Abnormal mucociliary transport is improvement by the action of theophylline, and this effect can be attributed to several mechanisms. The drug may directly and indirectly mediate the increase in the secretory output of bronchial glands, and this effect is enhanced by the vagal gastropulmonary reflex which is stimulated by the irritant action of theophylline on the stomach. Theophylline can increase the transepithelial secretion of fluid into the respiratory tract lumen by stimulating the chloride pump which is controlled by cyclic AMP. Ciliary motility is stimulated by theophylline; most of this effect is confined to the proximal part of the respiratory tree. However, much of the improvement in mucociliary clearance may be a consequence of the bronchodilation induced by theophylline, since the improved airway patency is generally a prerequisite for enhanced mucokinesis. Nevertheless, the multiple sites of action of theophylline in the respiratory tract suggests that this drug should be considered to be of significant value in any disorder characterized by mucostasis.

One of the important modes of action of theophylline in asthma and chronic obstructive airway disease may be the inhibition of airway inflammation. This hypothesis is based on in vitro and in vivo studies demonstrating that theophylline at therapeutic concentrations has an inhibitory activity on airway inflammation induced by allergic and nonallergic stimuli. Indirect evidence suggests that airway inflammation is an important determinant in the long-term outcome of chronic obstructive airway disease. The effect of theophylline on the long-term evolution of chronic obstructive lung disease remains to be proven.

Recent investigations have shown that theophylline improves diaphragmatic contractility of the respiratory muscles in isolated muscle preparations in animals and in normal human subjects. It has also been demonstrated that theophylline can reverse diaphragmatic fatigue and prevent fatigue of the diaphragm when given prophylactically. These effects have also been demonstrated in patients with severe chronic obstructive pulmonary disease, all of whom retained CO2 (PaCO2 53 +/- 3 mm Hg) and had hypoxia (PaO2 57 +/- 8 mm Hg). Theophylline, which increases respiratory muscle strength and delays the onset of diaphragmatic fatigue therefore could be a very useful agent in the treatment of patients with chronic airway obstruction.

Theophylline has been utilized widely as a bronchodilator. However, recent studies have shown the potential for administering this drug to enhance cardiovascular performance in patients with chronic obstructive pulmonary disease (COPD). Administered to COPD patients orally as a sustained-action preparation or intravenously as aminophylline, theophylline enhances both right and left heart systolic pump function and lowers both pulmonary artery pressure and pulmonary vascular resistance. These favorable cardiovascular actions suggest an additional use for theophylline in COPD beyond its effects as a bronchodilator.

Dyspnea is influenced by both physiologic and psychologic factors. Breathlessness is common in patients with chronic obstructive pulmonary disease (COPD) and often is the reason that the individual patient seeks medical attention. In order to evaluate the different clinical studies involving the use of theophylline in COPD patients, it is important to consider the three distinct approaches for measuring dyspnea--psychophysical testing, clinical methods, and ratings during exercise. Four randomized, double-blind, placebo-theophylline trials from one to four weeks in duration have evaluated the impact of theophylline on lung function and breathlessness. In these studies, the overall improvement in forced expiratory volume in one second was quite consistent for theophylline compared with placebo therapy. When appropriate clinical methods for measuring dyspnea were used, theophylline showed a positive reduction in breathlessness. These reports suggest that theophylline provides modest objective and subjective improvement in patients with symptomatic chronic air flow obstruction.

The bronchodilating action of theophylline in COPD has been examined, with emphasis on its combined use with inhaled beta 2 agonists. The suggestion is made that failure to recognize the nonlinearity of the dose-response curves for bronchodilators has resulted in underestimating their combined action. Recent studies suggest that systemic theophylline has somewhat different actions on the airways in COPD than inhaled beta agonists, and that more bronchodilation may be possible when the two are used together than large doses of either one. By analogy, with asthma the suggestion is also made that the addition of theophylline is also likely to provide a more constant bronchodilation, reducing peak-trough variations in flow. The most complete clinical comparison to date suggests that, in currently sanctioned doses, a regimen containing both theophylline and an inhaled beta 2 agonist provides significantly greater bronchodilation than either drug alone, with fewer patient withdrawals. Further carefully designed studies are needed to resolve this issue, and particularly, to identify those patients who will derive the greatest benefit from a combined regimen.

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and beta 2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled beta 2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for beta 2 agonists may improve the efficacy of these agents in the future.

