Back to PNEUMOLOGYClementino Fraga Filho University Hospital / The Federal University of Rio de Janeiro
Asthma is a chronic lung disease that reaches about 10% of the world population, and although being such common it presents considerable racial and geographic variations in its prevalence ranging from 1 to 20% in different countries. The reasons for those huge variations are not known and asthma experts believe in genetic factors, climate or differences in the degree of antigen exposure. The lower incidence of asthma in countries nearby the tropics have been related to a protective effect of high serum IgE levels induced by parasitic infestation.
A clear definition for asthma has not been reached yet, but we know that is a complex lung disease with the following characteristics: spontaneous (or drug responsive) reversible airway obstruction, airway inflamation and increased airway responsiveness to a variety of stimuli. With the development of immunology and molecular biology an incredible complex network of independent mechanisms interconnected by some common pathways was discovered and allowed us to understand at least part of the events triggered from the very first moment when the inhaled antigen touch the airways to the final event of reduction of bronchial caliber and bronchospasm. Lymphocytes, mast cells, eosinophils, platelets, macrophages and epithelial bronchial cells secreting lymphokines, interleukines, leukotrienes, and an enormous list of mediators, associated with neural mechanisms, are directly involved in the airway inflamatory process driving to the well known respiratory functional disturbs, clinical manifestations, therapeutic responses and in some extreme cases, death caused by untreatable respiratory failure.
There are still lots of questions to be answered about asthma, allowing us to compare this entity with a misterious "iceberg" showing a very shy top at the surface. The aim of this article is a brief revision of the recent known mechanisms of this challenging disease, with a special focus in treatment according to the new develloped drugs and the World Health Organization - WHO- new classification of asthma.
Is asthma a genetic disease? There are lots of evidences that point the way of close interaction of genetic (Mendelian pattern, heterogeneous and poligenic) and environmental factors in the pathophysiology of the disease.The main characteristic of asthma, the bronchial hiperresponsiveness commonly associated with high serum IgE levels, seems to be determined by an autossomic dominant trait. Atopy has a genetic base too, being a condition usually present in asthmatic patients. In atopic people, the constant contact with inhaled allergens (mainly the acari - now considered actually as causing asthma and the principal isolated risk factor for the development of the condition), drives to sensibilization, inflamation and finally bronchospasm. In 1992, Slaving et al. plublished interestingly data about asthma, concluding that: 80% of asthmatic people have concomitant rhinitis; by the other hand, only 15% of patients with rhinitis have asthma; 50% of patients with asthma+rhinitis are AAS (acetylsalicylic acid) sensibilized; 10% of patients with gastroesophageal-reflux disease (GERD) are respiratory complainers, however, 60% of the asthmatic population have GERD ( small chronic bronchoaspirations, inducing vagal reflex).
The most extensively researched field in asthma pathophysiology is the one related to the inflamatory basis of airway hiperresponsiveness. The inflamatory process observed in asthmatic patients is the final result of a complex network of interactions between various cells lineages, its mediators and secreted substances. There takes place an amplification of the immunological response to the inhaled antigens, conducted by the T-lymphocytes (Th1 and Th2) which activity is regulated by lymphokines secreted by themselves, mast cells, eosinophils, macrophages and epithelial cells. With the triggering of the immunological cascade, the bronchial architecture becomes different, due to infiltration of the airways from the epithelium to the smooth muscle and surrounding peribronchial tissue, by eosinophils and Th2-lymphocytes. The cytokines, associated with a logical sequence of events, will finally induce B lymphocytes to produce IgE, increasing the amplification of the allergic response. By the other side, the activated eosinophils play a chemotactic role, potencializing the inflamatory response. In addition, the smooth muscle suffers hypertrophy/hyperplasia, there is desquamation of epithelial lining cells, intersticial edema and deposition of collagen fibers types III and V bellow the basal membrane, causing thickening of the bronchial wall and amplifying the mechanical changes provoked by bronchospasm. Into the bronchial lumen we can observe mucus plugs (the inflamation causes mucus gland hypertrophy), sloughed epithelial cells - the "Creola bodies", eosinophils, Charcot-Leyden crystals (eosinophilic proteins), and Curschman's spirals (eosinophils+mucus). In summary, a conjugation of factors occurs and results in reduction of the bronchial caliber, rising the airway resistance and finally driving to the functional disturbances so characteristic of asthma.
