Actual therapeutic management of allergic and hyperreactive nasal disorders.

Allergic rhinitis (AR) and hyperractive disorders of the upper airways, depending upon the type of releasing stimuli, are defined as nasal hyperreactivity, for example in the case of AR, or as non-specific nasal hyperreactivity and as idiopathic rhinitis (IR) (synonyms frequently used in the past: non-specific nasal hyperreactivity; vasomotor rhinitis) in the case of non-characterised stimuli.An early and professional therapy of allergic disorders of the upper airways is of immense importance as allergic rhinitis is detected in comorbidities such as asthma and rhino sinusitis. The therapeutic concept is influenced by new and further developments in pharmacological substance classes such as antihistamines and glucocorticosteroids. Specific immune therapy, the only causal therapy for AR, has been reviewed over the past few years in respect of the type and pattern of application. However, to date no firm recommendations on oral, sublingual and /or nasal immune therapy have yet been drawn up based on investigations of these modifications.Therapeutic management of IR is aimed at a symptom-oriented therapy of nasal hyperactivity as etiological factors relating to this form of rhinitis are not yet sufficiently known. Drug groups such as mast cell stabilizers, systemic and topic antihistamines, topic and systemic glucocorticosteroids, ipatroium bromide and alpha symphatomimetics belong to the spectrum of the therapeutics employed.

1. Definition

Allergic rhinitis (AR) and hyperractive disorders of the upper airway are characterized by nasal hyperreactivity [1] that, depending on the type of releasing irritants, is described as specific nasal hyperreactivity, for example with AR, or as idiopathic rhinitis (previously conventional synonyms: unspecific nasal hyperactivity, vasomotor rhinitis) in cases where irritants are not more precisely identified and characterized [2], [3].

In the case of the latter, the nasal mucosa reacts and symptoms include sneezing, itching, nasal obstruction and hypersecretion to non-specific irritants that at the same intensity can be tolerated asymptomatically by healthy persons. The symptoms can appear individually or in varying combinations. This has to be distinguished from the physiologically normal nasal cycle (interactive periodical congestion and decongestion of the nasal mucosa) [1], [2], [3].

1.1 Definition of allergic rhinitis

Allergic rhinitis (AR) is a common global disorder with increasing prevalence and a current incidence of, on average, around 15% in populations of industrial nations [4], [5]. Although allergic rhinitis does not per se represent any severe illness, the socio-economic influence of the illness on the population is classified as significant [2]. It is characterized by a high comorbidity such as asthma, food allergy, atopic eczema, (atopic dermatitis, neurodermatitis) and sinusitis. In the case of patients with allergic rhinitis, the risk of suffering from asthma is 3.2 times higher than in the normal population [6]. These links were a reason for the action group "Allergic Rhinitis and its Impact on Asthma (ARIA)", in cooperation with the World Health Organization, to review AR and its therapeutic concepts [2], [3], [7], [8].

The cause of the prevalence of inhalationally induced allergic rhinitis is a controversial issue in Germany and other European countries [5]. Amongst other things, changes in the character of the early childhood immune system are seen as the decisive factor in AR. Clinical studies have shown that children from families that live on farms exhibit considerably fewer allergic disorders than children living in cities [9]. The increasing stimulation of the TH1 immune reaction is postulated as an explanation for the regional differences (=hypothesis of the TH1 immune modulation - TH1 T-lymphocyte helper cell).

An above average amount of organic particles are inhaled and ventilated by farmers in livestock agriculture. This dust contains very different types of microbes, for instance parasites, bacteria and fungi, as well as their component parts, such as endotoxines (lipopolysacharides from the wall of gram-negative bacteria) and glucanes (analogous substances from fungi). These are regarded as positive TH1 immune stimulators. In farming, high concentrations of endotoxines occur in the air in connection with animal husbandry, particularly in enclosed spaces (stable but also living areas). The adjustment of farm children in respect of aeroallergens can be explained by a continual stimulation of the TH1 immune reaction via anthropozoonotic infections. The assumption that endotoxines have a protective effect on the development of IgE-transmitted allergies is formulated in the so-called hygiene theory [10].

A TH1/TH2 correlation is cited as an explanation for the hygiene theory, in other words as a result of stimulation of the immune system with endotoxines, a displacement of the TH1/TH2 correlation in favour of the TH1 helper cells occurs. The hygiene theory has been the focus of much controversy for several years [11] and is by no means accredited.

Alongside the hygiene theory, the so-called western lifestyle is described as the cause of the rising prevalence of allergies. Western lifestyle is broadly defined as comprising modern living conditions, better medical care and medicinal treatment, as well as trips abroad and the resulting frequent contact with foreign allergens [12], [13].

Air pollutants are also included in the discussion on the increasing prevalence of allergic disorders [14], [15]. In many countries outdoor air pollution in cities is caused primarily by motorized traffic. Amongst the most important atmospheric or gaseous pollutants are ozone, nitric oxides and sulphur dioxides. Particulate air pollutants (PM) contain fine dusts with particle sizes of below 10µm and diesel soot particles that, although they do not themselves have any allergenic features, are nevertheless involved in the exacerbation of nasal symptoms in patients with allergic or non-allergic rhinitis. It could be demonstrated experimentally that diesel causes an increase in the production of IgE from B lymphocytes.

Indoor air pollution is of great significance in as far as the population of industrial countries spends more than 80% of their time in enclosed spaces [16], [17]. Living space allergens and gaseous pollutants, the main source of which is tobacco smoke, characterize pollution in interior spaces. Although tobacco smoke itself is not allergic, it reduces mucociliary transport in the nose, triggers a non-IgE-mediated inflammation characterized by presence of eosinophil granulocytes. This type of non-specific inflammatory reaction induced by passive smoking increases by a factor of two to four risk of suffering from an IgE-transmitted airway allergy [18].

Today, allergic rhinitis is defined as a symptomatic disorder of the nose induced by an IgE-mediated inflammation of the mucous membrane after exposure to allergens. The symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, an itching nose and sneezing. These symptoms are either spontaneously reversible or reversible under treatment. On the basis of temporal exposure, in the past allergic rhinitis was classified as either seasonal, perennial or occupational. Whilst perennial allergic rhinitis is caused mostly by interior space allergens such as house-dust mites, animal epithelia, fungi and other allergens, seasonal allergic rhinitis is determined by a wide spectrum of ambient air allergens such as pollen and fungi. However, the division into seasonal, perennial and occupational allergic rhinitis appears today to be no longer satisfactory as some seasonal allergens such as grass pollen and parietaria pollen function as perennial allergens in southern California and the Mediterranean region. It is also know that symptoms of perennial allergies are not determining factors for a disorder during the course of a year, but also vary seasonally in their exposition [2], [15].

For this reason a new classification of allergic rhinitis was undertaken based upon the duration of the illness (Tab. 1). Allergic rhinitis was divided into an intermittent and a persistent disorder. Based upon the degree of severity, allergic rhinitis is classified as either slight or moderately severe, depending upon symptoms and quality of life. However, the terms "seasonal" and "perennial" may continue to be used in order to enable us to refer back to earlier studies. As far as the symptoms are concerned, there are also differences: rhinitis conditioned by pollen is distinguished above all by sneezing, secretion and concomitant conjunctivitis, whilst the most important symptom arising from rhinitides conditioned by mites is an obstruction [2], [3], [15]. With persistent rhinitis, according to the latest definition, all symptoms are equally strongly expressed.

Table 1

2. Therapy of allergic rhinitis

The early and professional therapy of allergic disorders of the upper airways is of immense importance as allergic rhinitis is detected in co-morbidities that encompass various aspects [3]. The disruption of quality of life and physical impairment due to AR range from insomnia with daytime tiredness [19] to diminished learning ability, particularly amongst children [20]. In a study of 69 children with seasonal allergic rhinitis [21], 80% had pharyngitis, 70% conjunctivitis, 40% asthma and 37% atopic eczema. Asthma in particular was recognized in a number of studies as an important comorbidity of AR, with rates at 32% with children and 16% in adults [22]. Conversely, over 80% of asthma sufferers also suffer from AR. With a coincidence of 25% [23], sinusitis is an additional and now common illness contributing to the co-morbidity of patients; rhinosinusitis must be included in the differential diagnosis of AR [24]. Evidence shows that serous otitis media is also frequently related to an allergy [25]. Furthermore, at least in the case of children, there is a demonstrable relationship to habitual snoring and obstructive sleep apnea syndrome [26]. Therapy for allergic rhinitis can be divided into several therapeutic approaches: allergen elimination (where possible), pharmacotherapy, specific immune therapy, and surgical therapy that may also be used in combination. Of importance here is an understanding of the inflammatory mechanisms of AR that are modulated in each therapeutic approach.

2.1 Inflammatory mechanisms of allergic rhinitis

The immune response presupposes a coordinated function of a number of control loops of the immune system. For this, the immune system requires not only the humoral and cellular immune response, but also messengers and mediators. Amongst the cell messengers are the so-called cytokines that can be synthesized and released from practically every cell and which develop their biological effects for the most part over short distances - frequently only between two cells. They can increase or reduce the synthesis capacity of target cells, prolong or shorten the duration of life and regulate the migration of immunocompetent cells. All cells active in the immune system are bound together in a network by means of cytokines. The term cytokine covers a range of mediators with polypeptide structure that are named after their production centre. In this way interleukins, which define an interaction between leukocytes, lymphokines and monokines are all used synonymously. However, as a large amount of tissue cells such as fibroblasts and epithelial cells determine the synthesis capacity of identical polypeptide mediators, the generic term cytokine is used for the various mediators. Cytokines are highly effective proteins and already develop their effect in the picomolar area of concentration.

The effects of cytokines are described as redundant, pleiotropic and synergistic, that is to say a number of different cytokines can produce similar effects in a cell, a cytokine can exercise different effects on different cells and the combined effect of two cytokines can differ from the additive effect of the individual cell messengers. Finally, these effects are subject to natural regulatory systems through antagonists and soluble cytokine receptors [27].

Sensitisation

On first contact (Fig. 1) of an allergen with the mucosa, allergens are phagocytised by antigen presenting cells, intracellularly degraded and small fragments of the allergen (peptide) are transported back to the surface of the antigen presenting cells (APC), in which they are then bound to class 2 histocompatibility antigens (MHC class 2). This MHC peptide complex is now recognised by the T cell receptor (TCR) on the T cell side. Thus the peptides of the allergen presented on the MHC molecules are thus also described as T cell epitopes and consist of linear protein fragments.

Figure 1

Antigen processing

After first contact of the antigen with the antigen presenting cell (APC) the antigen is processed and than presented on the cell surface within the major histocompability system class II (MHC) to the T-cell receptor. An additional protein on the antigen presenting cell that binds to CD 28 on T-cell serves a costimulus.

In the antigen presenting cells, antigen processing with the aid of the MHC complex is necessary as the T cells themselves, in the same way as an antibody, are not able to bind directly to the antigen determinant or the epitope. Only when an antigen with an MHC class 2 product is presented, is the differentiation of a dormant T cell in a T helper cell (CD (cluster differentiation) 4+ T cell) activated [28]. The surface molecule CD 4 of the T then binds to the MHC products of its target cells. Consequently the T cell is then enabled to recognise the antigen structure and to react to it. Here, the CD28 molecule works as a co-stimulant on T cells which together with the CD80 receptor reacts to the APC.