Bronchial challenge for determination of bronchial reactivity is widely used in the diagnosis of asthma, the grading of severity, and evaluation of effect of treatment with new antiasthmatic drugs. Allergen challenge is also used for diagnosis of specific IgE-mediated asthma and evaluation of the effect of immunotherapy. A number of factors influence the result of the challenge test including the selection of patients, criteria for carrying out the challenge test, a number of technical factors concerning the challenge, the dosing schedule, pulmonary function tests carried out and analysis of the data. All these factors have to be taken into consideration before reproducible challenge tests can be performed. Detailed description of the equipment and procedures used and inclusion criteria for the patients should be included in all publications concerning challenge tests in order to be able to compare results from different laboratories. Each clinic or laboratory needs to perform reproducibility studies on bronchial challenge testing procedures and equipment used in their clinic.

Clinical, physiologic, and questionnaire approaches can be used to identify subjects with asthma in an epidemiologic investigation. Each method, however, may select differing subsets of the population. At present, a comprehensive asthma questionnaire is unavailable; the difficulty of defining asthma in operational terms has been a major obstacle in the development of such a questionnaire. This review describes the questionnaires prepared by the British Medical Research Council and the American Thoracic Society and suggests modifications.

We summarize current understanding of the genetics of human diseases and of the major histocompatibility complex related factors regulating immune responsiveness. Special factors are involved in atopic diseases as a result of the intersection between the immune system, the targets in the tracheobronchial tree and the endocrine, neurologic and genetic mechanisms affecting both the effectors and the targets. The evidence from investigations of human subjects and their families and from laboratory animals for the underlying genetic and immunologic mechanisms of asthma are reviewed. The genetic control of asthma is complex. The evidence suggests a gene or genes associated with and linked to HLA. The disease phenotype may also be regulated by genetically determined levels of IgE and the outcome of the balance between immune response and immunosuppression.

Allergic bronchopulmonary aspergillosis (ABPA) complicates asthma and results in immunologic lung destruction. Respiratory failure or fatalities from end-stage fibrotic lung disease have occurred in patients in the third and fourth decades of life. Allergic bronchopulmonary aspergillosis may be confirmed in patients with varying severity of asthma from minimal to corticosteroid-dependent and has been reported to occur in approximately 10 percent of patients with cystic fibrosis. It has been documented in infants and children, the geriatric patient with asthma, in the presence of a normal chest roentgenogram, in the corticosteroid-dependent asthmatic patient, and on a familial basis. The pathogenesis of ABPA is unclear, but may be related to the array of immunologic abnormalities including: elevation of total serum IgE, not all of which is directed to Aspergillus fumigatus (Af); elevated serum IgE-Af, IgG-Af and IgA-Af; precipitating antibodies to Af; hyperreactivity of peripheral blood basophils to Af and other molds; and sensitized lymphocytes. Research in ABPA should be multidisciplinary and initially should include investigators in allergy-immunology, mycology, pulmonary, and epidemiology.

The possible role of bacterial, viral and fungal infections in the development, exacerbation and treatment of asthma are discussed. Although bacterial allergy has in the past been advocated as an important etiologic factor for asthma, the evidence is inconclusive. Hyposensitization with bacterial antigens is no longer an accepted treatment. Bacterial infection of the nasal sinuses and bronchi may exacerbate an asthmatic attack and in some cases patients benefit from antibiotic therapy. However, bacterial infections in asthma and allergic rhinitis do not always require treatment and if treated this is not sufficient alone to reverse symptoms. Opinions vary as to the importance of viral infections. There is evidence that the immunologic consequences of intrabronchial infection with Aspergillus fumigatus may cause exacerbations of asthma.

Airflow limitation in exercise-induced asthma is related to the thermal events in the intrathoracic airways. This article reviews the present knowledge about the exchange of respiratory heat and water. The evidence for the various theories proposed for the basic mechanisms involved in exercise-induced asthma are discussed. The evidence suggests that exercise-induced airways obstruction may be a vascular phenomenon dependent on the rapidity and magnitude of airway rewarming. Obstruction is induced if a thermal gradient exists at the end of exercise and the greater the gradient the greater the resultant hyperemia and edema. The basic mechanism of control of reactivity is still not known and directions for future research are outlined.

Asthma is a heterogenous disease triggered by a large number of different stimuli. This article presents a theory of the metabolic mechanisms of asthma. The theory is based on the growing understanding of the activity of lysophosphatidylcholine (LPC). Since the effect of LPC on cell membranes, membrane bound enzymes and the various types of cells involved in the pathogenesis of asthma, this may represent a unifying link between the various types of asthma.

This article review recent developments in the study of occupational asthma and implications for the overall understanding of asthma. Occupational asthma is a clinical syndrome caused by many different agents. Contribution of studies of experimental inhalation challenge using occupational agents to the knowledge of asthmatic reactions and their mechanisms is discussed. Investigations in the occupational environment into predisposing factors and persistence or recovery after exposure to an allergic agent or nonspecific irritant are reviewed. Approaches to diagnosing asthma in the occupational environment and to assessing functional impairment and disability are outlined. Directions for future research are identified.