A pattern of behaviour of the inflamatory response that leads to the final event of bronchospasm is observed and divided in two phases. The first, called immediate reaction is caused by the release of mediators by mast cells, on a hyperresponsive smooth muscle after contact of the inhaled antigen with the sensibilized airway. It reaches the peak of activity arround 20 or 30 minutes subsequently to inhalation. The second one, called late reaction, provoked by the release of chemotactic cytokines responsible for the attraction of the main inflamatory cells like eosinophils, Th2 lymphocytes, neutrophils and monocytes from the sistemic circulation to the sensibilized airways. Then it hapens a new triggering of the immune cascade, and more bronchospasm. In conclusion, asthma is increasigly recognized as involving complex cell-to-cell interactions via interleukins and cellular recruitement, involving chemotactic factors and expression of adhesion molecules on vascular endothelial cells. Its important to remember that there are evidences of two extrems of asthma: the mildest form, with most of the inflamatory process being dictated by mast cells and the severe form, being the T lymphocytes the main mediators of the bronchial inflamation process.
Another mechanism associated with the generation of bronchospasm is the tittled "neurogenic inflamation process". The basis of this model of inflamation is supported by the existence of local sensory nerve endings present throughout bronchial mucosa an submucosa. The inhalation of an irritating antigen is capable to generate the called "axonal reflex" which consists in retrograde conduction of neural impulses releasing neuropeptides in the local milieu. These substances (substance P, neurokinin A, calcitonin gene-related peptide) are potent bronchoconstrictors, mucus secretagogues, venodilators and chemoattractans; mimicking the effects of mediators of immediate hypersensitivity. An abnormal pattern of secretion or degradation of these neuropeptides might contribute to the pathogenesis of "intrinsic" asthma. Recently, it has been postulated that the inhibition of the metabolism of substance P by neutral endopeptidase found in some patients using angiotensin converting enzyme inhibitors (ACE) may be the mechanism of ACE inhibitor-induced cough.
On clinical ground asthma, can be divided according to the degree of severity in a spectrum that varies from mild to severe. Recently, the WHO proposed a classification that consists in: mild, persistent mild, moderate, persistent moderate and persistent severe according to symptoms and lung functional tests. Specific forms of asthma are classified separately like nocturnal (aggravation of symptoms at night), exercise induced (triggering of bronchospasm due to cooling and drying the bronchial tree during the exercise practice), occupational (chemicals and antigens chronically inhaled in workplace acting as sensitizers, overtime creating bronchial hiperresponsiveness in previous normal persons), aspirin sensitivity (found in 10 to 20% of asthmatic people, explained due to hyperproduction of leucotrienes caused by cross-reactivity with NSAIDs) and sulfite sensitivity asthma (found in less than 5% of asthmatics, due to substances present in food restaurant, beer and wines).
Current WHO recomendations for the treatment of asthma are subdivided according to the symptoms severity, focusing the long term prophilatic anti-inflamatory approach and immediate symptomatic relief; as described below. The clinical classification is described in (table 1)
For a good management of this disease, the treatment of agravating associated disordes is extremely important. The main disordes pointed as agravating factors are: left ventricular insufficiency/congestive heart failure, COPD, allergic bronchopulmonary Aspergillosis, GERD and chronic rhinosinusopathy. Another important concept is related to the classification of "corticosteroid-dependent" and "corticosteroid-resistent" asthma. The first, involves the group of patients which cannot stay without oral glucocorticoids without becoming they become very symptomatic, and the former are related to the group that does not respond to oral or inhaled steroids. Some patients do not respond to oral prednisone, but have a very good response to inhaled beclomethasone - those are considered as steroid-dependent patients.
As a final consideration, I would like to discuss a little about two recent drugs: fluticazone, a inhaled corticosteroid 2 times more potent than beclomethasone and zileuton, a lipoxigenase inhibitor. Fluticazone should be considered in treating severe forms of asthma that are not responding satisfactorily to the instituted treatment with beclomethasone or in patients suffering from severe nocturnal asthma. Randomized controlled trials with this drug are lacking to support definitively these indications. About zileuton, its an oral agent with proved efficacy in AAS and cold-air induced asthma, but not approved for the FDA to treat the disorder. There are ongoing trials with this drug that will answer at least part of our questions, and probably add one more efficacious drug to the treatment of asthma. Ciclosporin and methotrexate are nowadays less indicated, as newest trials are showing us that the reductions in oral steroids are very mild against a big list of adverse factors. Those drugs should be used cautiouslly in specific well studied patients.
Just to reflex: As the time goes by, new drugs are discovered and appproved for the treatment of asthma. Treating asthma today is more difficult than treating in the past? Maybe yes...
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