The arrangement of the CD-4+-T cells is subject to their production of interleukins: T helper cells produce IL-2, IL-12 and γ-interferon (IFN-γ), TH2 cells IL-4, IL-13 and IL-5 [29], is based upon the work of Mosmann and Coffmann (1989) on cloned T cells (Fig. 2) in the mouse model.

Figure 2

TH2 stimulation

After T-cell activation through the T-cell receptor TH2 lymphocytes synthesizing TH2 cytokines (interleukin-4, 5, 10 and 13) are generated.

The immune response to bacterial irritants, for example, is to a great extent associated with a TH1 cytokine pattern with immigration of neutrophil granulocytes. The immune response to allergens is classically related to a TH2 activation and thus to an increased production of IL 4 and IL 5.

IgE-Synthesis

Following activation of a native T cell in a TH2 cell, the cytokines needed for IgE synthesis into B lymphocytes, cytokine IL-4 or IL-3, are synthesized (Fig. 3). B and T cell contact is established via the surface proteins CD40/CD40L (receptor and ligand) and other proteins that stimulate the immune globulin synthesis. The so-called isotype switch or class change to immunglobulin E is induced via both cytokines, IL-4 or IL-13. The molecular interaction between the CD40 ligand and CD40- is described as allergen non-specific interactions or as a co-stimulatory signal.

Figure 3

B-cell stimulation

IgE synthesis is triggered by IL-4, which is generated from activated TH2 cells. During the IL-4 stimulation the expression of CD 40 enhanced on B- lymphocytes, that binds to the CD-40 ligand. The CD-40 binding promotes the class-switch or so called isotype-switch to IgE. Besides IL-4, IL-13 even has IgE inducing function. The interaction between CD-40 and its ligand is generally classified as allergen unspecific.

The B lymphocyte is, however, not only able to synthesize immunlobulin, but also to bind IgE to its surface. Special low affinity IgE receptors (FCεRII, termed CD23 after clustering differentiation) are available for this. The binding of IgE antibodies to the low affinity receptor allows the B lymphocytes to take part in allergen-specific interactions.

The B lymphocyte is, however, not only able to synthesize immune globulin, but also to bind IgE to its surface. Special low affinity IgE receptors (FCεRII, termed CD23 after clustering differentiation) are available for this. The binding of IgE antibodies to the low affinity receptor allows the B lymphocytes to take part in allergen-specific interactions. The binding of antigens to the surface immune globulin of the B cell initiates a humoral response. However, this response is not enough to bring about a proliferation into a mature plasma cell. In fact the B cell requires the help of an antigen processed by APC, the so-called B cell epitope consisting of a three-dimensional protein structure.

Immediate allergic reaction in the nasal mucosa

Via the high affinity IgE receptor FCεRII, IgE antibodies bind to the surface of mast cells (MC). In the course of the early allergy stages (Fig. 4) in a patient with an allergen, a so-called cross-linking of IgE occurs on the surface of the mast cell. Here the mast cell is degranulated and mediators of the allergic inflammatory reaction histamine, tryptase and sulfidoleukotriens (LT) are distributed that display their effect on nerves, blood vessels and seromucous glands. Clinical symptoms such as itching and sneezing can be explained by the irritation of sensory nerve fibres in the epithelium owing to histamine. After stimulation of the nerve fibres, a reflex arch is transmitted via the N. trigeminus and switched to the CNS. The nasal obstruction is based upon an increase in the distension of capacitive vessels in the submucosa. The parasympathetic stimulation of glandular cells and the plasma extravasation from capillaries lead to increased secretion and congestion of the nasal mucosa.

Figure 4

Allergic inflammation reaction

During the immediate phase of AR mast cells degranulate; mediators such as histamine, leukotrienes, prostaglines and tryptase are released into the tissue. During the late phase of AR, effector cells like eosinophils, neutrophils and basophils were recruited from blood flow to the nasal mucosa. Here, eosinophils synthesise cytotoxic proteins: eosinophilic cationic protein (ECP), major basic protein (MBP) and eosinophilic peroxidase (EPO). Additionally, a neurogenic inflammation reaction occurs after stimulation of afferent nerves with histamine. Stimulation of afferent nerves becomes part of trigeminal reflexes to the central nerve system. Parasympathic efferent fibers mediate as the second part of the reflexes the mucosal thickness by increasing superficial blood flow and regulating glandular activity. Besides central reflexes, nasal mucosa action is characterized by a local axon reflex (-----).

Action on glands and bloodvessels is controlled by neuropeptides as substance P (SP), and calcitonin Gene related Peptide (CGRP).

Later stage of AR

The later stage of AR is characterized by pathophysiological processes that lead to the immigration of inflammatory cells into the nasal mucosa (Fig. 4).

The immigration of immune-competent cells such as eosinophilic granulocytes, mast cells, basophiles and T-lymphocytes constitute an important component of the later stage [30]. The concept of the transendothelial migration (Fig. 1) of effector cells is a complexly regulated, finely inter-coordinated process that involves a large number of adhesion molecules, cytokines and chemokines. The migration cascade proceeds along venols (HEV) equipped with a folded surface designed for this purpose under the conditions of vasodilatation triggered by inflammatory mediators. Attractant substances (=chemokines) such as RANTES, eotaxin and IL-8 are generated by a number of cells and attract the effector cells into the tissue along a chemokine gradient of rising concentration [31].

Through proinflammatory chemokines such as interleukin 1 and TNF-α from macrophages, selectins are expressed within minutes on the endothelial cells that, due to the protein length, overtop the surrounding glycokalix. The selectin binding can trap the cell from the bloodstream and bind it loosely to the endothelium so that it rolls along the endothelial wall. For the chemotaxis of the eosinophil, strong binding between the eosinophil and the wall of the vessel results through the expression of VCAM-1 (vascular cellular adhesion molecule), and adhesion molecule of the immunoglobulin super family. On the eosinophil granulocytes, this task is taken on by VLA-4 (vascular-late antigen), a β1-integrin. The inflammatory mechanism triggered in the later phase is based upon specific granules present in the cytoplasm of human eosinophil granulocytes, the content of which consists of basic cytotoxic proteins and which correlates to the degree of activation in the cell [32]. Included amongst the cytotoxic proteins are MBP (major basic protein), ECP (eosinophil cationic protein), EPO (eosinophilic peroxydase) and EDN (eosinophil neurotoxin); as regards both the amount stored in the cell and its effect, MBP is the most potent pyotoxin with helminthotoxic and bactericide effect. MBP releases histamine from basophile granulocytes, activates neutrophiles and can lead to tissue damage or the desquamation of the epithelium [33]. Other metabolic products of eosinophils are LTC4 (LT= leukotrienes) and LTD4, which may be involved in the changes of vessel permeability in the nose, as well as prostaglandins and the platelet-activating factor PAF.

In vivo, the extent of the reaction of the nasal mucosa to allergen exposition is, amongst other things, dependent upon the state of inflammation of the mucosa and varies over the course of the year [34]. An increased reaction due to previous repeated exposition is termed priming [35].

However, it has also been demonstrated that after completion of allergen exposition, or in the case of low exposition, inflammation markers such as ECP and tryptase persist in the nasal mucosa even if the patients are largely symptom-free [36]. With persistent AR, allergens interact with this continuing inflammatory reaction. Today, this phenomenon is described as minimal persistent inflammation.

2.2 Allergen avoidance

The total allergen avoidance is the best form of treatment for allergic disorders. Possibilities for elimination for each individual differ greatly depending upon the type and amount of the available sensitisations. The precondition for an effective consultation on the elimination of allergens is the doctor's precise knowledge of the patient's individual sensitisation spectrum and of the characteristics and occurrence of the allergen. Treatment recommendations should be appropriate and practical [37] as elimination measures for intermittent allergies are not effective and thus not advisable (Tab. 2).

Table 2

Allergen avoidance constitutes an integral part of the allergy to house-dust mites. In the course of its two to four month life, a mite produces around 200 times its own weight in excrement. The small balls of faeces, which at first are still covered with a layer of slime-like substance, crumble after drying out into very small particles that then bind with house dust. Through the movement of textiles such as bed covers or mattresses, upholstered furniture and carpets, as well as through the draught caused by vacuum cleaning, this dust that contains allergens is dispersed and then inhaled through the air we breathe. The main reservoir of the mites is mattresses and beds. Other available habitats are found in textile upholstered furniture and carpets.

Today a number of different possibilities present themselves that can reduce mite accretion and allergen production in interior spaces [38] (Tab. 2). The most important measure is to encase the bed mattress in a mite-proof protective covering. In this way the mites are denied their main habitat and mite allergens are prevented from penetrating. Encasings for mattresses, pillows and bed covers may reduce the allergen load and asthma symptoms [39], [40], [41], [42], [43], but well-controlled studies on rhinitis with a sufficient number of cases are still not available [3]. Other measures for the reduction of house-dust mite allergens are outlined in table 2 [44]. However, the significance of washing temperatures [45], [46], elimination of carpets [47], steam cleaning [48], [49], vacuum cleaners [50], [51], [52], lowering of air humidity through air circulation [53], [54], [55] and acaricides [56], [57] for the reduction of symptoms with AR is unclear.

At first sight the keeping of domestic animals would appear to be an expedient elimination measure. However, here the characteristics of allergens must be allowed for. Cats produce seven different allergens, whereby in ca. 85% of sensitised patients, specific IgE against the major allergen Fel d1 are found [58]. Today, allergens are present everywhere, including households where cats have never been kept, or in public places [59], [60], [61], [62]. This circumstance is put down to the characteristic of the allergen that in 75% of cases binds to particles 10µm in size whilst 25% bind to particles 5µm in size. The latter is then able to float in the air and as a result of a lack of air circulation to remain in the air. In contrast to this, the sensitisation rate for the main allergen of dogs, Can f2, is considerably lower [63]. In the literature the more frequent keeping of the animal outside the house is cited as the reason for this. The elimination or reduction of cat allergens through vacuum cleaners or sprays has not proved of any value [64], [65]. Thus studies have established that high concentrations of allergens can also be measured in buildings where no cats or dogs are kept [66], [67]. For this reason elimination measures are not as important as those discussed and used in the case of house-dust mites and natural latex.

Latex (natural rubber) is a milky sap from a tropical tree. It is used to produce protective gloves, medical implements (e.g. syringes, infusion receptacles) and a variety of items in daily use (e.g. rubber bands). Sensitisation to latex results from particular proteins contained in it, mostly so-called monomers that are residually contained in production [68].

Allergen proteins from powdered latex gloves are released particularly easily and in large amounts: the allergen supply can result via direct contact (to skin, mucosa, op-situs, parenteral) or indirectly (aerogen) [69]. The spectrum of manifest allergies comprises all classic allergic reactions of the immediate response type; contact urticaria, generalised urticaria, rhino conjunctivitis, asthma and anaphylactic shock may occur [70], [71].

