests for as-needed medications and treatments (PRNs) by asthmatic patients scoring high, moderate, or low on the Asthma Symptom Checklist panic-fear category were studied for days when patients were matched at normal, intermediate, and subnormal levels of pulmonary function. Low panic-fear patients were the least likely to request PRNs regardless of the pulmonary function level. In contrast, high panic-fear patients often requested PRNs at each level of pulmonary function. Only moderate panic-fear patients made progressively more PRN requests on days when pulmonary functions were lower. These observations and others concerning the adverse influence of extreme panic-fear coping styles upon the treatment of asthma were discussed.     

Handle with care: targeting neutrophils in chronic obstructive pulmonary disease and severe asthma?

Neutrophils play an important role in the pathogenesis of airway inflammation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Currently available drugs have only limited effects on neutrophilic airway inflammation, particularily in COPD. Therefore, great efforts are undertaken to address neutrophilic inflammation in chronic respiratory disorders, in particular COPD. This review summarizes the rationale for anti-neutrophilic treatment in COPD and asthma and gives a critical overview of current developments in drug therapy. Moreover, unanswered questions and limitations of clinical trial design and choice of outcome parameters for proof-of-concept studies with novel anti-neutrophilic drugs are discussed as well as potential safety issues.     

Recent advance in pulmonary function tests--advance in pulmonary function tests for diagnosis and management of asthma

Development of new machine and small-sized equipment have the advantage on both diagnosis and management of various diseases. In terms of bronchial asthma, the understanding of pathophysiology has been changed from a disease with acute episodes of bronchoconstriction to a disorder with chronic airway inflammation. To verify bronchial responsiveness induced by chronic inflammation, a direct-writing respiratory impedance method(Astograph) is more useful compared with a conventional standard method with measuring FEV1.0. Peak expiratory flow(PEF), an index of pulmonary function test with effort, can be measured with peak flow meter which is small and handy. Repeated measurements of PEF have been recommended by the International Consensus Report on diagnosis and treatment of asthma. The PEF monitoring is effective not only on the understanding of individual pathophysiology but also on the long-term management of patients with asthma. It is needed to develop noninvasive simple technique to evaluate airway inflammation although many investigators have examined hypertonic saline-induced sputum or bronchial mucosal biopsy. Repeated measurements of exhaled nitric oxide may become to a safe and valid method to access inflammatory change in the airway.     

Clinical effects of theophylline in the therapy of intractable asthmatic children. II. Theophylline therapy and behavior problems in children with asthma

This study examined the relationship between long-term theophylline therapy and behavior problems in 14 asthmatic children that includes 5 intractable cases and 24 non-asthmatic children. Asthmatic children have received theophylline therapy and cromolyn inhalation for 3.6 +/- 3.8 years. Subjects were tested on neuropsychologic batteries; behavior problems and personality of children questionnaire, child behavior checklist, caffeine-like side effects questionnaire, manifest anxiety scale, visual attention test, Uchida-Kraepelin test and soft neurological signs. These tests were repeated with an interval of 1 to 12 weeks. Parents noted caffeine-like side effects, stomach ache and difficulty in sleeping, in their child during the theophylline therapy. The caffeine-like side effects decreased after stopping theophylline therapy. The rate of mistake in Uchida-Kraepelin test for the asthmatic group and for the intractable cases was significantly higher than that of the control group. Time of the sequential finger thumb opposition of the soft neurological signs was significantly prolonged in asthmatic group. There was no significant change in the other tests between asthmatic and non-asthmatic children and before and after stopping theophylline therapy. It seems that behavior problems and learning disability observed in the asthmatic children are due to the pathogenesis or symptoms of asthma rather than the effect of long-term theophylline therapy.     

Self-management training for children with chronic bronchial asthma.

We have described examples of behaviors that occur antecedent to, concurrent with, or as a consequence of childhood asthma. Ways these patterns can be altered have also been described. Three points should be emphasized: first, social learning techniques can contribute to a child acquiring self-monitoring and self-management skills over his or her affliction. Thus, youngsters with asthma can learn self-responsibility over their affliction. Second, while we do have follow-up data indicating that youngsters continue to perform similar behaviors once they leave the Center and return to their families, such generalization does not automatically occur. For this reason, we have initiated several programs for working with a child's family. Finally, what about the youngster who is never admitted to an asthma facility such as the national Asthma Center? It is here where we are beginning to focus most of our efforts. By teaching a child and his or her family ways that the youngster can learn to manage asthma means that the disease will become less of a disruptive influence within the home, that costs of the affliction can be contained, and that the youngster can remain within the mainstream of both his or her family and community. Future reports from the Center will describe efforts we are making in this direction.     

