Dr Matthew J Doyle MBBS MRCP(UK) FRCGP Indigo Medical, Jersey, Channel Islands:
Can you explain the pathophysiology of hayfever/allergic rhinitis?
Allergic rhinitis (AR), commonly referred to as hayfever (90% of patients in the UK are triggered by
grass pollen) is increasingly common, with up to 20% of the European population affected.1 Potential
allergens are wide-ranging and include pollens, house dust mite (HDM) and household pets. Patients may
be sensitive to only one allergen or several, giving variable peaks of symptoms throughout the year.
For a person to start reacting to an allergen, they must pass through three discrete stages; exposure,
sensitisation and subsequently allergy. A patient may remain sensitised to an allergen for many years,
showing positive reactions on skin-prick testing and abnormal levels of specific-IgE on blood testing
without demonstrating allergic symptoms when exposed to the allergen. An example of this in practice is
a young adult, growing up in a house with household pets such as cats and not showing any symptoms.
If that young adult leaves the household for an extended period (for example, going away to university
for three to four months), they are no longer experiencing daily exposure to the allergen. On their return,
they may find that the household pet now causes symptoms where before there were none. This is an
example of sensitisation transforming into an allergic response. This seems to be due to a skewing of
the immune response from a Th-1 (T helper cell type 1) to Th-2 pattern with the involvement of IL-2
(interkeukin 4) production. The interplay of this response, also involving T regulatory cells, is complex
and not clearly understood.
The mechanism of AR is well understood as an immediate-type allergic reaction, mediated via
the antigen or allergen cross-linking IgE attached to mast cells causing degranulation (Figure 1). IgE
antibodies, specific to the allergen, are carried on the surface of mast cells. When IgE specific to the
allergen cross-links in the presence of that particular allergen, it causes rapid degranulation, releasing
histamine and other inflammatory mediators responsible for the immediate symptoms. The release of
substances such as IL-4 (interleukin 4) can trigger a more chronic response. IgE receptors are also present
on other cells, such as B and T-lymphocytes, platelets and eosinophils, although these have a lower
affinity for IgE than the mast cell receptor.
What conservative measures would you recommend?
Generally, the first advice to patients should be for allergen avoidance wherever possible. As an example, simple advice for someone allergic to grass pollen should be knowledge of the season and steps they can take to limit exposure:
- Pollens often rise with the warmer air in the mornings and come down again in the evenings
- Staying indoors and closing windows at these times can be helpful
- Avoiding freshly cut grass or mowing lawns
- Keeping windows closed
during mornings and evenings
- Recirculate air in cars with windows closed when driving
- Using balm or petroleum jelly around the nostrils can help
- Do not dry clothes outside
when the pollen count is high.
Avoidance of the house dust mite is more difficult. There are many techniques sufferers can
employ to reduce exposure, but total avoidance, as with pollens, is impossible.
- Using a clean towel over the pillow when sleeping; pillows often contain a high level of HDM
- Where possible, removing soft furnishings from rooms: replacing carpets with wood or tiled flooring, replacing curtains with blinds etc.
- Regular vacuuming, ideally using a high filtration vacuum cleaner
- Damp wiping surfaces regularly
- Washing bedding frequently at temperatures above 60 degrees Celsius
- Using allergen-proof covers on bedding etc.
As mentioned in the previous section, adherence to such measures is challenging in a busy household, and families or patients should be reassured that even some of these measures can help reduce exposure.
Allergy UK has helpful factsheets for patients on its website (https://www.allergyuk.org/information-and-advice/
conditions-and-symptoms/12-asthma-and-respiratory-allergy) which can be downloaded and printed out as required.
Can you offer any non-pharmacological advice to relieve symptoms?
Saline nasal sprays and sinus rinses are easily available from pharmacies and online. They use a saline solution to douche the nasal passages and are excellent for short-term relief from congestion. For milder nasal symptoms sprays are generally preferred. Additional products available include red light treatment probes for the nostrils and small canisters of CO2 (Serenz), which can help clear nasal passages. Treatment with photodynamic therapy has been described in the literature for several decades and has shown some evidence in improving symptoms and quality of life scores. It has an immunosuppressive effect in conditions such as atopic dermatitis and psoriasis. Unfortunately, most studies on its use in AR performed no objective measurements of improvement in nasal blockage or airflow and so it is difficult to recommend these treatments with a strong evidence base.2 If the allergen is year-round and indoors then avoidance is more challenging. The house dust mite is present in all houses and is impossible to completely eradicate. Measures can be taken to reduce exposure, such as allergen covers on bedding, removing carpets and curtains in bedrooms and frequent vacuuming, but these can be difficult to maintain in the long-term.