Preventive measures for natural latex affect medical personnel in particular. With air concentrations (measured in the air filters of hospitals) of 0.6ng/m3, symptoms are already triggered in sensitised patients [71]. Due to the clinical significance of natural latex allergy, as a technical norm for dangerous substances (TRGS) 540 (sensitising substances) were determined in 1997: "powdered latex gloves are to be replaced by powder-free, low allergen latex gloves or other suitable gloves" (Federal Working Paper 12, December 1997, B1. 58ff.). For the purpose of this primary prevention, the use of low-protein and high quality, unpowdered natural latex gloves should be standard practice. One significant reason, at least for the sensitisation rate (an estimated 10-17% of medical personnel according to the DGAI and ADA policy document), is to be found in the increased production of poor quality, allergen-rich gloves as a consequence of the high demand for low-priced goods [72], [73], [74], [75], [76], [77], [78], [79], [80].

Diagnostics, therapy and care of persons allergic to natural latex and persons belonging to high-risk groups may only be undertaken as secondary prevention with natural latex-free products. Included among the high-risk group are hairdressers, medical personnel, people with an atopic disposition, people who have frequently undergone surgery, children with neurological illnesses and spina bifida patients [81], [82], [83], [84], [85]. As a result of studies with children suffering from spina bifida, a sensitisation rate for natural latex of up to 70% is described. The cause of this is due on the one hand to the number of operations that the children have undergone. On the other hand a hereto-unrelated risk of contracting a latex allergy is assumed to be the cause. Those people affected by natural latex allergies working in a medical field must be provided with allergen free products, in particular suitable protective gloves. In conclusion we can say that powdered natural latex gloves should no longer be used on principle and the necessity of natural latex disposable gloves in general should be reviewed; they should only be used in the cases where there is a specific danger of infection. If this is not the case, then the use of latex-free examination gloves is recommended: these gloves must comply with the requirements of the European norm (DIN EN 455) and satisfy the necessary impermeability in the form an accepted quality level (AQL) ≤ 1·5 in order to ensure complete protection against infection. Careful note should be taken of an appropriate AQL stamp [86], [87].

A list with recommendations of such alternative natural latex-free gloves and suitable, low-protein unpowdered examination and operating gloves of natural latex was compiled in cooperation with representatives of the German Association of Health Services and Welfare (BGW) and state-run accident insurance and is available from the BGW [87].

In everyday life there are still more sources of danger for people suffering from a latex allergy. At the same time it is often difficult to find out which articles contain latex. Special care has to be taken in the home and in the field of handicrafts. Many adhesives contain latex. Laying a carpet oneself would be taboo for someone suffering from a latex allergy as the back of the carpet is usually made of latex. Conventional emulsions contain, for example, synthetic latex (a mineral oil product) or acrylate components; both are quite safe. Organic paints also no longer contain natural latex today. However, latex was often present in older generations of organic paint and thus caution is advised when renovating. Places where fresh latex is being handled, or even where it is being stored openly in large amounts, should be avoided. These include car repair shops, tyre stores, bicycle shops and producers of adhesives. Other everyday items containing latex also pose a threat, e.g. balloons, rubber animals, chewing gum and rubber bands. Associated sensitisations can exist against certain fruits (especially bananas, avocados, chestnuts, kiwis) and as rubber plants kept in the home (especially ficus benjamina) [86].

Information under http://www.landesgesundheitsamt.de; /gewerbearzt/index.htm.

2.3 Pharmacotherapy

The pharmacotherapy of allergic rhinitis is aimed currently at evidence-based data that has been developed on the recommendation of the medial association of German allergologists and the initiative "Allergic Rhinitis and its Impact on Asthma (ARIA)" in cooperation with the World Health Organisation (WHO). Together with the WHO, the ARIA work group also offer recommendations that combine the treatments of both the upper and lower airway with respect to effectivity and safety (Tab. 2).

2.3.1 Active group of chromones

Mechanisms

The active group of chromones includes cromoglicin acid (DNCG=dinatriumchromoglycin acid) and nedocromil, the effect of which has not been fully explained. In vitro studies have shown that chromones bind to the cell wall of mast cells where they then stabilise it and thus inhibit antigen-induced degranulation of the mast cell [88], [89], [90], [91], [92], [93], [94]. Via DNCG, however, only tissue mast cells are stopped from degranulation whilst blood mast cells are unaffected [95]. IL-4 synthesis and eosinophil granulocytes are also stopped in vitro by DNCG and nedocromil [96], [97], [98]. A local anaesthetic effect is assumed through the effect of sensory nerve fibres in the nasal mucosa [99].

Safety

It could be demonstrated in vivo that after oral application, chromones are not reabsorbed and therefore are only available as local therapeutic agents [100].

Effect with allergic rhinitis

The therapeutic effect of DNCG applied four times a day was not proven in all tests [101] and control studies for seasonal AR [102], [103]. Chromones are less effective with adults and children as oral or topic antihistamines and topic glucocorticosteroids. Symptoms such as sneezing and rhinorrhea are better inhibited than the nasal obstruction. No effect is shown by chromones in idiopathic rhinitis. In contrast to DNCG, nedocromil has the advantages of only having to be used twice a day and in cases of seasonal allergic rhinitis is more effective than a placebo [104].

For adults, chromones are recommended with particular indication, for instance during pregnancy. Chromones (above all nedocromil) can be used as eye drops with allergic conjunctivitis [105].

2.3.2 Group of antihistamine active substances

Bovet and Staub in the Pasteur Institute discovered antihistamines, referred to as H1 blockers or H1 antihistamines, in 1937. In 1942, an H1 antihistamine, phenobenzodiamine, was used in the treatment of allergic illnesses for the first time. In the 1960s the first generation of antihistamines was developed. These were characterised by strong sedative and anticholinergic side effects. Around 15 years later, the second generation of H histamines was developed that are characterised by considerably higher potency, a longer action time and a minimal sedative effect.

In the past and also at the present state of research, the substance class of antihistamines has attracted interest through their recently discovered anti-inflammatory characteristics and their possible cardiotoxic side effects. However, it is assumed today that the antihistamines available at present meet the demands of medication safety and effectivity [106].

2.3.2.1 Effect

H1 blockade

The effect of an antihistamine consists of the suppression of the classic symptoms of rhinitis triggered by the H receptor agonism and histamine stimulation such as rhinorrhea, sneezing and itching in the nose. The nasal obstruction, on the other hand, is produced mainly by leukotrienes and other products of the archidonic acid metabolism, but also partly naturally through oedema and plasma exsudation, as well as filling the venous capacity vessels that represent H1-induced effects [106], [107].

Anti-inflammatory effect of antihistamines

As well as histamine, other proinflammatory mediators are distributed with AR. Anti-inflammatory characteristics of antihistamines from the second generation on are attributed to a suppression of the distribution of certain mediators with AR [108]. It is known that without the interaction of histamine, the H1 receptor is present in an active and inactive state. The active state of the receptor provides a positive regulation of a molecular transcription factor, NF-κB. In the nucleus of a cell, the transcription factor provides for the transcription of certain genes into mRNA (messenger RNA) that then transform into protein (translation). This mechanism affects mainly genes for proinflammatory proteins such as ICAM-1, VCAM-1, iNOS, IL-6 and GM-CSF. Antihistamines stabilise the inactive form of the receptor and for this reason possess receptor-dependent, anti-inflammatory characteristics. Here the anti-inflammatory effects are dependent upon the strength of the H1 receptor antagonism and can occur with physiological doses. Through a higher receptor binding affinity of new antihistamines, clinically positive effects can also be bronchially observed with AR on the nasal obstruction and the symptoms of simultaneously occurring asthma. Receptor-independent effects due to antihistamines are also described that intracellularly may possibly be based on the competitive effect of calcium binding [108].

2.3.2.2 Pharmacokinetics of antihistamines

The old generation of antihistamines was categorised as effective for the treatment of allergic rhinitis. First generation antihistamines, the so-called "classic" antihistamines, also have an activating effect on cholinergic, serotinergic and α-adrenergic receptors, but due above all to their lipophily they are common to CNS and thus all show the familiar side effect of sedation. Chemical structure and pharmacological characteristics are similar: following rapid and complete reabsorbtion in the gastrointestinal tract, the highest plasma levels are achieved after 1 to 3 hrs. The clinical effect is noticeable after around 30 to 45 mins and reaches its maximum after 1 to 2 hrs and lasts for 3 to 6 hrs. Exceptions are meclizine-HCl, the effect of which lasts for 12 to 24 hrs, and hydroxyzine with a half decay period (HDP) of around 20 hrs. Most compounds are transformed in the liver, frequently to active metabolites, which can extend the clinically relevant HDP considerably. Retard compounds of classic H1 antihistamines are above all used for the reduction of sedating side effects (low plasma and tissue peak levels), not, however, used for extending effect [107].

As a result of an improved risk-benefit relationship and improved pharmacokinetics, today new H1 antihistamines are being used as the first choice for allergic rhinitis. The low CNS toxicity of the new, "non-sedative" compounds is based primarily on the inability to pass through the blood-brain barrier. Chemical structure and pharmacological characteristics of individual substances are not comparable. In low concentrations, binding to the H1 receptor is competitive; in high concentrations non-competitive bindings with only a very slow dissociation from the receptor appear [107]. Following oral administration, newer H1-antagonists are also reabsorbed well and maximal serum level is reached within 1 to 2 hrs. In general, the duration of effect of the non-sedating H1-antagonist is longer than that of the classic variety, for which reason it is usually sufficient to administer them once a day. The elimination half-lives vary greatly and lie between ca. 10 hours (loratadine) and 20 hours (terfenadine). One week's administration of an H1 antihistamine causes a blockade of the histamine effect for 2 to 7 days depending on the substance: H1 antihistamines should therefore be discontinued in general at least 3 days before skin or provocation tests. With a few exceptions (cetirizine, acrivastine, pheniramine), the metabolisation of the new antihistamines also takes place via the liver. Nasal antihistamines are characterised by a quicker onset of effect compared with oral substances [107].

According to the ARIA Workshop Report [2], [3] and a statement made by the EAACI Group [109] in 2002, a third generation of antihistamines has meanwhile been defined. Antihistamines that in future will be assigned to this group should fulfil the criteria (Tab. 4) of a specific, potent H1 receptor antagonism, of effectivity beyond 24 hours after single daily administration and rapid onset of effect. In addition, no interference with ingestion/ other medication/ intestinal transport proteins, no sedation or interference with psychomotoric performance, no cardiotoxic effects or other side effects such as anticholinerg effects, weight increase, liver or kidney toxicity should occur. Proven additive anti-allergic effects in patients on all symptoms of AR including nasal obstruction have been postulated.

Table 4

Of the second-generation substances available to date, these criteria are partially fulfilled by desloratadine, levocetirizine and fexofenadine. Levocetirizine exhibits sedation and fexofenadine shows an interference with transport proteins or reduced reabsorbing. Along with topic glucocorticosteroids, antihistamines belong to the first choice of therapeutic agents in cases of intermittent or persistent AR [110], [109], [111].

