Allergic Rhinitis

Allergic rhinitis (hay fever} is a common condition that is characterized by inflammation of the mucous membrane lining the nose due to allergy to pollen, dust, or other airborne substances. Allergic rhinitis causes sneezing, a runny nose, nasal congestion, and, in most cases, watering eyes. The eyes, soft palate, and ears may also itch. The eyes may also be affected by conjunctivitis, making them red and sore.

Causes 

In some people, the inhalation of particles of certain harmless substances, known as allergens, provokes an exaggerated response by the immune system, which forms antibodies against them. These allergens also trigger the release of histamine and other chemicals that cause inflammation and fluid production in the linings of the nose and nasal sinuses (air cavities around the nose).

Allergens that cause allergic rhinitis include tree, grass, and weed pollens; moulds; animal skin scales, hair, or feathers; house dust; and house dust mites.

Seasonal allergic rhinitis is pollen-induced and is commonly known as hay fever. Tree pollens are most prevalent in spring, grass pollens in summer, and weed pollens in summer and autumn. Sufferers are worst affected during hot and windy weather, especially in heavily vegetated, low-lying areas.

People affected by household allergens, such as dust, tend to have less severe symptoms but are affected throughout the year, a condition that is known as perennial rhinitis.

Prevention and treatment

Antihistamine drugs and topical cortico-steroid drugs are used to treat mild attacks of allergic rhinitis. The drug sodium cromoglicate, if inhaled regularly throughout the pollen season, may help to prevent attacks by blocking the allergic response. Long-term relief of symptoms can sometimes follow desensitization to an allergen by a course of injections (see hyposensitization).

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Rhinitis

Allergic rhinitis - technical

Allergic rhinitis in more detail - technical

Essentials

Allergic rhinitis affects more than 20% of the population of Westernized countries and has a significant impact on quality of life and school/work performance.

Aetiology and clinical features—important environmental factors include tree and grass pollens (seasonal allergic rhinitis); house dust mite and domestic pets, most often cats (perennial allergic rhinitis); and a variety of occupational exposures (occupational rhinitis). Many genetic loci confer susceptibility. Immediate symptoms (itching, sneezing, and watery nasal discharge) occur as a consequence of allergen cross-linking adjacent IgE molecules on the surface of mast cells in the nasal mucosa, resulting in the release of histamine and tryptase, and the generation of bradykinin.

Diagnosis and classification—diagnosis is usually straightforward and based on the history, examination and (when indicated) the results of skin prick tests and/or serum allergen-specific IgE levels. Classification is according to the severity and duration of symptoms as defined by ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines, which describe four categories of disease: (1) mild intermittent, (2) moderate/severe intermittent, (3) mild persistent, and (4) moderate/severe persistent. Differential diagnosis and management of more complex cases are helped by flexible or rigid nasal endoscopy and CT of the nose and paranasal sinuses.

Management—allergen avoidance, topical intranasal corticosteroids, and nonsedating oral antihistamines are the mainstay of treatment and are effective and safe. Treatment failure often results from poor compliance or inadequate technique in use of nasal sprays. Allergen injection immunotherapy, which has been shown to induce long-term disease remission, is indicated in patients with severe seasonal allergic rhinitis who fail to respond to usual measures. Rhinitis is often accompanied by significant comorbidities that include conjunctivitis, sinusitis, otitis media, and bronchial asthma: these require separate recognition and treatment.

Introduction

Rhinitis means inflammation of the nasal mucosa: in clinical terms it may be defined as symptoms of nasal itching, sneezing, discharge, or blockage, that occur for more than 1 h on most days.

The lining of the nose and paranasal sinuses is in continuity with the lower respiratory tract such that diseases of the upper and lower airways frequently coexist. The World Health Organization position paper ‘Allergic Rhinitis and its Impact on Asthma’ (ARIA) recognized this association and provided a classification of the disease based on the severity and duration of symptoms as a basis for the modern management of allergic rhinitis. In this section a historical perspective and the aetiology, epidemiology, and pathogenesis of allergic rhinitis are described, followed by practical guidelines for the diagnosis and management of the condition. Finally, immunotherapy (desensitization), including novel approaches are discussed.

