The clinical expression of allergy in the lungs
Authors: P.M. O'Byrne, M.D. Inman
Journal: Allergy (1999)

The main function of the lungs is gas exchange. This is achieved by moving inspired air down a dichotomous series of branching airways to the gas-exchange portions of the lungs, the alveoli. The average tidal volume for an adult at rest is 500 ml and the respiratory rate is 12/min, giving an average minute ventilation at rest of 6 l/min. This means that, on average, more than 8500 l of air is inspired each day by an adult at rest. However, during exercise, the minute ventilation can exceed 120 l/min. The inspired air reaching the alveoli must be fully humidified at a temperature of 37°C, sterile, and free of noxious agents. The responsibility for conditioning the inspired air falls on the extra- and intrathoracic airways. The intrathoracic airways begin with the trachea, which divides into the right and left main-stem bronchi. The latter subsequently divide into bronchi supplying the upper and lower lobes of the left lung and the upper, middle, and lower lobes of the right lung. After approximately 25 more divisions, the bronchi become bronchioles, which then become respiratory bronchioles and then alveolar ducts, leading to the alveoli. Bronchi all contain cartilage and airway smooth muscle, while bronchioles lack cartilage, and alveolar ducts do not have smooth muscle. The inspired air contains many noxious and irritant agents, including air pollutants, such as oxides of nitrogen or sulphur and ozone, as well as environmental allergens. The prevalence of sensitization to environmental allergens (atopy) in most countries in which it has been carefully evaluated is 25-30% (1). These atopic individuals are at risk of inhaling environmental allergens to which they have become sensitized. The main clinical expression of atopy in the lungs is asthma, although lung anaphylaxis can occur in patients with specific allergies, such as shellfish or peanut allergies. Asthma is a common, chronic inflammatory disease of the large and small airways (2). A particular type of allergic reaction that predominantly involves the alveolar structures, and not the airways, is extrinsic allergic alveolitis, also known as hypersensitivity pneumonitis (3). However, as asthma is the most common manifestation of lung allergy, it will be the main focus of this review. Asthma is a common respiratory disease; indeed, it is the commonest cause of acute hospitalization in children. Its prevalence varies from country to country, but a prevalence rate of over 25% of children and up to 20% of adults has been reported in Australia and New Zealand (4); in most developed countries, the prevalence rate is approximately 10% (5). The prevalence of asthma is also increasing in those countries where it has been measured over time (5) . The exact cause of this increased prevalence is not yet known. Asthma is characterized by symptoms of wheezing, chest tightness, coughing, and dyspnea, as well as characteristic physiologic abnormalities of variable airflow obstruction and airway hyperresponsiveness to bronchoconstrictor stimuli (6). Airway responsiveness is a term which describes the ability of the airways to narrow after exposure to constrictor agonists. Thus, airway hyperresponsiveness is an increased ability to develop this response. Airway hyperresponsiveness consists of both an increased sensitivity of the airways to constrictor agonists, as indicated by a smaller concentration of a constrictor agonist needed to initiate the bronchoconstrictor response (6), and a greater maximal response to the agonist (7). Asthmatics show airway hyperresponsiveness to a wide variety of bronchoconstrictor agonists . These include inhaled pharmacologic agonists, such as histamine (8), acetylcholine (9), methacholine (10), cysteinyl leukotrienes (11), and stimulatory prostaglandins (12). In addition, airway hyperresponsiveness is also induced by a number of physical stimuli such as exercise (13) and isocapnic hyperventilation of cold, dry air (14). The degree of the airway hyperresponsiveness to one pharmacologic or physical stimulus correlates with the degree of the airway hyperresponsiveness to most (10, 13, 14), but not all, other stimuli. For this reason, the term “nonspecific airway hyperresponsiveness” has been used to describe this phenomenon. This is in contrast to the specific airway responses that develop when subjects inhale substances, such as allergens (15), to which they have become sensitized. However, the term “nonspecific airway hyperresponsiveness” can be misleading. It suggests that a common mechanism exists by which these pharmacologic or physical stimuli cause bronchoconstriction. This is clearly not the case, as most of the pharmacologic agents act on specific receptors in the airways, and the mechanisms by which receptor activation causes bronchoconstriction are different for different agents. For these reasons, it is better to name the stimulus used to measure airway responsiveness, such as histamine or methacholine airway responsiveness, when describing the measurements. Asthma has been known to be a chronic inflammatory disease of the airways for more than 100 years (16); however, over the past 15 years, there has been a resurgence of interest in the pathogenesis of airway inflammation, and the importance of airway inflammation not only in causing asthma symptoms, but also in the physiologic abnormalities that characterize asthma. In addition, this has led to an emphasis on treating airway inflammation in asthma with inhaled corticosteroids. It is now clear that the main cause of airway inflammation in asthma is the inhalation of environmental