2.3.2.3 Substance-specific characteristics of antihistamines

Central nervous system

The most common side effect of classic H1 histamines is sedation [109], [112]. Clinically, sedation ranges from slight difficulty in concentration to dizziness and finally to a deep sleep. The central nervous effect is produced by the blocking of the histamine receptors in the CNS. Here histamine constitutes a considerable part of the local hormones and neurotransmitters. The new generation of antihistamines is characterised by a low lipophility so that it cannot pass through the blood-brain barrier [113].

Cardiologic side effects

Due in particular to first- and second-generation lipophile antihistamines, to date around 300 severe cardiovascular incidents are known of which 300 were fatal. This figure becomes relative, however, in view of the 150 million doses prescribed daily in Germany alone [114].

In the last ten years arrhythmogenic effects for terfenadine and astemizole have been recorded. For this reason terfenadine and astemizole have now been taken off the market in the USA in order to avoid these side effects. In Germany astemizole has been taken off the market whilst terfenadine is still available [115].

The effect of cardiovascular side effects is based upon an effect similar to that of quinidine that leads to an abnormal extension of the OT interval and a subsequent torsade de pointe, ventricular tachycardia and an anti-ventricular block, as well as cardiac arrest. The arrhythmogenic effect of H1 antihistamines is caused transmembranously in the myocyte by a change of the action potential. In this context, the blocking of potassium canals supports the cardiotoxic effect of the H1 antihistamines. The effect of cardiotoxicity is controlled subject to the substance concentration [116].

This is above all relevant for substances that are metabolised into active metabolites in the liver by cytochrome P450 (exceptions are ceterizine and fexofenadine). They are metabolised via the isoenzyme 3A4 of the cytochrome P450 and in doing so compete with macrolidantibiotics (erythromycine, oleandomycine, troleandomycine, to a lesser extent clarithromycine, josamycine, not, however, azithromycine and dirithromycine), imidazolderivates (ketoconazole, fluconazole, itraconazole), contraceptives, cimetidine, phenytoin, antiaarrhythmic agents of classes I and III, barbiturates, nifedipine and cyclosporine for the binding point. The result is a diminished reduction, that is to say a higher antihistamine plasma level.

Loratadine and ebastine have no intrinsic capacity for blocking the potassium canals, although they are metabolised in the liver. Cetirizine, fexofenadine and mizolastine are also metabolised in the liver; for these substances no cardiogenic side effects were detected in healthy voluntary test persons [117].

As well as the interaction of the drugs listed above, an already existing hypokalemia or inhibition of the potassium canal at the myocard due to quinidine or sotalol, for example, may be of significance. Liquids such as grapefruit juice can also inhibit the isoenzyme 3A4. The taking of classic antihistamines boosts the CNS-depressing effect of alcohol and sedating substances. MAO inhibitors (e.g. tricyclic antidepressants) extend and strengthen the anticholinergic characteristics of the older antihistamines in particular [118], [119].

As well as competitive inhibition through other drugs, it is also of relevance that the isoenzyme 3A4 is present in humans in a variety of amounts differing up to a factor of 10 and that therefore individual sensitivity varies.

The more recent virostatic agents for the treatment of HIV infection such as ritonavic or indinavir may likewise not be administered together with terfenadine or astemizole as they are also metabolised via cytochrome P450 [116].

2.3.2.4 Effect with allergic rhinitis

Along with topic glucocorticosteroids, antihistamines also belong to first choice therapeutic agents in cases of intermittent and persistent AR. Second-generation antihistamines have a positive effect on nasal and non-nasal symptoms of allergic rhino conjunctivitis caused by seasonal and perennial allergens. Antihistamines are less effective with nasal obstruction as the symptoms of nasal obstruction are transferred through histamine and other mediators via the H3 receptor. Other studies do verify the anti-obstructive in vivo effect, but this effect is not comparable with nasally administered steroids [110], [120].

The prophylactic effect of antihistamines for the development of allergic rhinitis has also been frequently discussed but until now it has not been able to be proved in vivo [121]. However, long-term studies have indicated the possible existence of a prophylactic effect of antihistamines on the onset of asthma in children with house-dust mites and grass pollen sensitisation [122], [123]. Anti-inflammatory effects of second-generation antihistamines were not clinically verified with people suffering from pollen allergies and those suffering from house-dust mite allergies through a reduction of steroids in the context of asthma treatment [124]. However, the clinical relevance of this phenomenon to date has not been sufficiently examined to enable us to draw any therapeutic conclusions from it.

On the whole we can postulate that the long-term use is of more value than a need-oriented use with symptoms [125].

In cases of intermittent AR; the use of topic antihistamines is indicated as "on demand" therapy. Today, 2 intranasal H1 antihistamines are applied for the treatment of allergic rhinitis: azelastine and levocabastine. Here, studies showed that both azelastine and levocabastine significantly reduce the particular symptoms of allergic rhinitis. Azelastine was also classified as effective with children [126]. The advantage of local application of antihistamines is to be found in the high dosage and attainment of higher concentrations in the effecter organs. Here the side effects are also avoided or greatly reduced. The topic antihistamines are available both for use in the nose as well as on the eye. They act quickly (within 15 minutes), are to be taken twice a day and are well tolerated.

2.3.3 Active agent group of the glucocorticosteroids (GCS), topic and systemic

With the introduction of beclomethasone dipropionate (BDP) in 1973, topic therapy for AR became possible with a glucocorticosteroid. Since then additional topic steroids have been available (budesonide, flunisolide, fluocortinbutylester, triamcinolonacetonide, fluticasonpropionate, mometasonfuroate). They differ primarily from the classic steroids (betamethasone, dexamethasone, hydrocortisone, prednisolone, methylprednisolone) by a C17 esterification that gives them a stronger lipophilicity (better penetration of the mucosa) and a higher affinity to the intracellular steroid receptor. In addition they achieve a greater metabolic stability through C6 and C9 halogen substitution [127], (Tab. 4).

2.3.3.1 Molecular effects of the GCS

The effect of the glucocorticosteroids (Fig. 5) is conveyed by cytoplasmatic receptors (glucocortocoid receptor: GR) [128], [129], [130]. Steroids are lipophile and can thus quickly penetrate the cell membrane. Binding to the receptor releases a protein that inactivates it in a resting state. The glucocorticosteroid receptor complex penetrates the cell nucleus and operates as a transcription factor of protein biosynthesis by bonding to special recognition sequences of DNA in the promoter region, so-called GRE (GCS responsive elements). GCS can either activate or suppress target genes by either raising or inhibiting specific mRNA production. In this way the transcription of numerous inflammatory mediators (e.g. cytokines) can be suppressed and the production of anti-inflammatory mediators and others raised. Furthermore, the GCS receptor complex can interact directly with other transcription factors such as, for example, NF-κB and the activating protein AP 1 [131], [132]. These are activated by a variety of cytokines. The interaction of GCS with NF-κB hinders their function as transcription factors and thus the effect of the cytokines on the cell and the further production of cytokines. Interestingly enough, as well as these time-consuming mechanisms there are immediate effects independent of the receptor. Thus, for example, vascular exsudation in the allergic immediate reaction phase can be significantly reduced 5-10 minutes after the application of nasal GCS. Furthermore, even after 30 minutes have elapsed, there can be a significant inhibition of the allergen-induced expression of the adhesion molecule E-selectin [133].

Figure 5

Molecular action mechanism of glucocorticostreoids

The effect of the glucocorticosteroids is conveyed by cytoplasmatic receptors (glucocortocoid receptor: GR). Steroids are lipophile and can thus quickly penetrate the cell membrane. Binding to the receptor releases a protein that inactivates it in a resting state. The glucocorticosteroid receptor complex penetrates the cell nucleus and operates as a transcription factor of special DNA sequences in the promoter region, so-called GRE (GCS responsive elements).

Due to their pharmacological properties (pronounced lipophilicity), new substances such as FP and MOM are extremely well absorbed into the nasal mucosa and are characterised by a high local level of effectivity (BMP (Beclometasone-diproprionate), budesonide (BU), flunisolide (FLU), triamcinolonacetonide (TRIA), fluticasone-17-Propionate (FP) and mometasone (MOM).

The oral bioavailability of the new substances is under 1%, which considerably reduces the systemic absorption of GCS.

2.3.3.2 Effect of topic GCS

At present, the following substances are available for nasal application, all of which have a clear and demonstrable effect in cases of AR. They are: dexamethasone, beclomethasondipropionate, flunisolide, fluocortinbutylester, budesonide, fluticasonpropionate (FP), mometasonfuroate (MOM) and triamcinolonacetonide (TRIA) [due to the high number of quotations in literature, quotation here is limited to surveys [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148].

Due to their pharmacological conditioning (pronounced lipophilicity), new substances such as FP and MOM are extremely well absorbed into the nasal mucosa and are characterised by a high local level of effectivity. The oral bioavailability of the new substances is under 1%, which considerably reduces the systemic absorption of GCS. The anti-inflammatory effect, however, does not begin until 12 hours have elapsed and only develops its maximum after days or weeks. For this reason the administration of an intranasal decongestive is first recommended in cases of extreme nasal obstruction, in order to facilitate the application of the topic steroid [141].

The anti-inflammatory effect of steroids attacks at various points in the inflammatory cascade. Here, primarily antigen-presenting cell fibroblasts, as well as eosinophil cell, basophile cell, mast cell and T cell fibroblasts, are affected on the cellular level [134], [135]. As well as the reduction of the synthesis of certain inflammatory mediators such as metabolites of arachidonic acid, histamine, tryptase, EDN, ECP and sICAM, the number of activated eosinophil granulocytes in the nasal mucosa is also reduced. Clinically, after the application of topic steroids a therapeutic advantage over antihistamines can be determined. The assumption that GCS only displays an effect in the later stages of AR has been disproved in a number of studies. Compared with each, the substances FP, MOM and TRIA (and to an extent BUD and FLU) [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148] exhibit a better effect in cases of allergic rhinitis with the recommended dosage in some studies than the older GCS [146], [149], [150].

2.3.3.3 Safety of GCS

Epistaxis

The GCS molecules of modern nasal steroids are not easily dissolved in water. They were therefore initially introduced as aerosols with CFC as a propellant. Due to the high linear speed of the aerosol near the opening of the applicator, the distribution of the medication into the nasal cavity with these sprays is poor. Furthermore, due to the high speeds (up to 120 km per hour), the mucosa, especially around the head of the lower nasal concha and in the Little's area, is damaged, whereby epistaxis can be observed as a frequent side effect. Due to the problems of CFCs, this propellant aerosol has been replaced over the past years by both ecologically and clinically more effective applicator systems. Watery suspension and pump sprays produce a better intranasal distribution than a propellant aerosol [151], [152], [153], [154].

Antidegradants

The added antidegradants (benzalkonium chloride) theoretically have a negative effect on cilium [155] that, however, was not observed in clinical studies even after long-term application [156]. Sprays without antidegradants (e.g. Comod®-System) are available. Newman et al. [154] showed that only a part of the medication applied in the nose reaches the cilium-bearing mucosa. The long-term benefit of modern GCS over a year did not result in atrophy or disturbances of the mucociliary clearance [157], [158].