Historical perspective

The term ‘hay fever’ was originally coined by John Bostock in 1819. It is a misnomer, since the disease is not caused by hay and there is no fever. Nonetheless, the term highlighted the seasonality of the disease ‘being associated with the effluvium of hay’ and the association of severe hay fever with constitutional upset. William Gordon in 1829 referred to “the aroma emitted by the flowers of grass…”, whereas Elliotson in 1831 considered “… it [hay fever] to depend upon the flower of grass and probably the pollen”. Charles Blackley, a physician in Manchester, referred in 1873 to hay fever (catarrhus aestivus) as “an aristocratic disease … rarely, if ever, met with but among the educated”, and measured pollen counts in the air and related them to the intensity of hay fever symptoms. He also reproduced the disease in himself by experimental challenge with grass pollen, a technique still widely used today to investigate pathogenesis and to test novel treatment approaches. In 1911 Noon and Freeman published their classic paper on desensitization for hay fever, and William Frankland, who was a student of Freeman at St Mary’s Hospital, London, published the first randomized controlled trial of desensitization for hay fever in the same journal in 1958 and continues to practice allergy in 2010.

Aetiology

Environmental factors

Seasonal allergic rhinitis

Pollens of importance include tree pollens in the spring and grass pollens during the summer. Weed pollens and mould spores predominate in the latter part of the summer and early autumn. Grass pollen counts above 50/m3 are considered high and are the threshold level at which most hay fever sufferers experience symptoms.

Perennial allergic rhinitis

By far the commonest cause of perennial allergic symptoms are house dust mites (Dermatophagoides pteronyssinus, D. farinae, and Euroglyphus maynei). These are found in almost every home, where they live in the dust that accumulates in carpets, bedding, fabrics, and furniture. They live on shed human skin scales and thrive in temperatures of between 15 and 20° C and a relative humidity of 45 to 65%, conditions which are typical of many modern centrally heated homes. The major allergen of the house dust mite (Der p1) is a digestive enzyme (a cysteine protease) present in the gut and excreted in high concentrations in the mite faeces.

Food allergy is unusual as a cause of rhinitis in the absence of other organ involvement. However, rhinitis may be one component of IgE-mediated food-induced symptoms commonly due to egg, milk, and nuts in children and to nuts, fish, shellfish, and fruit in adults. Preservatives such as tartrazine, benzoates, and sulphites may provoke symptoms of rhinitis. Important drugs that can trigger rhinitis include β-blockers, aspirin, and (occasionally) angiotensin converting enzyme (ACE) inhibitors.Domestic pets are the second important cause of perennial allergy, relevant in up to 40% of children with asthma and/or rhinitis. The major allergen (Fel d1) is a salivary protein that is preened on to the fur and released on very small particles (<2.5 µm diameter) which remain airborne for many hours, explaining why a sensitized person can experience symptoms almost immediately upon entering a home containing a cat, without being directly exposed to the animal. Dog allergens are less well characterized (Can f1). Cockroaches have been described as a cause of perennial allergic symptoms, particularly in inner-city areas.

Occupational rhinitis

Occupational rhinitis refers to rhinitis caused by an agent inhaled in the workplace. Like other causes of seasonal and perennial rhinitis, occupational rhinitis may also be associated with bronchial asthma. Occupations at risk include laboratory animal workers (rats, guinea pigs, mice), bakers (flour, grain mites), agricultural workers (cows, pollens, fungal spores), electronic solderers (colophony), and health workers and other users of rubber gloves (latex).

Genetic influences

Atopy (the predisposition to develop allergic disorders as defined by a positive skin prick test or raised IgE antibody level to one or more common allergens) and allergic diseases such as hay fever and asthma occur as a complex interaction between genetic and environmental factors. Twin studies in which a higher concordance rate of atopy and allergic diseases is found in monozygotic twins compared to dizygotic twins provides unequivocal evidence of genetic influences.