allergens. Almost all children with asthma, or adult asthmatics whose asthma began in childhood, are atopic, as measured by increased levels of serum IgE and/or by positive skin prick tests to common environmental allergens (17), while over 50% of patients with adult onset asthma are atopic. The observation that inhalation of an allergen can cause symptoms of asthma was originally made more than 100 years ago by Blackley, and, in 1934, Stevens described symptoms of asthma for several days after inhalation challenges with allergens (18). However, the first thorough description of the response to inhaled allergen was made by Herxheimer in 1952 (19), who showed that there could be two distinct components to the response to inhaled allergen, which he called the immediate and late reactions. In the late 196os, Altounyan described another important consequence of the inhalation of allergen, in that exposure to grass pollen during the grass-pollen season could increase airway responsiveness to inhaled histamine in sensitized subjects (20). Subsequently, Cockcroft et al. (21) demonstrated that the increase in histamine and methacholine responsiveness that occurs after inhaled allergen, occurs in association with the late asthmatic response after allergen, and that subjects who have only an isolated early response after inhaled allergen do not develop airway hyperresponsiveness. The inhalation of environmental allergens is the most important cause of asthma. Epidemiologic studies have demonstrated that close associations exist between the presence of atopy, especially to house-dust mite and cat dander, and the presence of airway hyperresponsiveness and symptomatic asthma (17). Occupational sensitizing agents, many of which do not act through a classical IgE-mediated allergic reaction, are an important cause of adult onset asthma (22). Thus, it is a plausible hypothesis that all asthma is initiated by inhalation of environmental stimuli, some of which have been identified, and some of which are not yet known. In many patients, regular exposure to environmental allergens or occupational sensitizing agents is the cause of persistent asthma. This has been best demonstrated by the studies which have removed allergic asthmatic patients from the regular daily exposure to the offending allergen (most often house-dust mite), and have demonstrated improvements in asthma symptoms, amounts of treatment needed to control symptoms, and physiologic abnormalities, such as airway hyperresponsiveness (23, 24). In addition, there is evidence that asthma is caused by exposure to the occupational sensitizing agent plicatic acid from western red cedar, and that prolonged exposure can result in persistent asthma, even after the exposure is removed (22). It is conceivable that similar effects occur with regular exposure to environmental allergens, although this has not been proven. Inhalation of allergens by sensitized subjects results in bronchoconstriction, which develops within 10 min of the inhalation, reaches a maximum within 30 min, and generally resolves within 1-3 h — the early asthmatic response (Fig. 1, upper panel) (15). Once this resolves, there is no further consequence of the allergen inhalation. However, in some subjects who develop an early asthmatic response, the bronchoconstriction persists and either does not return to baseline values or recurs after 3-4 h and reaches a maximum over the next few hours — the late asthmatic response (Fig. 1, lower panel) (15) — and may last 24 h or more. Furthermore, the late asthmatic response need not necessarily be preceded by a clinically evident early response. In a subset of sensitized subjects, the inhaled antigen does not cause an early response, but is followed 3-8 h later by a late asthmatic response. The prevalence of the late asthmatic response has been evaluated by various investigators (25, 26), who have demonstrated that approximately 50% of adults who develop an early asthmatic response will develop a late asthmatic response. However, the prevalence of late asthmatic responses appears to be higher in children, and studies have demonstrated that 70-86% of children sensitized to various allergens develop late responses (27). The cause of the apparently higher prevalence in children is not known. Whether the development of a late asthmatic response in an individual subject is dependent only on the individual's response to the allergen or also on the allergen inhaled is unclear. Price et al. (28) have documented that, in a small percentage of children studied, inhalation of one allergen caused both an immediate and a late asthmatic response, while inhalation of another allergen caused only an immediate response. This suggests that the late response may be allergen specific in some subjects. The factors which predict the development of a late asthmatic response have been examined by several investigators. These were mainly indices of high circulating IgE antibody to the inhaled allergen, such as a high IgE RAST with the allergen and a low antigen concentration in the skin eliciting a late cutaneous response (26, 29, 30). Boulet et al. (29) have also demonstrated that if a late cutaneous response followed a small early cutaneous response (wheal of <5 mm), then a late asthmatic response was more likely to occur after an early response. Thus, an important determinant of whether an individual will develop a late asthmatic response is the level of circulating IgE antibody, which may be considered the degree of sensitization to the allergen. The other major determinant of the late asthmatic response is the size of the early response (31). Thus, the greater the degree of airway narrowing during the early