Gennaro D'Amato

Recent years have marked a remarkable increase in the incidence of allergic respiratory diseases and bronchial asthma in particular, their most worrying clinical expression, and many a reason is linked with the so called “western lifestyle”. (1,2). In fact, modern man spends the greater part of his day indoors in houses and offices where the air is often polluted by tobacco smoke, dust and various allergens. When outdoors, he inhales air that is polluted by gas and the particulate exhaust of vehicles. Bronchial asthma arises in predisposed individuals when genetic and environmental factors converge. (Tab 1).

TAB. I Development of allergic bronchial asthma

- Asthma begins as a genetic predisposition that can cause, already during foetal life and/or during the early years of life, an IgE-mediated sensitization in response to early exposure to allergens. The latter would in fact guide the immunological response of the foetus or of the newborn towards phenotype Th2 of lymphocytes, which can stimulate the synthesis of IgE from B lymphocytes by producing interleukin 4 and 13. Other types of early stimuli such as bacteria would instead draw a Th1 response with the production, on the part of these cells, of interferon-gamma (IFN-gamma), which can inhibit the synthesis of IgE but cannot trigger it.

- Asthma causes the onset of an inflammatory process in the airways. This will remain underlying, even before presenting clinical evidence, with an activity that varies even during latency periods, that is in the absence of clinical symptoms.

- Asthma produces clinical evidence triggered by various agents such as allergens, airway inflammatory factors such as for example the components of air pollutants both outdoors (ozone, sulphur dioxide, breathable dust etc.) and indoors (tobacco smoke, pollutants in offices etc.).

- This pathology can progress to the reshaping of airways characterized in particular by collagen settling below the basement membrane of the epithelium.

Ozone, the main component of photochemical smog, forms in the atmosphere of sunny cities such as those along the Mediterranean, due to the action of UV-rays on the nitrogen dioxide (N02) produced by traffic, besides other gases and dust.

The action of unburnt particulate and gas released by our diesel powered engines. These compounds enhance airway inflammation and, in genetically committed individuals, they also trigger IgE synthesis by means of an immunologically adjuvant action.

Its numberless triggering factors and complex pathogenic aspects make this disease hard to outline and classify. It is a dynamic pathology, the severeness of which can vary from person to person and even in the same individual, at different stages and conditions. In short, asthma can clinically be defined occasional or persistent - the latter form can be mild, moderate and severe. Our knowledge of the pathogenic aspects of asthma has remarkably increased thanks to cytological and immunological studies performed on fluid taken during bronchoalveolar lavage, intrabronchial biopsies and cough induced sputum.

SOME CONSIDERATIONS ON POSSIBLE CAUSES OF THE RISING PREDOMINANCE OF ALLERGIC RESPIRATORY DISEASES IN THE INDUSTRIALIZED WORLD

An increased interest in these diseases and more advanced diagnostic techniques.

Changes in lifestyle involving better hygienic conditions - these on the other hand increase exposure to a number of allergens which are also partly new.

A lower incidence of infections - the immune system is thus directed mainly towards the synthesis of IgE.

Increased air pollution (both outdoors, mainly caused by the exhaust of vehicles, and indoors, associated especially with tobacco smoke).

Increased travelling with exposure to new allergens.