Candidate gene approaches (which study a narrow region of the genome around a suspected gene with highly polymorphic markers) have been difficult to interpret because of variability in the definition of clinical phenotypes within atopy and allergy. Nonetheless, multiple genetic loci have been identified, including the high-affinity IgE receptor β-chain (localized on chromosome 11q), and the interleukins IL-4, IL-3, IL-5, IL-9, IL-13, the β-glucocorticoid receptor, and leukotriene C4 (LTC4) synthase (all colocalized to chromosome 5q). All of these genes have biological functions consistent with a role in pathogenesis of allergic disorders.

With the completion of the Human Genome Project, the more usual approach now and in future will be to list all of the genes localized to the chromosomal region where a linkage marker has been identified. For example, a recent study identified strong linkage between asthma and bronchial hyperresponsiveness with the gene for ADAM-33, a cell surface protease that is part of the matrix metalloproteinase family, considered important in remodelling responses in the basement membrane to damaged epithelium and airway smooth muscle.

Epidemiology

Recent estimates based on community surveys in western Europe have suggested that more than 20% of the population have perennial and/or seasonal allergic rhinitis. The burden that this places on medical services is increasing: in the United Kingdom in 1955–56 there were 5.1 consultations with general practitioners for hay fever per 1000 population per year; in 1981–82 this had increased to 19.8. A recent telephone-based community survey in 6 European countries gave an estimated mean prevalence of allergic rhinitis of 23%.

The increased prevalence of hay fever in countries with a ‘Westernized’ lifestyle, together with the known increased prevalence associated with small sibships, has given rise to the ‘hygiene hypothesis’ which implies that reduced exposure to bacterial pathogens may be the basis of the modern epidemic of allergic disorders. These observations tie in with Blackley’s recognition of hay fever as a disease more common in the privileged classes over 130 years ago.

Pathogenesis

Immediate symptoms of allergic rhinitis occur as a consequence of allergen cross-linking adjacent IgE molecules on the surface of mast cells in the nasal mucosa (in Coombs’ classification, type I, immediate hypersensitivity). This results in the release of granule-derived mediators, including histamine and tryptase, and the generation of bradykinin. IgE-dependent activation of mast cells also results in the release of newly formed membrane-associated mediators derived from arachidonic acid associated with the membrane lipid, including LTC4, LTD4, LTE4 and prostaglandin D2.

In patients with allergic rhinitis, eosinophils, basophils, and T lymphocytes are prominent in biopsies of the nasal mucosa. The mechanisms of selective localization of inflammatory/effector cells to allergic tissue sites is currently under investigation: the chemokine receptors (CCR3 and CCR4) and their ligands—eotaxin monocyte derived chemokine (MDC) and thymocyte associated and released chemokine (TARC)—may be particularly important, thereby representing a potential target for therapy. Cytokines released predominantly from T lymphocytes—but also from mast cells, eosinophils and other cell types—are known to be critically important in allergic inflammation. The biological properties of Th2 cytokines are also consistent with their involvement in allergic rhinitis, and increases in cells expressing these cytokines have been detected in the nasal mucosa during the ‘late’ nasal responses that occur in sensitized subjects between 6 and 24 h following experimental nasal provocation with allergen. Allergen-immunotherapy has been shown to alter the Th2/Th1 balance in favour of Th1 responses, and a distinct population of antigen-specific regulatory T cells are also detectable following immunotherapy. These down-regulate Th2 responses directly by mechanisms involving cell–cell contact and by production of the inhibitory cytokines IL-10 and TGFβ.

Clinical diagnosis

The diagnosis of allergic rhinitis is usually straightforward, but the differential diagnosis should be considered in every case: frequently more than one cause coexists.

History

A careful history is essential both to establish the diagnosis of rhinitis and to assess the severity of symptoms. An allergic aetiology is suggested by dominant itching, sneezing, and watery nasal discharge. Associated eye or chest symptoms (asthma) also point to an allergic cause, and a history of potential allergic triggers should always be sought. However, in addition to provoking immediate nasal symptoms, allergen may also cause late symptoms several hours after exposure, and these may not be recognized as being related.

A history of potential allergic triggers includes enquiry into the seasonality of symptoms and whether symptoms are work-related (i.e. do they occur at work or in the evening following work, with improvement at weekends and during holiday periods). The home environment, including the presence of domestic pets, birds, fitted carpets, central heating, and the use of blankets on beds should be established. A personal or family history of atopy is extremely common in patients with allergic rhinitis.