Long-term treatment of children

In order to avoid systemic effects, GCS with low bioavailability should be applied, particularly with children and more long-term use (Fig. 5). With intranasal long-term treatment of children and adults with AR, the risk of systemic GCS side effects is very slight [157], [159]. Information on the inhibition of growth rate amongst children and juveniles after long-term use of beclometasone dipropionate and other topic steroids [157], [159] frequently do not take into account the fact that temporary studies on growth rate have no relevance to the decisive question of ultimate body length. On the basis of the data available till now, the British (Committee on Safety of Medicine of the Medicines Control Agency) and US (Food and Drug Administration) authorities have published a "class labelling" system that recommends the use of medicinal products with as low as possible systemic availability, particularly for children (Fig. 5).

2.3.3.4 GCS with AR

In summary, along with oral antihistamines, topic glucocorticosteroids also belong to first choice therapeutic agents in cases of intermittent and persistent AR in adults and children. They should be applied particularly with persistent moderate to severe symptomatology with nasal obstruction [3]. Corticosteriods are regarded as the most effective medical substances for AR therapy. Through local application, a high concentration of mucosa with minimal risk of symptomatic side effects can be achieved with continual application [160].

The regular use of topic corticosteroids reduces all nasal symptoms, including the nasal obstruction more effectively than oral antihistamines, and reduces with lasting effect the concentration of a number of different inflammatory mediators (including histamine) in the mucosa. However, topic GKS are inferior to oral antihistamines with regard to the suppression of allergic eye symptoms. For this a combination of topic GKS and antihistamine might be advisable [161], [162], [163], [164], [165], [166], [167], [168]. The patient should be informed about the protracted onset of the effects (effects begin after some hours up to a day, the maximum is after a few weeks), about proper use (applying a spray parallel to the nasal septum in the sagittal plane), the safety of modern nasal GCS, as well as the possibility of dosage reduction with symptom control after 3 months. At the beginning of therapy or in cases of severe symptoms, it is possible to use a double dosage initially.

Oral as well as depot preparations of systemic GCS are frequently used on a daily basis without there being sufficient studies available for this [169]. A study on the comparison of an oral with a depot preparation showed the superiority of the depot preparation [170], however, the controllability with the oral dosage is greater and rare muscle atrophy after depot injections can be avoided.

The application of oral GCS can be considered in the case of rhinitis otherwise resistant to treatment, as well as an initial therapy in the case of severe rhinitis and nasal blockage. With children, pregnant women and patients with known contraindications, oral GCS should be avoided. The known side effects of systemic GCS, particularly in the long term, should be observed.

2.3.4 Agent group of the decongestive agents

Via adrenergic receptors on the nutritive and capacitative vessels of the nasal mucosa, sympathomimetics take effect on the nasal obstruction and leave all other symptoms untouched [171], [172]. A difference is made between α-adrenergic substances (phenylephedrine), α2-adrenergic substances (oxymethazolin, xylomethazoline, naphazoline), noradrenaline releasers (ephedrine, pseudoephedrine) and inhibitors of the noradrenaline re-uptake such as cocaine and tricyclic antidepressive agents [173], [174]. The effect of locally applied decongestive agents starts within the first 10 minutes and lasts for a maximum of 10-12 hours with oxymethazoline. Ephedrine, phenylephrine, phenylpropanolamine and pseudoephedrine are also offered as oral decongestive agents for the nose. The effect of oral decongestive agents begins as a rule after 30 minutes to 6 hours and lasts 8-24 hours [175], [176], [177].

2.3.4.1 Safety of decongestives

Local nasals effects

Burning in the nose and dryness of the nasal mucosa to ulceration are described as local side effects. Septum perforations a can also occur after use of intranasal decongestive agents.

For decongestive agents with a required time of less than 10 days, no functional or morphological changes of the nasal mucosa are detected with intranasally applied decongestive agents [178]. When applied for longer than 10 days, a tachyphylaxia and a rebound phenomenon occur [179]. Here, the nasal mucosa swell after the decongestive agent has been administered and this eventually leads to a rhinitis medicamentosa. One further side effect is caused by benzalkonium fluoride, which is often added as a preservative agent [180], [181].

Systemic effects

Included in the side effects of systemic decongestive medication are tachycardia, restlessness, sleeplessness, and hypertension [182], [183], [184], [185].

2.3.4.2 Decongestive agents with AR

The indication for topic decongestant sympathomimetics is at best restricted to initial, short-term, additive administration as a pathfinder for a therapy with other substance groups. Oral decongestant drugs are weaker and effective for a shorter period than the topic variety; in combination with an antihistamine, they are often superior to monotherapy [186], [187], [188], [189], [190], [191], [192], [193], [194], [195]. Pseudophedrine should not be prescribed for patients over 60, pregnant women and patients with high blood pressure, potassium myopathy, hyperthyreoidism, glaucoma or psychiatric illnesses where monoamine oxidase inhibitors have been prescribed [3].

2.3.5 Leukotriene receptor antagonists (LT-RA)

Leukotrienes are produced in the metabolism of arachidonic acid that is released in allergic inflammatory processes involving eosinophilic leucocytes and mast cells in particular. They cause an increase in blood vessel permeability, bronchoconstriction, mucous secretion, complement receptor expression and trigger the release of lysosomale enzymes and the production of oxygen radicals.

Leukotrienes are among the most important transmitters in allergic inflammation and are a major factor in secretion and obstruction. For this reason leukotriene receptor antagonists (LT-RA) could be considered as a treatment for allergic rhinitis. They can be used on their own or in combination with an antihistamine [196], (Tab. 3). In the treatment of allergic rhinitis single medication therapy involving a LT-RA is less effective than a monotherapy involving a nasal steroid [197], [198], [199], [200], [201], [202]. A combined therapy is clinically as effective as a monotherapy using a nasal steroid [197], [203], [204]. Although leukotriene antagonists can potentially clear a nasal blockage on account of their physiological properties, clinical tests have yet to verify this. In view of current research data, definite conclusions can be drawn (Tab. 3).

Table 3

2.3.6. Alternative therapeutic approaches

2.3.6.1 Topically applied anticholinergics

Parasymphathetic fibres in the nasal mucosa originate in the nucleus salivatorius superior in the brain stem and are switched in the ganglion spheno-palatinum. Seromucous glands and blood vessels innervate the fibers' parasymphathic ventral branches [205]. The parasympathic stimulation produces an aqueous secretion (generated by the neurotransmitter acetylcholine) and a vasodilatation of the blood vessels. The muscarine receptor of the seromucous glands in the nasal mucosa can be inhibited using anticholinergic medication such as ipatropiumbromide [206].

Ipatropiumbromide

Ipatropiumbromide is a quaternary isopropanol-noratropine derivate that is not easily absorbed through the nasal mucosa. It cannot pass the blood brain barrier on account of the lipophilitate level [207], (Tab. 3).

Safety

Side effects are nasal dryness, irritation and burning, a dry mouth and headaches. Sense of smell and mucous clearance remain unaffected. Systemic bioavailability of intranasally applied ipatropiumbromide lies at around 10%. Systemic effects are extremely rare and only occur when larger doses are used - for instance 100 μg per day [207].

Ipatropiumbromide in allergic rhinitis

Random control studies have demonstrated that ipatropiumbromide is extremely effective in treating nasal aqueous secretions in allergic rhinitis [208], [209], [210], [211]. After production of methacholine in the nose there can be an approximately 3 hour-long secretion reduction after the single administration of a 42 μg ipatropiumbromide dosage in each nasal cavity [212]. Response is fairly rapid and occurs 15-30 minutes after initial dosage. However, maximum response only takes effect several hours after treatment has begun. No tolerance induction in the nose has been observed to date [213]. Another study has shown that combination therapy involving ipatropiumbromide and terfenadine appears to be more effective than therapy based exclusively on terfenadine [214]. The combination of ipatropiumbromide- and beclomethasone spray also appears to be more effective than the separate use of these substances [215]. Ipatropiumbromide is available in aerosol form or diluted in a pump spray. It is taken 3-6 times daily in a dosage ranging between 120 and 320 μg [212].

Ipatropiumbromide spray can be used to treat aqueous rhinorrhea. A combination involving intranasal glucocorticosteroids or H1-antihistamins can be considered for patients suffering from aqueous rhinorrhea where no other medication can be used.. Such cases include geriatric nasal changes and patients suffering from rhinorrhea after exposure to cold air (cf. also IR treatment).

2.3.6.2 Alternative therapies

The homoeopathic medication luffa (luffa operculata, galphemia glauca, histamine, sulphur) produced a DNCG comparable response in research on seasonal rhinitis [216]. However no placebo group results were recorded, which means that the therapeutic effect remains open to question. In respect of other so-called alternative or complementary medicine such as acupuncture [217], [218], Chinese medicine and phytotherapy no clear empirical evidence is as yet available [219]. However, choice of medication depends on a wide range of other criteria. There is an urgent need for more random clinical control studies on alternative therapies for allergic illnesses and rhinitis. There is a dearth of scientific data on clinical effectiveness [3], [4].

2.4 Pharmacotherapy in children, during pregnancy and in older patients

Allergic rhinitis is rare among children under the age of two, but its incidence increases markedly in school age children and is part of the so-called "allergic trail" of childhood. Allergy tests can be carried out at any age but must take age into account (for instance prick test) and must be evaluated (for instance IgE identity).

The basis for treatment in children is the same as that for adults. Special care must be taken to avoid typical side effects. Medication dosage must be altered accordingly. Few drugs have been tested on children aged two years and under.

Allergic rhinitis can adversely affect children's cognitive functions and academic performance. Further adverse effects from H1 antihistamines which are taken orally and which have sedative properties should also be avoided. Intranasal glucocorticosteroids are also effective in allergic rhinitis treatment in children. The possible effect that certain topical steroids have on growth should be noted. These are used for long term simultaneous asthma treatment. The recommended dosages of mometasone and fluticasone have been shown not to affect growth in children suffering from rhinoconjunctivitis [157], [220]. Glucocorticosteroids taken orally and injected into the muscle should be avoided in rhinitis treatment in children.

Pregnancy

Rhinitis is a common problem during pregnancy as nasal obstruction can be aggravated at this time. Any medication during pregnancy should be taken with care as most medication passes through the placenta. There are only a few studies based on small target groups and these are short-term studies only. To a degree, first generation antihistamines show teratogenic effects on animals. No adverse side effects have been noted in respect of DNCG and topical steroids taken during pregnancy. There is, however, a lack of relevant research in this area [2].

Old age

Some medication can give rise to specific side effects in older patients. Previous generation antihistamines with anticholinergic effects can cause urinary reaction in patients with prostatism. They can also have central and cardiovascular effects, particularly when used in combination with oral decongestives. Side effects from sedative antihistamines may become more pronounced. Previous generation antihistamines with an anticholinergic effect are contraindicated in glaucoma patients. Antihistamines and second-generation topical steroids produce few or no side effects [107].

