The epidemic of asthma and allergy
Authors: S. T Holgate
Journal: Journal of the Royal Society of Medicine (2004)

In his treatise On Asthma: Its Pathology And Treatment first published in 1860, Henry Hyde Salter (Figure 1), a physician at the Charing Cross Hospital, London, differentiated asthma from other causes of breathlessness as `paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration between attacks'.1 6 years later, from an analysis of 150 unpublished cases, he described many of the characteristic features of this disease including hyperresponsiveness to cold air and exercise and attacks provoked by exposure to chemical and mechanical irritants, to particular kinds of air as well as to certain foods and wine.2,3 His observations were further enhanced by the use of the spirograph, the earliest record of a water spirometer.4 In these publications Salter identified asthma as a spasmodic stricture occurring throughout the conducting airways, and differentiated the condition from bronchial catarrh, recent bronchitis and old bronchitis (Figure 2). He drew special attention to the musical rhonchus that characterized asthmatic bronchoconstriction and indicated that the sibilant bronchi could not be relieved by coughing. Also of great significance was his observation of cells in the asthmatic sputum, which he identified by the presence of a nucleus, nucleolus and cell wall. The identification of eosinophils in sputum had to await the development of eosin by Paul Ehrlich some 15 years later.5 Sir William Osler, in his first edition of Principles and Practice of Medicine,6 likewise drew attention to the factors that could exacerbate asthma including allergens, air pollutants, infections, exercise, weather, food and emotions.



Figure 1

Henry Hyde Salter (1823–1871)





Figure 2

Plate from Salter's Treatise (1860) illustrating the different causes of airflow obstruction



Hyperresponsiveness of the conducting airways, a characteristic feature of all forms of asthma, can be quantified in the laboratory by use of inhalation bronchial provocation tests with such agents as methacholine and histamine. In asthma the dose–response curve to these agonists is displaced to the left in proportion to disease severity, and at high agonist concentrations there is loss of the normal protective plateau (Figure 3). As pointed out by both Salter and Osler, hyperresponsiveness is in part the result of a characteristic type of inflammation that affects the conducting airways and is accompanied by marked structural changes to the airways which include an increase in airway smooth muscle and deposition of matrix leading to an overall thickening of the airway wall (remodelling). The pathological features of asthma are vividly illustrated by Huber and Koessler in their classic paper of 1922.7 These combine to make the airways contract too much and too easily in response to exogenous and endogenous stimuli, as well as contributing to the diurnal variation in airway calibre that is characteristic of the disease.



Figure 3

Typical dose–response curves in normal and asthmatic individuals on aerosol bronchial provocation with increasing concentrations of methacholine



Today, fibreoptic bronchoscopy allows ready access to airways, and lavage and mucosal biopsy samples confirm the presence of a special type of inflammation characterized by infiltration of the airway wall with activated T lymphocytes, mast cells, basophils, eosinophils and macrophages. In addition, morphometric studies on airways from patients who have died from or with asthma have quantified the impressive increase in airway smooth muscle that occurs in this disease, along with structural changes that include shedding of epithelial cells and epithelial mucous metaplasia, deposition of collagen and other matrix proteins in the lamina reticularis beneath a normal epithelial basement membrane, increased deposition of proteoglycans and repair collagen throughout the airway wall, and an increase in submucosal microvessels and nerves—all changes tantamount to airway remodelling. The fact that these structural changes occur in early childhood, at the inception of asthma,8 indicates that they are fundamental to pathogenesis and occur parallel to, rather than as a consequence of, airway inflammation.9