Over 200 materials encountered at the work-place are known to give rise to occupational asthma. The important causes are recognized occupational diseases in the UK and patients in insurable employment are therefore eligible for statutory compensation provided they apply within 10 years of leaving the occupation in which the asthma developed. The development of asthma following exposure to some of these materials is linked to the development of specific IgE antibody in serum in some cases, whilst in others the cause has yet to be determined.
The proportion of employees developing occupational asthma depends primarily upon the level of exposure. Proper enclosure of industrial processes or appropriate ventilation can greatly reduce the risk. Atopic individuals develop occupational asthma more rapidly when exposed to agents causing the development of specific IgE anti body. Non-atopic individuals can also develop asthma when exposed to such agents, but usually after a longer period.
The characteristic feature of bronchial hyperreactivity in asthmatics means that as well as reacting to specific antigens their airways will also respond to a wide variety of non-specific stimuli.
COLD AIR AND EXERCISE. Most asthmatics experience an attack of wheezing after prolonged and continuous exercise. Typically, the attack does not occur during the exercise period but at its conclusion. The inhalation of cold, dry air will also precipitate an attack. In both cases the wheezing is thought to be precipitated by the cooling and drying of the epithelial lining of the bronchi. Exercise and cold air provocation tests can be performed.
ATMOSPHERIC POLLUTION AND IRRITANT DUSTS, VAPOURS AND FUMES. Many patients with asthma experience worsening of symptoms on contact with cigarette smoke, car exhaust fumes, strong perfumes or high concentrations of dust in the atmosphere. Further minor epidemics of the disease have occurred during periods of heavy atmospheric pollution in industrial areas, caused by the presence of high concentrations of sulphur dioxide, ozone and nitrogen dioxide in the air.
EMOTION. It is well known that emotional factors may influence asthma, but there is no evidence that patients with the disease are any more psychologically disturbed than their non-asthmatic peers.
DR UGS. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have an important role in the development and precipitation of attacks in approximately 5% of patients with asthma. This effect is almost universal in those individuals who have both nasal polyps and asthma. The precise mechanism involved is unknown but it is thought that treatment with these drugs leads to an imbalance in the metabolism of arachidonic acid. NSAIDs inhibit arachidonic acid metabolism via the cyclooxygenase pathway, preventing the synthesis of rostaglandins. It is suggested that under these circumstances arachidonic acid is preferentially metabolized via the lipoxygenase pathway, resulting in the production of leukotrienes, previously known as the slow-reacting substances for anaphylaxis.
The airways of the lung have a direct parasympathetic innervation that tends to produce bronchoconstriction. There is no direct sympathetic innervation of the smooth muscle of the bronchi, and antagonism of parasympathetically induced bronchoconstriction is critically dependent upon circulating adrenaline acting through t32-receptors on the surface of smooth muscle cells. Inhibition of this effect by t3-adrenoreceptor-blocking drugs such as propranolol leads to bronchoconstriction and airflow limitation, but only in asthmatic subjects. The so-called selective t3,-adrenoceptor-blocking drugs such as atenolol may still induce attacks of asthma; their use in asthmatic patients for hypertension or angina should be questioned and calcium antagonists such as nifedipine should be used if appropriate.
The experimental inhalation of allergen by atopic asthmatic individuals leads to the development of four types of reaction, as illustrated.
The commonest reaction is immediate asthma, in which airflow limitation begins within minutes of contact with the allergen, reaches its maximum in 15-20 min and subsides by 1 hour. Many asthmatics subsequently develop a more prolonged and sustained attack of airflow limitation that responds poorly to inhalation of bronchodilator drugs such as salbutamol-the late-phase reaction.
The combination of an immediate reaction followed by a late reaction is known as a dual asthmatic response. The inhalation of some materials, particularly occupational sensitizers such as the isocyanates, usually causes the development of an isolated late reaction with no preceding immediate response.
The development of the late-phase reaction is associated with an increase in the underlying level of airway hyperreactivity such that individuals may show continuing episodes of asthma on subsequent days- recurrent asthmatic reactions.
The pathogenes is of asthma is complex and not fully understood. It involves a number of cells, mediators, nerves and vascular leakage that can be activated by several different mechanisms, of which exposure to allergens is the most important.
MAST CELLS (see p. 133). These are increased in both the epithelium and surface secretions of asthmatics and can generate and release powerful smooth muscle and vasoactive mediators, such as histamine, prostaglandin D2 (PG D2) and leukotriene C. (LTC.), which cause the immediate asthmatic reaction. Since potent J32-adrenoceptor agonists such as salbutamol have little effect on airway inflammation or hyperreactivity but inhibit mast cell mediator release, many other factors are now considered important in the pathogenesis of late and recurrent asthmatic reactions leading to more severe asthma.
EPITHELIUM. Epithelial cells are shed during exacerbations of asthma (they can readily be identified in sputum), causing increased permeability to inhaled allergens, exposure of afferent nerve endings, loss of the putative epithelial-derived relaxant factor, possibly nitric oxide, and neutral endopeptidase capable of breaking down sensory neuropeptides, and generation of chemoattractant factors such as 15-hydroxyeicosatetraenoic acid (l5-HETE). Epithelial cells can also produce cytokines, particularly granulocyte macrophage colony stimulating factor (GM-CSF), tumour necrosis factor-a (TNF-a) and interleukin 8 (IL-8), all capable of initiating and enhancing inflammation.
BASEMENT MEMBRANE. Recently biopsy studies have shown that the sub-basement membrane region, the lamina reticularis, is widened even in the mildest asthmatics owing to increased deposition of collagen types III and V and fibronectin, indicating that inflammation occurs at the earliest stages of the disease.
NERVES. Damage or loss of epithelial cells exposes Cfibre afferent nerve endings that can release the sensory neuropeptides substance P, neurokinin A and calcitonin gene-related peptide, contributing towards bronchoconstriction, microvascular leakage and mucus secretion.
MACROPHAGES AND LYMPHOCYTES. These cells are abundant in the mucous membranes of the airways and the alveoli. Macrophages may play a particularly important role in the initial uptake and presentation of allergens to lymphocytes. They can release prostaglandins, thromboxanes, leukotriene B. (LTB.) and platelet activating factor (PAF). T-helper lymphocytes (CD4) showevidence of activation and the release of their cytokines may play an important part in the migration and activation of mast cells (IL-3) and eosinophils (IL-S). In addition production of IL-4 leads to the switching of antibody production by B lymphocytes to IgE. The activity of both macrophages and lymphocytes is influenced by corticosteroids but not t32-adrenoceptor agonists.
EOSINOPHILS. These cells are found in large numbers in the bronchial secretions of asthmatics. When activated, they release LTC., PAF and basic proteins such as major basic protein (MBP) and eosinophil cationic protein (ECP) that are toxic to epithelial cells. Both the number and activation of eosinophils is rapidly decreased by corticosteroids.
MEDIATORS. The exact role of the many potent smooth muscle and vasoactive mediators, including LTC., LTD., thromboxanes and the sensory neuropeptides, as well as the chemoattractants LTB. and PAF, remains unknown and awaits the introduction of effective and specific antagonists. Studies with potent selective HI antagonists have shown that histamine plays only a small role in the pathogenesis of the persisting airflow limitation of asthma.