OPINION ARTICLE
Clinical polymorphism of respiratory allergy
F. Muñoz-López
The respiratory tree, from the nasal cavities to the alveoli, is a functional unit with a characteristic mucosa that has the specific mission of defense against the many harmful elements that penetrate the airways. The ciliary system of the epithelial cells and the various types of mucous glands and immune system cells present in the subepithelial layer underlying the mucosa cause the entire lining of the airways to act as a unit in the defense system (1). Similarly, airways can respond as a unit to allergens in persons with an atopic predisposition or in other circumstances, although the responses vary. This is why allergic disease of the airways exhibits symptoms that affect the entire bronchial tree (the common coincidence of asthma and rhinitis or rhinosinusitis), although involvement can also be more limited, resulting in clinical manifestations of upper respiratory involvement (rhinitis, rhinosinusitis, rhinopharyngitis). In contrast, lower respiratory tract involvement (tracheobronchitis, asthma) is always accompanied by symptoms of rhinitis or rhinopharyngitis. However, the bronchoconstriction characterizing the initial phase of asthmatic episodes requires the presence of a notable degree of broncholability involving the smooth muscle that constitutes part of the bronchial structure. The mechanism of smooth muscle constriction/relaxation involves complicated intracellular metabolic processes (2).
To summarize, there are two main types of respiratory allergic pathology:
1.Allergic rhinitis, which may occur alone. However, neighboring organs often are involved and rhinoconjunctivitis, rhinosinusitis, or rhinopharyngitis may occur.
2.Asthma, which is defined by bronchoconstriction, which is a consequence of broncholability or bronchial hyperresponsiveness (3). Inflammation is a consequence of late immunologic reaction, and may be present in all respiratory mucosa. When bronchoconstriction is absent, inflammatory responses of the lower respiratory tract mucosa cause symptoms of tracheitis or tracheobronchitis without dyspnea, which can be characterized as asthma equivalents. Often it is difficult to recognize the symptoms of this condition because of the way they are described by patients or their family members, in the case of children. Between episodes, examination of the bronchial response can provide diagnostic clues. This has therapeutic interest because asthma equivalents generally require less bronchodilator agents. Due to the predominance of the secretory component of the allergic reaction, it is better to facilitate expectoration in the acute phase.
ALLERGIC RHINITIS
One of the main functions of the nasal cavities is to condition the air that flows into the lungs by heating it and filtering particles in suspension to impede their entry into the bronchoalveolar tree. Many of these particles are allergens, which explains why allergic reactions are so frequent in the nose and why treatment so often fails, since the external aggression is continuous and difficult to avoid.
In most cases of asthma beginning in childhood, the child has manifestations of rhinitis or rhinopharyngitis for some time before symptoms of the lower tracheobronchial tree appear. It is not uncommon for newborns and young infants to present manifestations characteristic of allergic rhinitis, but at this time of life it is difficult to demonstrate the existence of specific sensitization, although these manifestation undoubtedly are evidence of the presence of special predisposing circumstances.
In adults, one can distinguish fairly well between seasonal and perennial rhinitis. Seasonal rhinitis, which is due mainly to sensitization to pollen, usually is designated with the incorrect term "hay fever" in the english-language literature. This term is inappropriate because the condition courses without fever and rarely is caused by "hay", although the original description of the process was of farmers in contact with hay. A more appropriate term would be "pollinic or seasonal rhinitis" because the primordial cause is pollen sensitization in most cases.
In children, rhinitis appearing at any time of the year (perennial rhinitis) is much more common. Pollen sensitization usually occurs in the second or third stage of childhood. Therefore, in most cases involving young children, other allergens than pollen are responsible (pneumoallergens or trofoallergens) and in other cases symptoms are produced by non-immunological mechanisms.
ASTHMA AND ASTHMA EQUIVALENTS
The definition of asthma is debated, because there is no unanimous opinion regarding the evaluation of symptoms or the physiopathological substrate. Since there are known differences in relation to age and trigger factors, it is understood that there are different types of asthma. On the one hand, it is argued that bronchial hyperresponsiveness is a necessary condition for diagnosis and, at the opposite extreme (4, 5), the concept of "asthma-equivalent coughing" is being admitted without consideration of the degree of respiratory distress (6, 7). There is a risk that the concept of asthma will come to include many obstructive diseases of the respiratory tree if the terms "asthma" and "dyspnea" become equivalent. As for the trigger factors, it is agreed that allergy has a preponderant role in most pediatric cases, but other causes are involved in adult cases, particularly the occupational environment.
Acceptance of bronchial hyperresponsiveness as the pathogenic basis of the disease, regardless of its cause, has the advantage of being an objective condition that can be demonstrated in the functional testing laboratory, as will be analyzed later. The absence of broncholability establishes the diagnosis of asthma-like processes that produce similar symptoms, except for dyspnea. The presence of dyspnea would establish the diagnosis of asthma.
From a clinical vantage point, asthma is a chronic disease manifested by episodes of respiratory distress (dyspnea) that sometimes begin abruptly and are recurrent and reversible, either spontaneously or with bronchodilator medication. The pathogenic substrate is an inflammatory reaction of the bronchial mucosa and, possibly, broncholability. As an etiological factor, atopy predominates in childhood. Genetic predisposition is important and certain environmental factors strongly influence the course of the disease.
Aside from atopy, asthma episodes can be triggered by other causes, such as exercise, climatic variations, environmental irritants, tobacco smoke, viral infections, acetylsalicylic acid, and emotional state, which should be considered when studying the etiology of each particular case (8).