Is there any relationship to atopy and asthma, and how can this be explained?
There is an important relationship between atopy and some forms of asthma and particularly between asthma and AR. It has been shown that around 80% of patients with asthma have AR3 and that children who have AR are more likely to subsequently be diagnosed with asthma. Correlations have been shown between nasal eosinophilia and bronchial hyper-reactivity in children with both asthma and allergic rhinitis suggesting that upper airway
exposure to an allergen can lead to lower airway reactions. More importantly, patients with asthma are substantially less likely to experience an unplanned emergency admission for asthma if they are receiving treatment for their AR.6 In a study published in 2005 it was noted that there was a significant difference in admission rates between children with asthma alone and those with asthma and allergic rhinitis. The former group of 7,643 children had an admission rate of 0.5% against a rate of 1.4% in the 1,879 children in the latter group. Both the upper and lower airways share a similar columnar epithelium, pseudostratified (a term describing the appearance of layers of cells when in fact all are attached to the basement membrane) and ciliated with goblet cells. In atopic asthma and AR the response to allergen in a sensitive individual is similar, with both an immediate and latephase response. It should be noted that not all asthmatics have allergic triggers. Increasingly, multiple phenotypes (or endotypes, a term encompassing not just the variation of physical disease but also the pathological variations seen) of asthma are being described. It is primarily in the atopic patient that the relationship of upper and lower airway should be recognised, the ‘one airway, one disease’ concept.8
If a patient has co-existing asthma, should we consider a leukotriene antagonist?
The current British National Formulary (BNF) indicates the use of leukotriene receptor antagonists (LTRAs) for exercise-induced asthma with concomitant rhinitis, and in some guidance LTRAs are suggested as add-on treatments for patients with allergic rhinitis if intranasal steroids (INS) and antihistamines have been ineffective in controlling symptoms. The guidance produced by the British Society of Allergy and Clinical Immunology (BSACI) states that LTRAs ‘may have a place in patients with seasonal AR and asthma’. There appears to be a variable and individual response by patients treated with LTRAs suggestive of a polymorphism so that in clinical practice some patients respond far better than others. The current NICE CKS summary for AR does not recommend LTRAs as a first-line treatment, stating that there is a lack of evidence for their effectiveness. They have been shown to be less effective than INS in reducing symptoms and to be similar in effectiveness to antihistamines. A study in 2001 did suggest benefit of LTRAs12 in combination with antihistamine above INS, though this was short-term. The bottom line appears to be that these drugs should only be considered if other more effective treatments are not tolerated or have failed, and should not be considered a first-line treatment.
Should patients with asthma and hayfever take an antihistamine for the duration of the pollen season even if they are not especially symptomatic with their hayfever? And if so, for how long?
Antihistamines are generally more effective for AR if taken regularly rather than on an ‘as required’ basis.13 Generally, intranasal antihistamines (azelastine) tend to be more effective for nasal symptoms with a faster mechanism of onset compared to oral antihistamines.14 However, many patients find the taste unpleasant and discontinue treatment accordingly. Oral antihistamines are also more effective for symptoms of allergic conjunctivitis. Some experts (American College of Allergy, Asthma and Immunology (ACAAI) http://acaai.org/allergies/types/hay-fever-rhinitis) advocate starting regular antihistamines at least a week prior to an identified pollen season to start blocking the effects of histamine before symptoms begin. By taking an effective and detailed history, a pollen season may be identified and patients advised accordingly to start before onset and continue treatment throughout the season. Skin prick testing (SPT) or specific-IgE blood testing can be used to confirm a suspected allergen.
Is there any evidence that fexofenadine is more effective than other antihistamines?