There are many alternative causes of rhinitic symptoms. It is common for there to be more than one cause, and important to consider the differential diagnosis (Bullet list 1). The presence of facial pain, fever, systemic upset, and mucopurulent discharge suggests infection. Nasal obstruction, which alternates with the nasal cycle, is common to both allergic and infective causes. Nasal crusting and/or bleeding may occur in granulomatous disorders, atrophic rhinitis, or (rarely) tumours (particularly if associated with persistent unilateral symptoms). Impaired taste and/or smell may occur with many forms of rhinitis, but is particularly common with nasal polyposis and may occasionally follow trauma (olfactory nerve damage).

The presence of infertility and recurrent respiratory infections (including bronchiectasis) should raise the possibility of mucus abnormalities (Young’s syndrome or cystic fibrosis) or ciliary dysfunction (primary ciliary dyskinesia, Kartagener’s syndrome). Recurrent respiratory infections or a history of chronic rhinosinusitis should also raise the possibility of immune deficiency disorders including hypogammaglobulinaemia and AIDS.

Enquiry regarding associated chest disease is important. Rhinitis and asthma frequently coexist and recognition and appropriate treatment of rhinitis may improve asthma control. Similarly, allergic conjunctivitis may be particularly bothersome in patients with seasonal disease and requires recognition and treatment. The efficacy, frequency, and regularity of previous treatments should also be considered, as should the patient’s perception of possible side effects of treatment, a frequently missed cause of poor compliance.Hormonal imbalance (premenstrual symptoms, pregnancy, hypothyroidism, or acromegaly) may be associated with rhinitis. A history of trauma or previous nasal surgery should be sought.

Examination

Local examination may be performed with a head mirror and speculum or an auroscope. Allergic rhinitis is accompanied by a pale bluish ‘boggy’ appearance of the nasal mucosa only if the patient has current symptoms. A red inflamed appearance with pus suggests an infective cause. A granular appearance with fine pale nodules is diagnostic of sarcoidosis. Enlarged turbinates may be confused with polyps by the unwary. If doubt exists, further examination with a rigid and/or flexible endoscope should be performed. The identification of structural abnormalities such as polyps, deflected nasal septum, or enlarged turbinates is important: surgical treatment may be indicated (a major advance being the development of minimally invasive endoscopic sinus surgery).

Examination of the nose should also include tests of smell and examination of the ears, eyes, mouth, and throat. Examination of the chest and a general examination should be performed when indicated in view of the common association of nasal disease with lower respiratory and systemic conditions.

Investigations

Skin prick tests

In the presence of a clear history, particularly of seasonal hay fever symptoms, skin prick testing is not essential. However, skin prick tests are useful for several reasons (Bullet list 2). They should only be interpreted in conjunction with the clinical history, and not performed when the patient is taking antihistamines, if ‘dermographism’ (wealing in response to pressure) is present, or in the presence of severe eczema. In these circumstances measurement of serum IgE antibodies by radioallergosorbent test (RAST) or enzyme-linked immunosorbent assay (ELISA) is indicated.

Bullet list 1 Causes of rhinitis

  • Allergic
    • • Seasonal (tree or grass pollens)
    • • Perennial (house dust mite, domestic pets)
    • • Occupational (latex, laboratory animals, antibiotics, etc.)
  • Nonallergic
    • • Infective (acute, chronic)
    • • Autonomic
    • • Hormonal (premenstrual, pregnancy, hypothyroidism)
    • • Drugs (aspirin, β-blockers)
    • • Mucociliary abnormalities (Kartagener’s, Young’s syndromes)
    • • Immunodeficiency syndromes (congenital and acquired, including HIV)
    • • Atrophic
    • • Idiopathic
  • Differential diagnosis
    • • Structural (polyps, deflected nasal septum, etc.)
    • • Connective tissue disorders
    • • Granulomatous disorders (sarcoid, Wegener’s)
    • • Tumours (benign, malignant)
    • • Cerebrospinal fluid rhinorrhoea (secondary to trauma or surgery)