The results of these studies have enabled us to define bronchial asthma as a disease in which a leading role is played by airway inflammation caused by immunoallergic mechanisms and others, involving various cell types and chemical pro-inflammatory mediators. In persistent asthma, inflammation is present during the latency period too, when broncho-obstructive crises are not clinically evident. This has confirmed the need to prolong drug treatment in these phases of well being too, to avoid sliding towards chronic obtsructive airways’ disease (COAD) and emphysema. These observations have been supported by the clinical improvement of asthma symptoms that can be noticed in prolonged treatment with glucocorticoids administered by inhalation (nebulizers), which are known to reduce airway inflammation. These studies have also proved that the sporadic use of short acting B-2 adrenergic bronchodilators, limited to emergencies, is wrong in the treatment of asthma. (3). These drugs (salbutamol, terbutaline, phenoterol etc.) are undoubtedly useful in a sudden asthma attack or to forestall exercise-induced bronchospasm, but they cannot represent a prolonged treatment since they have no anti-inflammatory effects and tend to cause tollerance. Asthma does not set on when bronchial hyperactivity is absent (Picture 1). This condition, which represents the substrate on which triggers act, be they immunoallergic (especially aeroallergens) or other, but anyhow with asthma generating properties (for example tobacco smoke or gas from the exhaust of vehicles, which encourage the onset of bronchial obstruction), can be observed even apart from the presence of airway inflammation and in turn expresses an alteration of homeostatic mechanisms that control the functions of the various bronchial structures, resulting in a complex mismatch in various levels (epithelial, muscular etc). Clinical manifestations, characterized especially by dyspnea and coughing, generally arise when etiological triggering agents present in the environment intervene in a particular manner (high concentrations of allergens, viral respiratory infections, high exposure to environmental polluting agents both outdoors and indoors etc.). Allergic bronchial asthma arises in individuals that are defined atopical (Tabel I). The atopy, understood as a constitutional tendency to synthesize IgE in high concentrations in response to allergenic triggers that are unable to evoke an IgE-mediated response in non-atopical individuals, represents in fact an important risk factor in the development of bronchial asthma.

POSSIBLE INTERACTION (THEORETICAL AND/OR ATTESTED) OF AIR POLLUTANTS AND POLLEN ALLERGENS, RESULTING IN A GREATER INCIDENCE OF POLLEN ALLERGIES

Interaction between pollutants (especially unburnt diesel exhaust particulate) and pollen - the latter thereby releases a larger number of antigens with modified allergenicity.

Interaction between pollutants and paucimicronic or submicronic allergen-carrying particulate of vegetal origin.

Inflammatory effects of pollutants on airways of exposed individuals with a subsequent increase in permeability of airway mucous tissue. This facilitates the penetration of allergens thus bringing them easily in contact with cells of the immune system.

Adjuvant immunological effect of certain air pollutants (especially unburnt diesel exhaust particulate ) on IgE synthesis in atopical individuals.

Increased airway reactivity in predisposed individuals, caused by air pollution, with subsequent hyper bronchial reactivity towards pollen allergens.