Surgical measures

Surgical intervention may be necessary in the case of nasal obstruction that has failed to respond to treatment as a result of hypertrophy of the lower or middle nasal passage, or as a result of subsequent illnesses such as chronic rhinosinusitis or anatomical obstruction (septum deviation) which can aggravate hypertrophy of the nasal passages. While surgery in cases of nasal passage hypertrophy has no impact on allergic inflammation, one study has shown clear and long-term effects on all symptoms of chronic allergic rhinitis [221]. Surgical intervention may therefore be advisable when drug therapy has failed or when there is anatomical impairment.

3. Specific immune therapy SIT

Specific hyposensitisation treatment, otherwise known as immune therapy (SIT), involving subcutaneous injection of increasing allergen dosages was first developed by Noon in 1911 [221]. Along with the allergen diet, SIT is the only causal treatment for allergic illnesses. There is evidence to suggest it may prevent the development of bronchial asthma or other allergic reactions [222], [223], [224], [225], [226]. These studies are based on current scientific data. They take into account recommendations made by the WHO [227], the EAAIC and the German Medical Association of Allergologists.

3.1 Immunological mechanisms

The treatment's immunological effect is not yet entirely understood. The effect on T-lymphocytes would appear to be important [228], [229], (Fig. 6). Depending on their cytokine production the so-called CD4+ T-helper cells are divided into TH1-cells, which produce, for instance, interferon (IFN)-gamma, tumour-necrosis-factor (TNF)-α and interleukin (IL)-2, and into TH2-cells which produce for instance IL-4, 5, 6, 10 and 13 [230]. TH2-cells, in particular, induce the formation of IgE through interleukin production IL-4. By means of IL-5-production they induce allergic inflammation in the affected tissue through eosinophilic granulocytes. During immune therapy it is not clear whether TH2-cells are re-orientated (to TH0- or TH1) or are functionally inhibited. Both outcomes can be generated through the application of strong allergen dosages. Over the long term this causes reduced allergen specific IgE production [231], [232], [233], [234], [235], [236], [237], [238], [239], [240], [241], [242] and impacts on so-called effector-cells such as mastocytes, basophiles and eosinophilic granulocytes [243], [244], [245], [246], [247], [248], [249], [250]. During immune therapy it would also appear that IgE is syntheticised and that this competes with IgE for the bonding of the allergen.

Figure 6

Mechanism of action of SIT

Immunologic action mechanisms of SIT are still unknown and have to be elucidated. Discussed action mechanisms of SIT are functional inhibition of TH2 cells, orientation of TH2 cells to TH1 cells and synthesis of specific IgG that bonds to the allergen.

3.2 Allergen extracts and application types

As allergen extract manufacturers use different standardisation methods it is not possible at present to make a comparative assessment of extract quality. During manufacture international guidelines on the standardisation and production of allergen extracts (for instance. total allergen activity, biological activity of individual allergen components and main allergen content) should be taken into account [227], [251]. Extracts with native allergens differ from chemically modified extracts (allergoids) that have reduced bonding capacity with IgE antibodies. The absorption of proteins (for instance aluminium hydroxide, calcium phosphate, tyrosine) produces a depot effect. Therapies involving the use of standard manufactured medication (single allergens or compound allergens) and those tailored to the individual patient are used in immune therapy. These are determined according to the individual requirements of each patient (DGAI-Committee decision 25.7.2000).

3.3 The therapeutic effect of subcutaneous immune therapy

Numerous clinical studies involving subcutaneous injection of allergens or allergoids have demonstrated the therapeutic effect of immune therapy [251], [252], [253], [254], [255], [256], [257], [258], [259], [260]. The studies were random and placebo-controlled (exception - children) and doubleblind. In one favourable assessment there was an at least 30% symptom and medication reduction in the group treated compared with the control group [261]. This research demonstrated high efficacy in the case of grass/rye [262], [263] and ragweed allergies [264]. Good efficacy was also shown in other pollen allergies such as birch, alder and hazel [265], mugwort [266] and parietaria [267], [268]. The therapeutic effect of SIT for all year respiratory illnesses caused by house mites [259] and domestic pets (cats, dogs [269]) is well documented. SIT has only seldom been researched using placebo controls on mould allergies [270]. SIT often reduces nasal symptoms more effectively than conjunctival symptoms or an oral allergy syndrome induced by pollen content in foods.

3.4 Therapy procedures for subcutaneous SIT

Advice varies as to best practice in allergen immune therapy. It should be stressed that all courses of treatment are based on empirical experience / evidence. To date there are no guidelines on best practice regarding allergen immune therapy. However, standard allergy immune therapy programmes do exist and are based on data collected from control studies. According to a WHO specialist committee, standard allergy immune therapy consists of dosages that are increased in stages until a fixed dosage is reached that is tailored to the individual patient's needs. This assessment corresponds to guidelines developed in Europe and the USA.

3.4.1 Pre-seasonal hyposensitisation

Pre-seasonal hyposensitisation is the most common form of allergen immune therapy for seasonal allergens (Fig. 7). Hypo-sensitisation drugs are prescribed at the end of the allergy season and treatment begins anew each year with the build-up of the treatment. This starts with a minimal and individually prescribed quantity of allergens prescribed on a weekly basis. When this reaches a fixed level the dosage is repeated until the onset of the pollen season. Treatment is then suspended and the medication is re-administered in increasing dosages in the following year after the end of the allergy season.

Figure 7

Different forms of conventional SIT

3.4.2 Perennial hyposensitisation

In the case of perennial hyposensitisation, at the beginning of the pollen season and after initial build-up of treatment, the dosage is continued (co-seasonal portion) but reduced significantly by, for example, one third (Fig. 7). After the end of the pollen season the dosage is then slowly increased once more up to the maintenance dosage. Here the guidelines of the drug manufacturer can be followed. However, treatment must be tailored to the individual patient. The advantage of this is that treatment does not have to start again in the same way every year but can be resumed at the level established during the allergy season. Overall, this leads to a cumulatively larger prescribed dosage and in some cases a more successful therapy.

Pre-seasonal and perennial subcutaneous immune therapy is, as a rule, administered over a three-year period. However, if there are no signs of improvement after the first or second year of treatment there is a good case for re-examining the choice of the allergens prescribed. Immune therapy can, of course, be repeated with the same or other allergens if the effectiveness of the treatment diminishes. Simultaneous use of common symptomatic anti-allergic pharmacons does not adversely affect immune therapy results but can influence patients' reaction to allergen injections. This should be borne in mind particularly in the case of reduced pharmacotherapy.

Treatment and the use of immune therapy on children largely matches that used for adults Children show good tolerance and benefit in particular from the immuno-modulatory effects of immune therapy.

3.4.3 Short-term programmes

As an alternative to long therapy there are several short-term immune therapy programmes. These include pre-seasonal short-term immune therapy and rush-and-cluster immune therapies. In the past extracts suspended in solution were used for rush-and-cluster immune therapies and these produced a higher incidence of side effects. However, depot medications / preparations proved to have fewer side effects with these dosages. For this reason more research is being carried out to determine optimal dosages using depot preparations. Rush immune therapy has been used to treat allergies to wasp stings in particular (Fig. 8).

Figure 8

Different Short-term therapy forms of SIT

With an asterisk marked therapy forms - rush and ultrarush - are only indicated in patients with venom allergy.

Pre-seasonal immune therapy

Pre-seasonal immune therapy entails six to seven injections depending on the medication in question. Several studies have focused on and vindicated the clinical effect of this form of immune therapy with the result that it can now be recommended for the treatment of allergic rhinitis [270], [271], [272]. However, it should be noted that research does not show a shift towards TH2. In this respect it is still unclear how long these positive results last. Moreover, the total allergen dosage used is less than that used in standard SIT immune therapy (Fig. 8).

3.5 Mucosal Immune therapy

The principle of oral immune therapy is to encourage T-Cell tolerance induction within the mucous membrane (mucosa-associated lymphatic tissue, MALT). It is now known that macromolecules (for instance - proteins) can be reabsorbed through the intact mucosa in an immunologically effective form [273]. Here they come into contact with dendritic cells that process and generate antigens. These then reach regional afferent lymph nodes and T-Cells are generated in their paracortical region [274]. It can also be shown that high dosage birch pollen extracts taken whole or in capsules that are resistant to gastric juice can alleviate allergic rhinitis symptoms during the pollen season [275], [276], [277]. For this type of treatment, however, it is necessary to employ an allergen concentration that is 100 to 1000 times greater than that used in conventional subcutaneous immune therapy. Few studies show oral immune therapy to be effective in grass pollen allergies (particularly with children). Oral immune therapy is generally more effective in the treatment of birch pollen allergies [278], [279], [280]. The breaking down of allergen extract solutions by saliva and gastric juice results in a 90% allergenicity reduction by the time the extract reaches the small intestine. - as demonstrated in the RAST-inhibitions studies [281]. Allergens are destroyed in the duodenum and therefore de-activated. Accordingly, there is no impact on the immune system [282].

In addition to oral immune therapy - in which the allergen is taken orally - wider use is being made of sublingual immune therapy or combined sublingual/oral immune therapy [2]. In sublingual treatment the allergy extract is placed in the mouth for a certain time and then spat out. In the combined sublingual/oral the extract is placed in the mouth, is left there for a while and after which it is swallowed.

This works by stimulating the immune system of the mucous membrane and inducing so-called low-zone-tolerance [283], [284]. These treatments can be compared with the effects of subcutaneous immune therapy but have not yet been fully researched. However, numerous studies have demonstrated SLIT's effectiveness and suitability. This included research [283] carried out on 976 patients in 22 separate studies that were placebo-controlled and double blind or in double-dummy design. The research shows significant results for SLIT's effectiveness in terms of symptom reduction and use of drugs. In a study by Passalacqua [285] the incidence of asthmatic symptoms in children undergoing SLIT was markedly lower five years after the termination of treatment. Moreover the incidence of asthmatic symptoms was significantly lower than in a control group that had been given standard medical treatment. Wilson's analytical study [283] showed overwhelming evidence of SLIT's effectiveness and suitability / tolerance level. As regards tolerance levels all results demonstrate that SLIT possibly compares favourably with traditional subcutaneous immune therapy. No serious and systemic side effects have been observed.

A number of studies have been undertaken to examine the effectiveness of nasal immune therapy (NIT) as a treatment for allergic rhinitis. These studies have focussed on grass and early blossom pollen and house-dust mite particle [286], [287], [288], [289], [290], [291], [292], [293], [294], [295], [296], [297], [298], [299], [300], [301], [302]. Nasal hyper-reactivity was reduced demonstrably when NIT was used. As with oral and sublingual immune therapy, it would appear that nasal immune therapy induces immunity in the nose's mucous membrane. However, NIT also causes a persistent allergic reaction in the mucous membrane when applied directly on the nose. For this reason, NIT as a treatment for AR is used only in individual cases. SLIT and NIT can also be used for certain patients with allergic rhinitis and/or asthma caused by pollen and house-dust mite particles - in cases where pharmacological / standard medication has proved unsuccessful and in cases of systemic side effects in respect of traditional SIT. Oral immune therapy cannot, however, be recommended at present.