Bullet list 2  Advantages of skin prick tests

  • They diagnose atopy—the underlying predisposition to develop allergic disorders
  • They provide helpful supportive evidence (positive or negative) for the clinical history
  • They are essential when potentially expensive and time-consuming environmental control measures, the removal of a family pet, or a change of occupation are involved
  • They have educational value, providing a clear illustration to the patient and reinforcing verbal advice

A useful basic skin prick testing kit should include the following:

  • a positive control (histamine 10 mg/ml)
  • a negative control (allergen diluent solution)
  • house dust mite (D. pteronyssinus)
  • grass pollen
  • cat fur
  • Aspergillus fumigatus

Skin prick tests should be performed with a sterile 23-gauge needle or lancet, which is lightly inserted through the epidermis without inducing bleeding. Responses are recorded as the mean weal diameter at 15 min, a positive test being defined as a weal diameter 3 mm or more greater than that of the negative control test.

Treatment

Treatment for allergic rhinitis involves the avoidance of provoking allergens where possible and the use of topical corticosteroids and H1 selective antihistamines. Allergen immunotherapy has a place in patients who do not respond to these measures. The approach is summarized in Bullet list 3 and summarized in relation to the ARIA classification, which emphasize that rhinitis and asthma are associated and that patients with one condition often also have the other.

Allergen avoidance

It is impossible to avoid pollens, although sensible advice includes wearing sunglasses and keeping car windows tightly shut. All windows should be kept closed, particularly in high buildings. Walking in parks and wide open spaces should be avoided, particularly during the late afternoon or evening when pollen counts are highest. A holiday by the sea or abroad during the peak pollen season may be helpful.

House dust mite control and avoidance measures should be considered in sensitive individuals with disease. Although some success has been achieved in children, the value of mite avoidance measures in adults, such as a single intervention with mite-proof bedding, has been questioned. Further studies involving more effective and multiple interventions are needed, including—in addition to covers for the pillow, duvet and mattress—restriction of soft toys, which should be washable, changing to hardwood, vinyl, or cork flooring, and thorough vacuum cleaning and damp-dusting at least once weekly. There is no firm evidence to recommend the additional use of air conditioners, air ionizers, or acaracides.

Bullet list 3 Treatment of allergic rhinitis

  • Allergen avoidance (house dust mite, animal danders, occupational causes)
  • Nonsedative antihistamines, either alone or in combination with topical corticosteroids
  • Topical corticosteroids; check technique and place emphasis on regular use even when symptoms are absent
  • Sodium cromoglicate or nedocromil is useful for allergic eye symptoms
  • Immunotherapy is helpful in pollen-sensitive patients unresponsive to the above measures
  • If the patient fails to respond, review the diagnosis and treat any associated conditions (e.g. antibiotics for infection, surgery for structural problems)

Where animal exposure is relevant, there is frequent resistance to advice to remove a family pet. However, patients can be advised to avoid replacing animals, to confine them to the kitchen or outdoors where possible, and to avoid contact with them or with contaminated clothing.

Pharmacotherapy

The availability of potent specific histamine H1 receptor antagonists with a low potential for anticholinergic side effects and a low sedative profile has been a major advance. Antihistamines are particularly effective for sneezing, itching, and rhinorrhoea, but unlike topical corticosteroids they have less effect on nasal blockage. They are also effective for eye and throat symptoms.

A rare but important complication of older antihistamines, including terfenadine and astemizole, is prolongation of the QT interval on the ECG. This only occurs when doses in excess of those recommended are employed, or in the presence of hepatic impairment or concomitant use of ketoconazole or erythromycin, both of which modify the hepatic metabolism of terfenadine. Modern antihistamines including acrivastine, loratadine, desloratidine, cetirizine, L-cetirizine, fexofenadine, and mizolastine are effective H1 antihistamines with an extremely low (or absent) potential for cardiac side effects. H1-selective antihistamines can also be given as a topical nasal spray (levocabastine, azelastine). Antihistamines should be avoided when possible during pregnancy, particularly during the first trimester. If antihistamines are considered essential then recent guidelines from the United States Food and Drug Administration include the use of loratidine and cetirizine.