The so called “atopical” individuals have high IgE serum levels but they present, in a peculiar manner, specific IgE for environmental allergens, be they seasonal as the airborne-pollen of certain plants, or perennial, released by dust mites, domestic animals, mould etc. In atopical individuals there is a prevalence in the bloodstream of Th2 lymphocyte activity, which produces cytokines such as interleukin 4, 5 and 13 (IL-4,IL-5 and IL-13), which enhance the IgE-mediated response, while in non-atopical subjects there is a prevalence of Th1 lymphocyte activity, which mainly produces interferon gamma (IFN-gamma), which does not enhance, but inhibits, the IgE response. The immunological sensitizing process towards the main environmental allergens begins during foetal life or during the first months of life (4,5), period in which the immune system is highly vulnerable to a variety of environmental stimuli; hence the impact with allergens, especially those derived from Dermatophagoides, can induce it to turn towards the Th2 phenotype ( 6,7 ) and thereby towards the synthesis of IgE on the part of B lymphocytes. It has in practice been observed that already during foetal life lymphocytes T are stimulated by common environmental allergens that pass through the placenta (8). The clinical manifestations of asthma in childhood begin when the etiological agents intervene in a specific manner, that is especially in high environmental concentrations of asthma generating agents with allergenic activity and by exposure to large quantities of agents with aspecific non-IgE-mediated inflammatory action on the airways. In practice it has often been observed that asthma attacks arise following the combination of one or more such factors, which encourage the consolidation of immunological sensitization with the spreading of Th2 allergen-specific lymphocytes, with the onset of airway inflammation and bronchial hyperactivity. It must also be mentioned that according to certain hypotheses (9), which however require ascertainments, the early contact with antigens, derived especially from domestic animals, could perform a protective action which can decrease the risk of IgE-mediated sensitization of the airways and hence the development of asthma. Asthma at a prepuberal age is present especially in males, very likely due to various factors such as narrower airways and an increased tone in bronchial smooth muscle when compared to females. The average serum IgE values are also generally higher in males who are therefore generally more allergic than females. This diversity between the sexes tends to disappear after puberty, probably because the mentioned differences then cease to exist. The “hygiene” theory concerns the increase in allergic respiratory diseases related to excessive hygiene in the modern world and the subsequent lack of stimuli by microbic agents which draw the immune system’s Th1 responses (10,11), with a prevalence therefore of Th2 allergic responses. Despite its unquestionable logic that is supported by many observations, it does not correspond with the increased incidence of asthma as an IgE-mediated pathology among the poor, black population in the US. These people, despite precarious hygienic conditions, present an increase in allergic respiratory diseases, with widespread sensitizing to Dermatophagoides besides cockroaches which represent a common allergenic agent in the US, while they do not seem to be as aggressive in Europe. In early childhood the onset and/or the worsening of acute asthma attacks are mainly caused by viral respiratory infections while, a few years later, the main triggering factor will be aeroallergens, especially those released by dust mites, which in atopical subjects stimulate the production of IgE, interacting later with these antibodies bound to the high and low affinity receptors of inflammatory cells. The importance of atopy decreases in adults and the main etio-pathogenic role is mainly played by infecting agents and by those that act with an aspecific irritating mechanism on the airways (tobacco smoke, pollutants of urban areas and offices etc). Such factors increase aspecific bronchial hyperreactivity. Dermatophagoides, with antigens carried especially by its fecal particulates, represents a perennial allergenic agent which is often associated with bronchial asthma (12). This is very likely due to the peculiarity of the immunological response of airways in sensitized individuals and also because the greatest antigens of these mites present a proteolytic enzymic activity which makes the closely joined airway mucous cells to move apart, thereby assisting the penetration of the very same allergen in the submucosa, thus magnifying the inflammatory response. ( 13). Of particular interest is also asthma caused by allergens released by domestic animals and spread especially by their dander. The cat is the guiltiest of them all as it releases allergens, in particular Fel d I (Felis domesticus), which are extremely aggressive on the airways. In fact, Fel d I is carried by very small particles (average diametre < 2,5 micron), which spread all over the environment, penetrating even in the lower airways, causing bronchial hyperreactivity in sensitized subjects due to its remarkable pro-inflammatory action. This can enhance the onset of chronic asthma especially when the indoor concentration of Fel d I exceeds 40 mcg/m3. However these levels are greatly exceeded where there is even one cat. We have recently proved that Fel d I is carried by people, in their clothing, from an environment where there is a cat to one where the animal is not present (14), while its presence is greatly decreased by frequently washing the clothes of people who live with cats. (15). This confirms the evidence that cat allergens can be considered ubiquitous. Fungi are among the aeroallergens present in the environment throughout the year. They generally represent a minor factor in allergic sensitization (16 ), though Alternaria, present in the outdoor atmosphere especially in summer, is an airway allergy triggering factor in about 10% of Europeans, especially infants ( 17). The reason why allergy to Alternaria can at times cause acute asthma attacks is still unknown. Sensitization to pollen allergens with seasonal symptoms especially in spring tends to be clinically evident after puberty, though recently the age of onset has gradually decreased (18,19). Concerning seasonal respiratory allergies, it has been noticed that they are more frequent in urban areas rather than in rural ones. This difference in distribution is caused by air pollution in cities with heavy traffic, which enhances the clinical evidence of pollinoses in cities. Pollinoses have also been chosen as a model for studies on the possible interaction between air pollutants and aeroallergens ( 20,21). They can interact directly in the atmosphere, modifying the antigenic characteristics of pollen aeroallergens, or in the airways of the allergic individuals, where the polluting compounds (especially ozone and breathable particulate ( 22) cause inflammation or have a possible immunological adjuvant effect on the synthesis of IgE (especially polyaromatic hydrocarbons present in the unburnt particulate of diesel exhaust ( 23).

(Translated by interpres sas)

Gennaro D'Amato
Direttore Divisione di Malattie Respiratorie ed Allergiche - Azienda Ospedaliera ad Alta specialità "A. Cardarelli" Napoli