Not really. Most second generation antihistamines are equally effective for patients. Though they have a lesser tendency than first-generation agents to cross the blood-brain barrier and cause drowsiness, some patients do report such symptoms even with a secondgeneration agent. A review of the effectiveness of fexofenadine, desloratidine and levocetirizine in 2009 found all three drugs demonstrated equal effectiveness. Cetirizine was found to have a greater benefit in symptoms when compared to fexofenadine and have a longer duration of effect when compared at a dose of 10mg with fexofenadine 180mg. Fexofenadine has been shown to be less sedating than cetirizine in a double-blind, placebo controlled study, so may be an appropriate choice for patients who experience sedation with other second-generation agents. As some patients report different benefits and side effects with individual antihistamines, it is often worth trialling alternate agents if symptom control is poor.
Should patients use a saline douche as well as a steroid nasal spray?
Saline douches (sinus rinses) and saline nasal sprays are safe and well tolerated treatments. They have been shown to reduce symptoms in both children18 and adults19 by helping clear mucus from the nasal cavity, and should be recommended to patients as non-pharmacological therapies. Saline eye drops have also been shown to improve the symptoms of allergic conjunctivitis20 and can be safely suggested to patients.
What are the common side effects of antihistamines?
Antihistamines are generally safe and well-tolerated drugs, available widely without prescription. The primary
side effect noted by patients tends to be sedation or drowsiness. Generally, first-generation antihistamines, such as chlorphenamine, should not be recommended to patients due to their sedating effects as they have been shown to reduce academic and work performance.21 These drugs are more able to cross the blood-brain barrier than second-generation antihistamines such as cetirizine, desloratidine and fexofenadine. Some patients report other side effects with antihistamines such as dry mouth and headache. Antihistamine nasal sprays, effective as rescue therapy because of their rapid onset of action, can cause a bitter taste which may not be tolerated.
Recent press articles have focussed on the link between dementia and regular use of antihistamines. This link was suggested in a prospective study of 3,433 participants aged over 65.22 It was noted that patients taking antihistamines with anticholinergic effects (e.g chlorphenamine) at standard dosing daily for more than three years had an increased risk of dementia. No effect was seen on lower levels of dosing or intermittent treatment. It should be noted that secondgeneration antihistamines such as fexofenadine or cetirizine have no anticholinergic action and so patients can be reassured regarding these drugs.
Which patients are eligible for immunotherapy and what does this entail?
Immunotherapy is given either sublingually (SLIT) or subcutaneously (SCIT) and involves the repeated administration of allergen in order to reduce symptoms. It is highly effective and the only potentially long-term treatment for allergic disease. Whilst not curative, immunotherapy has been shown to give long-term benefits to patients and has been shown to reduce development of asthma in children with AR. Immunotherapy was first described in 1911 by Noon and Freeman at St Marys Hospital in London where they noticed that intradermal injections of pollen extract could improve symptoms in susceptible patients.25 They also saw that higher doses could precipitate severe allergic reactions. Immunotherapy has been increasingly studied over the subsequent years and there is robust evidence for benefit and long-term effectivity. Studies have shown a 30-50% reduction in symptoms for seasonal AR and 20-40% reduction in use of rescue medication. The pathological mechanism of immunotherapy is complex, but appears to be due to an increase in ‘hyporesponsiveness’ to the allergen by increasing levels of IL-10 (interleukin 10) and IgG4 leading to reduced levels of specific-IgE and a skewing from a dominant Th1 response to Th2.
Grazax is a sublingual immunotherapy, licenced in the UK for the treatment of grass pollen allergy. Treatment consists of a daily tablet, started four months before the onset of the pollen season and continued for thirty-six months. There is good evidence for both safety and effectivity. Immunotherapy should be offered to patients in whom standard treatment repeatedly fails or is not tolerated. Chronic asthma is a contraindication to such treatment in the UK,8 and treatment should only be recommended and provided by a specialist allergy service.
Do people grow out of allergic rhinitis?
Just as allergies appear to start at any age, the prognosis for growing out of the allergy is similarly variable. In some cases, repeated exposure appears to induce a more ‘hyporesponsive’ immune system over time and in others the allergy continues for life. It is impossible to predict whether an allergic response will diminish over time in an individual patient so the focus should always be on the most effective treatment and control of symptoms.