3.6 Indications and Contra-indications of SIT

SIT is suitable for patients with demonstrable and clinically specific sensitivity towards allergens producing immediate reaction, and exposure to which leads to clinical complications (Tab. 5). The course of treatment and prescription of allergens are determined by a doctor with relevant allergy training or specialisation. The nature of the allergy and course of treatment adopted are selected on the basis of symptoms manifested. Cost, practicability and patient agreement are factored in to these considerations.

Table 5

Treatment can also be determined on the basis of allergens. In the case of SIT and pollen allergens the criteria listed in table 6 (Tab. 6) are all fully valid. In the case of demonstrable mite allergy SIT is applicable so long as there is no effective mite control. Allergen control is applicable for animal epithelium allergies. Should this not be possible, then it can be used in exceptional cases for pet allergies. In the case of mould, allergy avoidance wherever possible is the preferred treatment. Treatment with mould allergens can be considered in rare cases and here extracts must be well defined (for instance - alternaria, cladosporium). Extracts from insufficiently defined allergen sources such as house dust, bacteria, candida albicans and trichophyte-species are not suited to SIT. If SIT is used, specific contraindications, technical / medical and patient information should be factored in.

Table 6

For health reasons SIT should not be initiated during pregnancy. If beta-blockers have to be used in individual cases, SIT can be used. Adrenalin therapy may become less effective.

4. More recent therapeutic and experimental strategies for the treatment of AR

Side effects arising from traditional / standard hyposensitivity treatment can be summarised as follows: immediate localised or generalised reactions. On the whole, the biochemical structure of the allergens used in the treatment accounts for such side effects. Native allergen extracts are used in traditional hyposensitivity treatment. These are administered in solution form or in chemically modified form. Native extracts contain non-allergic and allergic constituents and contaminating allergen structures. The latter do not share the same basis as native allergens. The various constituent elements of a native allergen have differing immunogenic properties.

The allergens should be large molecular structures. IgE should also be able to bond on the allergen surface. T-cell epitopes have short linear fragments and B-cell-epitopes have three-dimensional configured areas that bond to IgE. As outlined above, the T-cell requires a processed (MHCII-complex) T-cell epitope.

Over the past decade the DNA of most relevant antigens has been isolated and cloned. The clones were used in the reproduction of various recombinant allergens whose epitopes demonstrate the same degree of complexity as those of native allergens. Further developments in recombinant DNA technology have made it feasible to produce modified allergens or allergen fragments that are now being SIT-tested [303].

4.1 T-Cell peptide therapy

With regard to mast cell triggering there has been a shift away from treatment involving complete allergens towards treatment using allergen parts with T-cell epitope characteristics.

Such peptide therapy was first tested and assessed in the case of cat allergy Fel d 1 in animal experiments. Mice that were initially sensitised using the complete allergen were subsequently desensitised when the major epitope was administered. This is approximately 50 amino acids long and is part of the Fel d 1 molecule. The desensitisation effect was characterised by reduced T-cell activity [304].

Although the first clinical study with such cat allergen peptides proved successful, patients did exhibit side effects. On a clinical and pathomechanical level they differed from the side effects observed in conventional hyposensitisation therapy described above [305]. Patients treated with peptides did not develop immediate but delayed hyposensitivity that disappeared 4-6 hours after the allergen was administered. Reactions ranged from rashes and swellings where the allergen had been applied to asthma attacks with persistent bronchial obstruction. Further investigation suggested that this was caused by (unintentional) stimulation of allergen-specific T-cells. Major-epitopes had been singled out from the allergen reactive T-cells. This in turn activated the pro-allergic T-cells. By contrast, other studies involving the cat allergen peptide demonstrated that the delayed reaction was suppressed when T-cell peptide was administered [306], [307].

In another study the Der p peptide was modified in vitro. This resulted in a T-cell clone suppression that recognise the original native antigen. Suppression of the CD40 ligands and IL-5 and IL-4 proteins was also noted [308]. As a result of the induction of these anergen T-cells, IgE synthesis would also be reduced because the B-cell would be dependent on an activated T-cell for the isotope-switch.

4.2 Hypoallergenic recombinant allergens

Allergen derivatives are regarded as modified allergens. In some cases only one amino acid distinguishes them from the original allergen (point mutation). One example is birch pollen allergy. Native birch pollen allergens may differ only by one or a few amino acids. Such cases are derivatives of the birch pollen allergen Bet v. These derivatives can also be produced using recombinant DNA technology in the laboratory. Here the aim is to synthesise isoforms which are still distinguishable from T-cells and which do not activate but deactivate these [308], [309], [310], [311], [312]. A team of researchers developed recombinant trimer of the Bet v1 allergen consisting of three covalent bonded copies of the Bet v 1 allergen. Although the isoform possesses the same B and T-cell epitope as the original form of the Bet v 1 allergen, a TH1 shift in the T cells was observed. It was noted that the trimer induced the immunoglobin type IgG [308]. The therapeutic administering of such derivatives could lead to a significant reduction in side effects as no further B-cell epitopes are injected and there is a marked increase in efficacy. However, it is not clear whether such treatment would also produce the same results in practice.

4.3 DNA vaccines

The discovery of the sequencing of amino acid and the encoding of the DNA sequences may demonstrate another form of hyposensitivity. The DNA sequence cytosinphosphate-guanosine (CpG) oligonucleotide ODN), also known as CpG ODN, imitates characteristics of bacterial DNA in that it induces a TH-1 response. In an allergy experiment on mice, DNA encoded as CpG ODN was channelled through a vector and inhibited eosinophilia tissue and bronchial hyper-reactivity [313]. The effects lasted 6 weeks after initial administration. Another way to inject CpG ODN into the cells consists of coupling the DNA to an allergen protein. With the creation of such a hybrid vaccine a TH-1 re-orientation of the T-cells was produced in an in vitro test [314], [315], [316].

4.4 Humanised monoclonal antibodies vs. IgE

Currently there are two humanised monoclonal antibodies - RUMab-E25 and CGP - that target the Cε3-domain of the IgE-molecule. During inflammation the Cε3-domain of the IgE molecule normally bonds to the high affinity IgE-receptor FcεRI. In treating patients suffering from seasonally allergic rhinitis significant results were observed with E25 compared with the placebo control. However, the results were not comparable with those observed in traditional drug therapy and did not show significant results compared with conventional pharmacotherapy. In another AR study the humanised antibody was not found to be superior to other anti-allergic drugs. The reason for this could be attributed to a lack of reliable and substantial research on dosage effects [317], [318]. However, anti-IgE treatment has a supplementary effect when used with immune therapy with the result that combined treatment can benefit polysensitised patients in particular [319].

4.5 Targeted Modification of Cytokine Production

In allergic inflammation T-cell activity is characterised by a change in the cytokine profile towards T-Helper-2. It would be possible to use antibodies to obstruct the immunopathological behaviours of the cytokines such as IL-4 and IL-5 and thereby elicit a therapeutic benefit.

These types of treatment are used in particular for bronchial asthma and are presently undergoing clinical testing. First of all we can discuss the use of Anti-IL-5 and the inhibiting of IL-4 with soluble receptors [320], [321], [322], [323], [324]. With anti-IL-5 treatment, for instance, a significant reduction in eosinophilia in asthmatics can be measured in the bronchial lavage [322]. Cytokine receptors involve soluble cytokine receptors which occur naturally and which can be secreted from immunocompetent cells. Their function is to bond the cytokine to a receptor in a soluble environment. The functional outcome of the formation of a complex between cytokine and its soluble receptor has not yet been entirely understood. Such soluble cytokine receptors have now been identified for a large number of mediators whose detailed function is, however, still unclear. On the one hand soluble receptors could act as antagonists in surplus cytokine production in the sense of a negative reverse coupling. On the other hand the bonding of cytokines to their soluble receptors could also trigger agonistic effects. It is quite conceivable that this kind of cytokine receptor bonding is reversible and that the cytokine dissociates itself again from its soluble receptor (for example after the cytokine has been transferred to a compartment removed from the place of production) and might then still develop its functional effect away from its place of production. There is a wealth of direct and indirect evidence for both possibilities, but the detailed regulatory mechanisms for the production of soluble receptors have still not been completely understood. In an experiment carried out on mice on allergy and asthma it was shown that the soluble IL-4-receptor can suppress the development of an allergic immune response including the formation of of positive skin test reactions and bronchial hyper-sensitivity. Clinical studies are currently being carried out on asthmatics [324].

The controlled tests involving the inhibition of chemokines, chemokine receptors and adhesion molecules are also mentioned in connection with the treatment of asthma [325], [326], [327], [328].

5. Definition of idiopathic rhinitis

According to a consensus report published in1997 [329] nasal hyperreactivity covers a complex range of symptoms - including nasal obstruction, rhinorrhea, pruritis and sneezing - typical of the clinical symptoms for AR. AR, however, is only one of many conditions causing nasal hyperreactivity. Nasal hyperreactivity is also characteristic of a range of other rhinitis-related conditions (Tab. 6). Owing to lack of terminology, definitions and etiology, no standard classification of non-allergic rhinitis has been drawn up. The dearth in terminology and definitions is attributable to incomplete understanding of pathophysiological processes. On the basis of immunological and cytological criteria Settipane and Liebermann among others describe a non-inflammatory, non-allergic rhinitis, which comprises drug-induced rhinitis, rhinitis sicca, hormonal-induced rhinitis, reflex-induced rhinitis and vasomotor rhinitis [330]. In classifying rhinitis the ARIA working group / research team has replaced the term vasomotor rhinitis with idiopathic rhinitis (IR) (other synonyms that were used: 'non-specific nasal hyperreactivity'‚ 'non-infectious, non-allergic rhinitis'‚ 'perennial non-allergic rhinitis' or 'vasomotor rhinitis') [3]. Typical non-specific local triggers of IR nasal symptoms are sudden temperature variations in the nasal mucosa (example - skiers), strong smells and chemical irritants (perfumes, cigarette smoke etc.). Physical changes in the body or body temperature, physical activity and consumption of hot meals are examples of extranasal stimulus triggers [2]. Besides these stimulants drugs such as central sympathomimetics, antidepressives, anti-sympathomimetics and secalealcaloids produce nasal hyperrreactivity in non-inflammatory, non-allergic rhinitis. Changes in the hormone balance (honey moon nose, pregnancy, contraception, gestagen deficiency, thyroiditis, acromelagy) can also induce temporary or chronic rhinitis.

The transitions from physiological response to physical or chemical stimuli to excessive pathological stimulus response are often fluid. A study on normal test subjects showed that sneezing four times and nose blowing four times per day do not yet count as pathological. The physiological nasal cycle exhibiting a periodic swelling and contraction in the nose is not necessarily attributable to IR [331].

Nasal tests can be used for nasal hyperreactivity diagnosis [332] that involve the use of histamindihydrochloride or methacholinchloride as stimuli [333]. The tests only have limited suitability for individual diagnosis of nasal reactivity and standardised methods for routine diagnosis are lacking. Some studies indicate that the frequency of non-allergic rhinitis is between 23% and 50% among patients suffering from rhinitis [334], [335], [336]. The frequency of non-allergic rhinitis lies at around 57% for those suffering from chronic rhinitis [335]. The figure for vasomotor rhinitis accounts for 61%.