response, the more likely a late response will develop. In tum, the size of the early response is dependent not only on the quantity of mediators released, which is indicated by the size of the early cutaneous response to the concentration of allergen inhaled, but also on the degree of histamine or methacholine airway responsiveness of the subject (30). This means that a subject inhaling allergen at a time when airway responsiveness is increased, may develop a late response, while the same subject inhaling the same concentration of allergen when airway responsiveness is normal may not. Therefore, it is important to know the degree of airway responsiveness before all allergen inhalation tests. The bronchoconstriction that occurs during the early and late responses is largely caused by allergen-induced release of cysteinyl leukotrienes. This was initially suggested by Brockelhurst (32), who demonstrated the production of slow-reacting substance of anaphylaxis (SRS-A) after sensitized lung fragments were challenged by specific allergens. SRS-A is now known to consist of the cysteinylleukotrienes (LT) C4 and D4, and their stable excretory metabolite, LTE4 (33). Several investigators have demonstrated increases in urinary LTE4 after allergen-induced bronchoconstriction (34, 35). In one study, the increases in urinary LTE4 were significantly correlated with the magnitude of the bronchoconstriction (34). Interestingly, no significant increases in urinary LTE4 could be demonstrated during the allergen-induced late asthmatic response, even though the magnitude of the bronchoconstriction was similar to the early response (34). These data suggested that the cysteinyl leukotrienes were released during allergen inhalation and were important causes of bronchoconstriction during the allergen-induced early-phase, but not the late-phase, bronchoconstrictor responses. The best evidence for a central role for the cysteinyl leukotrienes in causing allergen-induced bronchoconstriction is that a number of different LTD4-receptor antagonists and leukotriene-synthesis inhibitors have been demonstrated to attenuate markedly the bronchoconstrictor responses after inhaled allergen (36, 37) (Fig. 2). These studies have indicated that LTD4 antagonists and leukotriene-synthesis inhibitors attenuate allergen-induced early responses by up to 80% (36, 37), and, surprisingly, considering the data on urinary LTE4 excretion during the late response, also attenuate the late response by up to 50% (37). The component of allergen-induced early responses not influenced by antileukotrienes is caused by thromboxane A2 (38) and histamine release, while the combination of cysteinyl leukotriene and histamine is mainly responsible for bronchoconstriction during the late response. Allergen-induced airway hyperresponsiveness is a transient increase in airway hyperresponsiveness which has been reported to occur as early as 3 h after allergen inhalation (39), and which can persist for day or weeks after allergen inhalation (40). In general, however, allergen-induced airway hyperresponsiveness lasts 2-4 day (40). Allergen-induced airway hyperresponsiveness is most marked in subjects who develop late responses (40), although very small and transient changes also occur in individuals with isolated early responses (40). In most studies (41, 42), the magnitude of allergen-induced airway hyperresponsivness is less than a two doubling dose (fourfold) change in histamine or methacholine airway hyperresponsiveness. This seemingly small effect has been viewed as being much less than the differences in airway hyperresponsiveness demonstrated between normal and asthmatic subjects, where more than a 100-fold difference exists (43). However, this view does not take into account the fact that these small allergen-induced changes are occurring in subjects already suffering from allergic asthma and airway hyperresponsiveness, in whom a fourfold increase may be clinically very important, and associated with increased symptoms, an increased risk of triggers causing bronchoconstriction, and an increased need for treatment. In human subjects, the late response after inhaled allergen is associated with airway inflammation (41, 44), with numbers of activated airway eosinophils and metachromatic cells being increased at 7-8 h, and eosinophils further increased at 24 h after allergen (41, 42). The appearance of metachromatic cells and activated eosinophils in the airways probably explains the development of late responses. These cells produce histamine and cysteinyl leukotrienes when activated. Neither histamine nor cysteinyl leukotrienes, released during the early response, can directly result in the development of late responses (9, 45). Therefore, the histamine and cysteinylleukotrienes, which together cause the late response, are released by the metachromatic cells and eosinophils recruited into the airways and activated after allergen inhalation. The site of origin of the inflammatory cells recruited during allergen-induced airway inflammation and the factors which regulate this have been evaluated in a canine model of allergen-induced airway hyperresponsiveness and airway inflammation. These studies have demonstrated that allergen-induced airway inflammation in dogs caused by inhalation of Ascaris suum, which is predominantly a neutrophilic infiltrate, is associated with an increase in the progenitors of neutrophils (GM-CFU) in the bone marrow (46), and this is caused by the allergen-stimulated release of a haematopoietic factor into serum (47) (Fig. 3). The presence of the serum factor, rather than the bone-marrow response to the factor, is what determines the subsequent increase in progenitors (48). The newly formed cells from the bone marrow are subsequently recruited into the airways after allergen inhalation (49). Therefore, the development of allergen inflammation is presumably determined both by the airway's ability to produce a factor to stimulate the bone marrow and the bone marrow's increased progenitor production. We have subsequently studied this in allergic asthmatic subjects and have demonstrated that the development of allergen-induced airway inflammation is associated with an increase in eosinophil progenitors (Eo/B-CFU) in the bone marrow, and that this may be determined by the bone marrow's responsiveness to the cytokine interleukin (IL)-5 (50), which is known to be important in eosinophil development, maturation, and survival. In addition, IL-5 is produced in increased amounts in the airways after allergen inhalation, in association with late asthmatic responses (51). Interestingly, individuals who develop late responses produce more IL-5 than those who develop isolated early responses, and the bone marrow of late responders is more responsive to IL-5, thus explaining the increased production of eosinophils available to be recruited into the airways. These results suggest the following hypothesis to explain allergen-induced asthmatic responses (Fig. 4). Inhaled allergens stimulate airway mast cells, which degranulate, releasing histamine, a process which begins the early asthmatic response. Mast cells also begin producing cysteinylleukotrienes, which continue the early asthmatic response, and which are responsible for most of the response. The inhaled allergen also causes the release of cytokines and chemokines, such as RANTES, eotaxin, and IL-5. RANTES and eotaxin are potent eosinophil chemoattractants, while our studies suggest that IL-5 is responsible for the increased production of eosinophils in bone marrow (50). IL-5 is also important for prolonged eosinophil survival in the airways. The airway inflammation subsequently caused by the inhaled allergen is responsible for the development of allergen-induced airway hyperresponsiveness, by mechanisms not yet elucidated. Allergic alveolitis, or hypersensitivity pneumonitis, is an inflammatory condition of the alveoli and lung interstitium caused by a hypersensitivity response to the inhalation of organic dusts or low-molecular-weight chemicals. This condition is usually associated with occupational exposure to the organic dust and this often labels the disease. For example, inhalation of actinomycetes from mouldy hay in farmers is called farmers' lung, inhalation of avian proteins is called bird fanciers' lung, and inhalation of rat urinary proteins is called laboratory technicians' lung. Indeed, more than 20 organic dusts have been shown to cause allergic alveolitis (3), as well as a number of low-molecular-weight chemicals, such as toluene diisocyanate (52) and phthalic anhydride (3). Allergic alveolitis presents usually as episodes of fever, chills, rigor, myalgia, malaise, and dyspnea, which begin typically 4-6 h after inhalation of the offending allergen. Chest radiographic abnormalities consisting of patchy, ill-defined alveolar densities can be found during the acute episodes. These episodes are often short-lived until the next exposure to the allergen. Repeated exposure to the allergen leads to lung fibrosis. Pathologic abnormalities found in lung biopsy specimens consist of lymphocytic infiltrates of the alveolar wall and septa, and the presence of plasma cells and increased numbers of macrophages in the alveoli (53). With progression of the disease, these cellular in filtrates are replaced by fi broblasts, with fibrosis and obliteration of the alveolar spaces. Removal of the offending allergen will prevent the repeated acute episodes and progression of the disease. However, as this often represents a change in occupation or hobby, it is necessary to stress to the patient that the disease, if progressive, results in irreversible lung impairment and disability. Inhalation of environmental allergens results in a variety of clinical manifestations in sensitized subjects, depending on the site of deposition, the mechanisms of the response to the allergen, and the structure of the deposition site. Thus, allergen deposited in the nose or eyes results in a different clinical expression than that deposited in the lower airways, which, in turn, is different from that deposited in the alveolar spaces. The most prevalent clinical manifestation of an allergic response in the lungs is allergic asthma. The lower airways of a sensitized subject respond to the inhalation of an allergen by developing acute bronchoconstriction (the early response) caused by airway smooth-muscle constriction and airway oedema. These responses are the result of the release of histamine and the cysteinyl leukotrienes released from sensitized mast cell s. More than half of the subjects develop a late bronchoconstrictor response caused by the influx and activation of mast cells, basophils, and eosinophils, again with histamine and cysteinyl leukotriene release. This inflammatory response increases airway responsiveness to constrictor agonists, such as methacholine, an effect which can last from days to weeks. The magnitude of the eosinophil influx and subsequent physiologic changes appears to be due to the release of airway cytokines, particularly IL-5. Deposition of allergens from organic dusts in the alveoli causes allergic alveolitis, which, although self-limiting if the exposure to the allergen is transient, may result in lung fibrosis and marked lung impairment with repeated exposure. P. M. O'Byrne is the recipient of a Medical Research Council of Canada Senior Scientist Award.