Allergic rhinitis.

Allergic rhinitis is a very frequent disease with a prevalence of 15-20%. Symptoms are most pronounced in young people while, for some unknown reason, the elderly become clinically hyposensitized. Pollen is the cause of seasonal allergic rhinitis, and house dust mite and animals are the main causes of perennial allergic rhinitis. Histamine is the main cause of sneezing and hypersecretion, while other mediators probably also play a role in nasal blockage. In polyposis, a local denervation is an important cause of vascular leakage, edema and polyp formation. Antihistamines have a positive effect on sneezing and hypersecretion, but not on blockage. As they have a quick onset of action they are useful in patients with mild and occasional symptoms. A nasal steroid is preferable in patients with persistent symptoms, since it is more effective on all nasal symptoms. Short-term use of a systemic steroid can be a valuable adjunct to topical treatment, especially in nasal polyposis, when there is a temporary failure of topical treatment in a blocked nose. A nasal vasoconstrictor can be added for short-term treatment, and an ipratropium spray can be beneficial in perennial non-allergic rhinitis, when watery secretion is the dominant symptom. Immunotherapy can be added in allergic rhinitis, when pharmacotherapy is insufficient. This chapter is based on the author's personal experience with allergic rhinitis, as a patient, a doctor and a researcher. Therefore, it is not a balanced review and the references will be highly selected as they largely consist of the author's own publications. As the text is mainly based on personal research, steroids are described in detail, while, with regard to immunotherapy, the reader is referred to another chapter. In addition to allergic rhinitis, nasal polyposis will be described. It was formerly believed to be an allergic disease, but we now know that it is not. However, with regard to histopathology and drug responsiveness this disease is very similar to allergic rhinitis.

Topical glucocorticosteroids in rhinitis: clinical aspects.

The introduction of nasal glucocorticosteroids, 30 years ago, has been the most important therapeutic progress in rhinitis management since the introduction of the first generation of antihistamines. Our knowledge of the mode of action of glucocorticosteroids in the nose has improved as the airway mucous membrane of the nose is easily accessible for investigation. However, the exact mechanism behind the marked clinical effect remains unclear. Topical glucocorticosteroids are highly effective in diseases characterized by eosinophil-dominated inflammation (allergic rhinitis, nasal polyposis), but not in diseases characterized by neutrophil-dominated inflammation (common cold, infectious rhinosinusitis). Experience for 30 years and a long series of controlled studies have shown that the treatment is highly effective and that the side effects are few and benign. Intranasal glucocorticosteroids can therefore be considered as first-line treatment for allergic and non-allergic, non-infectious rhinitis and nasal polyps.

Intranasal corticosteroids for nasal polyposis : biological rationale, efficacy, and safety.

Nasal polyposis, occurring in about 2% of the general population, is the ultimate form of inflammation of the upper airways. For unknown reasons, polyps develop preferentially in subtypes of inflammatory diseases and are associated with perennial non-allergic rhinitis, asthma, intolerance of aspirin (acetylsalicylic acid)/NSAIDs, allergic fungal rhinosinusitis, cystic fibrosis, and primary ciliary dyskinesia. In contrast to common beliefs, IgE-mediated allergy does not seem to play an etiological role in nasal polyposis.The polyps originate from the mucosa around the clefts of the lateral nasal wall, especially in the region of the ostiomeatal complex. The factors that determine the localization of the disease to a few square centimeters of the airways are not known.Polyps are edematous bags covered by respiratory epithelium and contain very few nerves, blood vessels, and glands that have undergone cystic degeneration. They contain degranulated mast cells, have a very high concentration of histamine, and are characteristically infiltrated by eosinophils. These cells accumulate due to the release of proinflammatory cytokines (in particular, interleukin-5).Nasal polyposis is preceded by a prolonged history of rhinitis accompanied by severe and persistent nasal blockage; typically, the sense of smell is seriously impaired when polyps develop. The diagnosis is based on anterior rhinoscopy or, preferably, endoscopy.Nasal polyposis is medically treatable. Surgical treatment is carried out when medication fails. Intranasal corticosteroids reduce rhinitis symptoms, improve nasal breathing, reduce the size of polyps, and prevent, in part, their recurrence, but this treatment has little effect on the sense of smell. Intranasal corticosteroids can, as basic long-term therapy, be used alone in mild cases or together with systemic corticosteroids and/or surgery in severe cases. Systemic corticosteroids administered for 2-3 weeks have a beneficial effect on all observed symptoms and pathology, including the sense of smell. When nasal blockage is a problem in spite of medical treatment, surgery is recommended. Simple polypectomy can be performed, but endoscopic surgery is recommended in more severe and persistent cases.

Clinical trial design, nasal allergen challenge models, and considerations of relevance to pediatrics, nasal polyposis, and different classes of medication.

Clinical trials in allergic rhinitis present several specific difficulties. In seasonal pollen-related disease, there are variations between subjects in the extent of pollen sensitization, individual variations in exposure to pollen even within a set area because of lifestyle differences, and variations between different areas in pollen counts and weather patterns. Thus, large patient numbers are needed in multicenter trials to account for such variations when the standard endpoint is symptom reporting. Furthermore, a pollen season may be relatively short (eg, lasting 6-8 weeks), and the pollen count is inconsistent during this period. Crossover study designs are thus inappropriate, and trials are usually conducted with a parallel-group design. This further increases the trial sample size as it reduces statistical power. These large patient numbers must be recruited over a very short period. Perennial house dust mite-sensitive allergic rhinitis presents other problems. Although there is less disease variation, it is appreciated that symptoms may be induced by nonallergic as well as allergic mechanisms because of the nasal hyperresponsiveness. The nonallergic symptoms may not be modified by treatments based on allergic disease mechanisms. Thus, symptom outcomes--although relevant to the patient--may not adequately reflect the pharmacologic efficacy of the specific intervention. To control variability and focus on allergic disease mechanisms, nasal allergen challenge has been used in drug development. Single-dose challenges in the laboratory or in a pollen chamber, which allow many volunteers to be studied at the same time, have proven useful in the evaluation of drugs that afford acute symptom relief. However, such challenges incompletely model naturally occurring disease, in which the repeated daily exposure to allergen modifies the mucosal inflammatory cell profile and in particular promotes the epithelial accumulation of effector cells. This alters the response to allergen exposure. To model this, repeated low-dose daily allergen exposure has been used to generate these mucosal changes artificially, and early studies suggest that this may be a more valid model for the evaluation of anti-inflammatory therapy. However, little has been published with this model. Different disease groups are associated with their own specific issues in clinical trials. The pediatric population, in which allergic rhinitis is common, has different requirements for education, quality of life evaluation, and adverse-event monitoring; nasal polyposis, because of the nature of the disease, requires additional means of assessment, such as nasal endoscopy and imaging (eg, computerized tomography scanning), as well as attention to additional outcome measures (eg, the measurement of sense of smell). Within clinical trial design, there are important questions to be considered in relationship to the therapeutic intervention. Should this be given topically or systemically? What are the appropriate timing and frequency of medication? Does the disease itself modify the treatment efficacy, and does combination therapy afford better clinical outcome than single-modality therapy? These issues are discussed, and the influences of current therapies on objective outcome measures in allergic rhinitis are reviewed.