Many other diseases course with symptoms that should be included in the differential diagnosis of asthma. Overall, they can be included in the broad clinical concept of "whistling chest", recalling the aphorism that "not everything that whistles is asthma" (Chevalier-Jackson).
BRONCHIAL HYPERRESPONSIVENESS
Since 1951, when Herxheimer described the bronchoconstriction produced by experimental inhalation of different substances (histamine, metacholine, allergens) in asthmatic patients, the diagnosis of asthma has been linked to that of bronchial hyperresponsiveness (BHR). For several decades, this response was a condition sine qua non for diagnosing the disease. It was confirmed that BHR to allergens (specific BHR) always occurred in persons who were hyperresponsive to these other substances (non-specific BHR).
Different theories have attempted to explain the disturbances that may be implicated in the anatomofunctional substrate of BHR and possible causes of these disturbances. Among the disturbances considered was possible hypertrophy or hyperplasia of the bronchial smooth muscle, or increased contractility, produced by an abnormality in intracellular Ca++ distribution. Other explanations considered were disturbances in the mechanisms of nervous regulation of muscle contractility caused by increased cholinergic activity or *-adrenergic activity, or reduced non-adrenergic inhibitor activity or, particularly, reduced ß2-adrenergic activity. This last explanation was supported by the so-called ß-adrenergic theory of Szentivanyl, which initially was well received. This author suggested a hypothetical abnormality of the ß2 receptors, such as blockade, a reduction in number, or a functional abnormality. Recent studies have disclosed mutations in codons of the gene that regulates these receptors (Arg 16*Gly; Gln 27*Glu; Thr 164*Ile), so modification of the receptor seems to be important in bronchial response, thus updating this author''s theory (9).
As for possible causes of BHR, at first a genetic substrate (congenital BHR) was considered likely, with the possible contribution of viral infection in early infancy, particularly by RSV, which causes bronchiolitis. In the 1980s, the idea that an inflammatory reaction was the substrate of asthma began to take form, and several mechanisms leading to this reaction were considered, including viral infection by RSV or the inhalation of substances harmful to the bronchial mucosa or the allergens themselves. Inflammation came to be considered the sole cause of bronchial hyperresponsiveness (acquired BHR) and the idea of a genetic predisposition was discarded.
In the case of an inflammatory substrate, the elements participating in the inflammatory reaction injure the bronchial epithelium, producing cellular descamation that exposes cholinergic receptors to stimuli and induces smooth muscle constriction, as noted above. The resulting muscular hypertrophy and hyperplasia lead to enhanced broncholability and obstruction.
Several studies have shown that persons without asthma can have bronchial hyperresponsiveness and that some asthmatics do not have broncholability (4). This suggests that the concept of BHR and its relation to the pathogenesis of asthma should be examined. It is obvious that the response elicited by different methods for studying BHR is not uniform. The response elicited by histamine can be considered equivalent to that obtained with metacholine because there are few differences between the two substances. In contrast, the response to cold air, to humid air, or to hyperosmolar saline solution can differ widely. On the other hand, the cutoff point for normal response to the first substances is 20% of the decrease in FEV1 (PD20-PC20), a somewhat arbitrary value, so there may be overlap between the responsiveness of normal subjects and asthmatics. Studies of non-asthmatics do not usually indicate smoking habits, living environment, or possible occupational factors. Another factor is the variability of response under different circumstances, such as the non-pollen seasons for patients allergic to pollen; the reduction of environmental allergens by suitable measures or by a change of climate; adolescence (11); or when the reduction in BHR coincides with patient improvement produced by anti-inflammatory medication or immunotherapy. For these reasons, it sometimes is difficult to evaluate bronchial responsiveness in asthmatic or non-asthmatic persons.
Early studies found a correlation between the intensity of BHR and the severity of asthma, a finding that later studies did not confirm. In fact, it is not rare that a patient''s sensitivity to metacholine does not correspond with the severity of her asthma, as determined by the frequency and intensity of symptoms and spirometric parameters.
For these reasons, the correspondence between the concept of "asthma" and BHR is under discussion. However, in spite of variations in the intensity of broncholability, BHR tests provide objective findings. In contrast, the evaluation of symptoms is more subjective, particularly when symptoms are described by patients or their family members. Dyspnea-like respiratory distress can occur for different reasons. However, the concept of "asthma" based on the presence of BHR can be differentiated from the concept of "asthma equivalents" without BHR. These are some of the reasons why the definition of asthma varies and will continue to vary, and why it often is difficult to compare studies made for different purposes. There still is no uniform agreement about the definition of the disease.
Recent findings support the existence of a genetic predisposition to BHR: familial incidence (although not all family members may have asthma), the coincidence on the same chromosome (Cr5q) of genes related with broncholability and atopy, the occurrence of asthma in identical twins raised in different environments, ß2-adrenergic receptor polymorphism, which is related with different degrees of asthma, and differences in the evolution of infants who suffer "asthma" or "wheezing bronchitis", which are two types of bronchoconstrictive crises that occur in early infancy (12).
In view of recent findings, there seems to be no doubt that inflammatory reactions produced in response to exposure to certain substances in the occupational environment give rise to late onset asthma in the absence of any previous predisposition of the patient. This is the most evident example of acquired BHR. Nonetheless, studies of bronchial biopsy material in patients with allergic rhinitis and no history of asthma demonstrate the existence of markers characteristic of the inflammatory reaction. Moreover, these markers are more closely related to atopy than to bronchial hyperresponsiveness. The causal relation between BHR and inflammation alone has been questioned and it is suggested that other factors may be important in the development of BHR.
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