IR mechanisms

Whilst inflammation is a dominant factor in AR, IR is thought to develop as a result of neurogenic inflammation of the nasal membrane. Neuropeptides are released from peripheral nerve endings through a variety of stimuli. Physical stimuli (thermal, mechanical and electrical), UV-rays and chemical substances such as histamine, capsaicin, mustard oil and xylene can trigger the release of neuropeptides and lead to the onset of neurogenic inflammation [cf. summary on [336]] and as a result produce nociceptive afferences. So-called irritant receptors play a decisive part in this process. On sufficient stimulation of irritant receptors, the stimulus is transferred through the N. trigeminus fibres to the central nervous system and then switched. Blood vessel capacity and gland activity are regulated through the efferent parasympathicus fibres. The nasal membrane also has a so-called local axonal reflex (Fig. 4) in addition to the centrally switched reflex arc. In this case stimulus transfer is not carried out via switched efferents in the brain. The local effect on glands and blood vessels is transmitted by neuropeptides such as substance P (SP), and calcitonin gene related peptide (CGRP). Hyperemia in neurogenic inflammation occurs as a result of arteriola dilation and is conveyed via CGRP. Extravasation of proteins, however, occurs in the postcapillary venulas and is mainly produced by substance P and neurokinin A. On the basis of current scientific knowledge it would appear that the early extravasation phase is triggered by the direct effect of substance P, whereas in the later phase mediators released at a later stage such as histamine, serotonin, prostaglandine, leukotrienes and other mast cells are effective [cf. summary [336]].

The hypotheses concerning IR pathogenesis have been validated. Histological incisions were made on nasal membranes in cases of acute chlorodioxide exposure. Chlorodioxide exposure resulted in desquamation of the epithelium surface and in an increased number of nerve endings. No difference was recorded in the neuropeptide pattern between the test group and the control group [337].

Studies examining nasal membrane changes in IR following exposure to cold air show evidence of increased mast cell degranulation. Here the nasal membrane is not able to moisten the air.

A great number of environmental and occupational noxae (such as dust, ozone, sulphur dioxide, cigarette smoke) are relevant to the discussion on nasal hyperreactivity. In experiments cigarette smoke was shown to reduce the frequency of cilium beat [338]. This has been seen to stop completely in workers exposed to saw dust [339]. Higher neutrophil levels have been observed in the nasal membrane following ozone exposure [340]. It is not known whether there is a connection between exposure frequency and the development of rhinitis [341].

5.1 Treatment for nasal hyperreactivity

As idiopathic rhinitis and non-inflammatory, non-allergic rhinitis show an extremely heterogeneous set of causes - some known, other not - it is not possible to single out treatment for nasal hyperreactivity to suit all cases. Anamnesis should indicate possible etiological factors. As is the case for AR, elimination of stimulus is always the the most effective form of treatment. Elimination of stimuli is recommended above all in cases where there is exposure to occupational and environmental noxae.

Where it is not possible to identify the cause or eliminate the stimulus in cases of nasal hyperreactivity, it will be necessary to resort to treatment. In IR, nasal obstruction and aqueous rhinorrhea tend to dominate as symptoms. Sneezing and itching are less common. In a survey of 678 patients with idiopathic rhinitis, the main symptom observed was nasal obstruction. In this group allergic people suffered eye problems as opposed to sneezing or itchiness in the nose [342]. Here Togias et al. have not been able to make any quantitative distinction between the two symptoms rhinorrhea and nasal obstruction [343].

For medical treatment (Tab. 7) of non-allergic, non-inflammatory rhinitis various drugs are available which are also used in AR. These include mast cell stabilisers, systemic and topical antihistamines, topical and systemic glucocorticosteroids, ipatropiumbromide, alpha-sympathomimetics. These drugs are used on account of their pharmacological properties.

Table 7

Anti-inflammatory and anti-obstructive treatment

Indication of GCS for the treatment of idiopathic rhinitis is based on reducing the range of nasal hyperreactivity symptoms. On account of GCS's anti-inflammatory effect, efficacy is increased the more the nasal membrane is inflamed. In both allergic and idiopathic rhinitis there was a reduction in the number of CD3-positve, MBP-positive and tryptase-positive cells in the nasal membrane. The incidence of IL-4-and IL-5mRNA was also reduced through steroid use [344]. For this reason a 2-4 week treatment period is recommended for idiopathic rhinitis [345], [346].

In addition to GCS, nasal drops to reduce swelling can be used for a short period - as used in AR treatment.

Anti-secretory treatment

Clinical studies have shown that locally applied azelastine (antihistamine) has an effect on the range of symptom complex rhinorrhea, sneezing and nasal obstruction [347], [348], [349]. Azelastine showed positive results in 82-85% of patients (n=200 patients), while placebo (sea water) also produced a high rate of success (73%). Azelastine took effect within 3 hours [347].

There are no other studies known that examine the local application of cooking salt in steam or liquid form to treat IR. However, the above study has demonstrated that sea water can alleviate hypersection and obstruction.

Only ipatropiumbromide-spray is now used for treating aqueous rhinorrhea where the latter is the main symptom. A combination of ipatropiumbromide spray with intranasal glucocorticosteroids or H1-antihistamines can be considered for patients with aqueous rhinorrhea who cannot be treated with other medication. This is above all the case for patients who suffer from "geriatric nose" cdition in which the tip of the nose drops which has an affect on the air flow in the nose) and patients who suffer from rhinorrhea following exposure to cold air [348], [349], [350], [351], [352], [353].

5.2 Surgical treatment

Surgical treatments for IR is an option should treatment with medication prove unsuccessful. Surgical intervention for treating nasal hypersecretion is based on the severing the parasympathetic nerve fibres. Severing the endoscopic N. vidianus and electrocoagulating the N. ethmoidalis anterior are both regarded as suitable surgical procedures designed to reduce hypersecretion Although secondary reinnervations can occur following these procedures, studies indicate long term improvements over a 12-24 month period [354], [355], [356]. To block the ganglion spheno-palatinum, 2-4 sessions are necessary, after which there is demonstrable improvement [357].

Nasal obstruction can be surgically treated by reducing the size of the inferior concha in case of hypertrophy or by correcting relevant and anatomical variations in the septum, adapting the structure of the nose and the lateral wall. Moreover a reduction in size of the inferior concha has a positive effect on hypersecretion [358].

5.3 Other treatment

Capsaicin

Capsaicin (8-Methyl-N-Vanillyl-6-Nonenamid) that is found in pepperoni is a derivative of homovanillic acid. On account of its stimulating effects as well as desensitising effects (when used over a extended period) on thin afferent nerve fibres it has come to the fore in research on neurogenic inflammations and nociceptive afferents. Capsaicin in pepperoni and chilli causes a burning sensation in the mouth. Use of capsaicin can cause irritation on the skin, in the knee joint, in eyes and in respiratory passages. This involves selective arousal of a subcategory of somatovisceral afferents with unmyelinated axons and, to a lesser extent, axons with a thin layer of myelin.

Capsaicin does not stimulate other C-fibre types such as C-mechanoreceptors or cold-sensitive thermoreceptors [summary [336]] Desensitisation as a result of capsaicin's use - i.e. the extent of vasodilation caused by capsaicin - increase in permeability and pain and burning sensations gradually decrease until no reaction occurs. Heat, electric stimulation or the application of chemical substances such as histamine and bradykinin produce no neurogenic reactions on skin that has been desensitised by capsaicin.

This desensitising effect of capsaicin is used experimentally, diagnostically and therapeutically. The absence of a reaction to a specific stimulus following capsaicin use (or desensitisation) demonstrates that this response is released neurogenically as a result of capsaicin-sensitive afferents. Capsaicin desensitisation has become standard procedure in relevant experimental research.

Capsaicin is not available as a medication in Germany but it is prescribable. To date its use in treating neural-reflectory hyperreactivity has been reserved for IR clinical studies [358], [359], [360], [361], [362], [363].

Botulinumtoxine

Botulinumtoxine is a cellular poison produced by the bacterium clostridium botulinum. It blocks the release of the neurotransmitter azetylcholine from the presynaptic vesicles and as a result blocks cholinergic transmission for a period of about 4 months. Although botulinumtoxine is one of the most potent toxins, it is now used in treating some conditions. It has a proven record in treating a range of ailments when used in specified dosages and in localised applications. The lethal dosage (LD50) for people is thought to be between 50 and 100 times the amount of what is normally required in treating acute spastic illnesses [summary [364] and [365]].

The literature in the field comprises on the use of botulinumtoxine in the localised treatment of hypersecretory forms of rhinitis [366], [367]. In an experiment conducted by Kim et al. in 1998, botulinumtoxine was used locally in the inferior and middle conchae of the nose (2 units each). This caused a significant reduction in nasal secretion. Nasal obstruction or sneezing were not affected. The effects lasted for approximately four weeks [366].

6. Current therapy approaches - an outlook

Current and future development of pharmacological substances such as antihistamines and glucocorticosteroids characterise current pharmacotherapy for allergic and idiopathic rhinitis.

Together with oral antihistamines topical glucocorticosteroids are first choice treatment for intermittent and chronic AR in adults and children. They should be used, in particular, in chronic cases of nasal obstruction where symptoms vary from moderate to extreme. Negligible systemic absorption particularly in the case of new generation topical GCS should be noted. This renders the administering of GCS for children safe.

The anti-inflammatory properties of second-generation onward anti-histamines are probably attributable to the histamine's impact on various inflammation cells conveyed through the receptor. The anti-inflammatory effects are dependent on the strength of the H1-receptorantagonism and can be observed when physiological dosages are used. Clinically positive effects are noted in cases of nasal obstruction. Along with allergen abstention, specific immune therapy (hyposensitisation) is the only causal therapy for allergic condition and should be used as early as possible in the illness. Its efficacy has been sufficiently demonstrated. The preventive aspect of SIT in preventing new sensitisations / allergic reactions and the development of asthma should also be stressed. SIT can be used in cases where the patient also suffers from asthma and it reduces nasal and bronchial symptoms.

Subcutaneous immune therapy is regarded as standard treatment. This is also the case where sublingual application involving swallowing of the medication (sublingual-swallow) is also recommended for seasonal AR To date there are no long-term research data for sublingual IT and there are few comparative studies involving subcutaneous and sublingual IT. Treatment programmes for subcutaneous therapy are pre-seasonal long- and short-term therapy and perennial therapy. Currently a minimum 3 year long therapy is recommended for patients interested in treatment. Cluster- and rush-immune therapies involving inhalative allergens have come to the fore recently. However there is as yet insufficient data here regarding risk and efficacy.

Removal / Elimination of stimulus is appropriate in the treatment of idiopathic rhinitis as long as the triggering agent can be identified and avoided. Medicinal treatment for idiopathic rhinitis focuses on a symptom-specific treatment of nasal hyperreactivity, because the development of idiopathic rhinitis has not been clarified from a pathophysiological viewpoint. Mast cell stabilisers, anti-histamines and ipatropiumbromide are suitable for the treatment of rhinorrhea, while glucocorticosteroids inhibit obstruction.