The topical anticholinergic agent ipratropium bromide is a potent inhibitor of glandular secretion and may be effective where watery nasal discharge is the dominant symptom, uncontrolled by the measures described above.Topical corticosteroids are highly effective in most hay fever sufferers, with preparations including beclomethasone, budesonide, fluticasone, triamcinolone, and mometasone. Aqueous formulations are better tolerated and have a better local distribution in the nose. Treatment should begin before the hay fever season for maximal effect, and the importance of regular treatment, even when symptoms are absent, should be emphasized. Side effects are minor. Systemic effects are virtually absent at conventional doses, but caution should be exercised in children, particularly those receiving additional corticosteroids by other routes (e.g. for associated asthma and/or eczema).

Sodium cromogliycate is available as a topical nasal spray for use four times daily. It is less effective than topical corticosteroids. Topical cromoglicate eye drops are effective for allergic eye symptoms in most patients. Topical nedocromil sodium eye drops have the advantage of a longer duration of action, allowing twice daily administration.

In the few patients whose symptoms are not otherwise controlled, there is a place for a short course of prednisolone (20 mg daily for 5 days). This approach may unblock the nose, thereby improving access for topical corticosteroids, which may then be more effective.

Topical decongestants (oxymetazoline) are effective in treating nasal blockage, although they should only be used for short periods (no more than 2 weeks) in view of the risk of tachyphylaxis and rebound persistent nasal blockage (so-called rhinitis medicamentosa).

Allergen immunotherapy

Immunotherapy (desensitization) is an alternative treatment option in patients with severe summer hay fever unresponsive to topical corticosteroids and antihistamines, and in those reluctant to take long-term medication. This involves the subcutaneous injection of increasing concentrations of allergen (standardized pollen extract) at weekly intervals for 6 to 12 weeks, followed by monthly injections of a maintenance dose for 3 to 5 years. It should only be given by those who are properly trained, with adrenaline (epinephrine) and facilities for cardiopulmonary resuscitation immediately available, and patients should be kept under medical observation for at least 60 min following injections.

Recent controlled studies have confirmed the efficacy of immunotherapy, particularly for patients with summer hay fever induced by grass pollen. It is less effective in those with perennial rhinitis and asthma, where the disease is frequently heterogeneous with multiple allergic sensitivities and/or other causes of ongoing symptoms. The risk/benefit ratio is less favourable in patients with chronic bronchial asthma, in whom the risks of systemic adverse reactions are greater. Recent data suggests that pollen immunotherapy may confer long-term benefits including prolonged disease remission, prevention of onset of new sensitizations and—in one controlled trial—a threefold reduction in the risk of progression of rhinitis to asthma in children with pollen-induced rhinitis that persisted for 10 years after initiating treatment. The data suggest that allergen immunotherapy, unlike pharmacotherapy, has the potential to modify the course of the disease.

Recent data support the sublingual route as an effective and safe form of immunotherapy suitable for home use, although the initial prescription and first dose should be administered by physicians trained in the diagnosis and treatment of allergic disorders. However, whether sublingual immunotherapy is as effective as the injection route or confers long-term benefits is not known. Recent studies suggest that daily use of grass pollen sublingual tablets may be as effective as the injection route and also confer long-term benefit.

Future prospects for immunotherapy include the use of adjuvants (lipopolysaccharide derivatives, bacterial CpG-containing DNA oligonucleotides) combined with conventional allergen extracts for subcutaneous immunotherapy, and the use of recombinant natural allergens and their mutated hypoallergenic variants. Low-molecular-weight allergen peptides have the potential to modify human T-cell responses with clinical benefit without the potential for IgE cross-linking and attendant risk of serious IgE-mediated side-effects. All of these approaches are currently at the stage of phase II–III clinical trials, their aim being to improve safety while preserving efficacy and long-term benefits.

Further reading

 
 
Durham SR (2008). Sublingual immunotherapy: what have we learnt from the ‘Big Trials’, Curr Opin Allergy Clin Immunol, 8, 577–84. 
 
Durham SR et al. (2010). Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol.
 
James LK, Durham SR. (2008). Update on mechanisms of allergen injection immunotherapy, Clin Exp Allergy, 38, 1074–88. 

Till SJ, et al. (2004). Mechanisms of immunotherapy. J Allergy Clin Immunol, 113, 1025–34.