Chronic hypoxia-hypercapnia influences cognitive function: a possible new model of cognitive dysfunction in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease that results in several complications, including cognitive dysfunction. Some evidences support that cognitive impairment is common and clinically important in COPD, but the exact mechanism is still unclear. It has been confirmed that chronic hypoxia-hypercapnia contributes a lot to the development in pathophysiology of COPD. Data from some pilot studies indicated that chronic hypoxia-hypercapnia influences cognitive functions both in patients and in animals, which includes some distinctive pattern of cognitive dysfunction in human being or impairment of spatial learning-memory in rat. Therefore, we propose that cognitive impairment is strongly related to combination of chronic hypoxia and hypercapnia, and chronic hypoxia-hypercapnia-induced animal models may mimic the cognitive dysfunction of COPD. Attempts to confirm this hypothesis may lead to new model of cognitive dysfunction in COPD.     

IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma

BACKGROUND: Asthmatic airways undergo chronic inflammatory cell infiltration by T cells and eosinophils, which results in sustained airway hyperresponsiveness. IL-5 is important for eosinophil-induced airway inflammation and airway hyperresponsiveness. Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma. The relationship between IL-5 and TBXA2R gene polymorphisms and pulmonary function in children with asthma has rarely been examined. OBJECTIVE: To determine whether IL-5 (T-746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma. METHODS: We conducted an association study between known polymorphisms of IL-5 (T-746C) and TBXA2R (T924C) and asthma phenotype and the parameters of atopy and pulmonary function in atopic and nonatopic Korean children with asthma. The subjects were 240 atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children. Asthma phenotypes and bronchial responsiveness to methacholine were determined by a physician. IL-5 and TBXA2R gene polymorphisms were determined by genotyping by using PCR-RFLP assays. RESULTS: The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma. A significant association was observed between the IL-5 polymorphism and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75% ; %; P = .002), and between the TBXA2R polymorphism and FEV 1 (%; P = .035) and FEF 25-75% (%; P = .042) in children with atopic asthma, whereas no such association between the polymorphisms and lung function was observed in nonatopic or control children. In atopic children with asthma, we identified a significant gene-gene interaction in that the combination of the IL-5 (T-746C) and TBXA2R (T924C) mutant alleles was shown to be associated with reduced pulmonary function as determined by FEF 25-75% (%) measurement. CONCLUSION: The current study indicates that IL-5 (T-746C) and TBXA2R (T924C) polymorphisms alone are associated with spirometric markers of asthma severity, whereas they are not associated with presence of asthma per se. In addition, the data suggest that an interaction between IL-5 and TBXA2R genes may contribute to the severity of asthma, especially atopic asthma. These results suggest that IL-5 and TBXA2R genes may be disease-modifying genes in Korean children with atopic asthma.     

Leukotriene pathway inhibitors in asthma and chronic obstructive pulmonary disease

Leukotrienes can be generated from a wide variety of cells including mast cells and eosinophils. The biological properties of these products include bronchial smooth muscle contraction, stimulation of mucous production, enhancement of vascular permeability, and recruitment of eosinophils. These properties can contribute significantly to the pathobiology of asthma. Recently, zafirlukast and montelukast, and zileuton, leukotriene D₄ receptor antagonists and 5-lipoxygenase inhibitors, respectively, have been developed and are available for treating asthma. Studies have found these compounds modify bronchospasm with exercise, the pulmonary reaction to aspirin in sensitive subjects, and the airway response to inhaled antigen. Furthermore, in patients with chronic asthma, leukotriene modifiers improve airflow obstruction, decrease the need for rescue medication, and diminish symptoms. Moreover, these drugs can prevent asthma exacerbations. However, there is little evidence that these medications have potent anti-inflammatory activity. Nonetheless, leukotriene modifiers represent new, and effective, therapeutics in the treatment of asthma; at present, the positioning of these products in relationship to inhaled corticosteroids, for example, in the treatment of asthma has not been fully defined but will emerge with further study and use in the clinic setting.