Asthma Management Handbook

Managing allergic rhinitis in children with asthma

Recommendations

In school-aged children with persistent or moderate-to-severe intermittent symptoms, prescribe or recommend an intranasal corticosteroid (even if the child is already using regular inhaled corticosteroids for asthma).

If symptoms do not improve significantly within 3–4 weeks:

  • review the diagnosis
  • check adherence and intranasal administration technique
  • consider allergy testing.

Figure. Management of allergic rhinitis in children under 12 years Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/107

How this recommendation was developed

Based on selected evidence

Based on a limited structured literature review or published systematic review, which identified the following relevant evidence:

  • Seidman et al, 201555
  • Bousquet et al, 200833
  • Brożek et al, 201017
  • Lohia et al, 20131
  • Bousquet et al, 20162
  • Wallace et al, 200831
  • Berger & Meltzer, 20153
  • Bachert & Maspero, 20114

In school-aged children with mild intermittent symptoms, consider starting treatment with an intranasal H1-antihistamine, second-generation (less sedating) oral H1-antihistamine or montelukast. Do not use sedating antihistamines.

Montelukast can be considered as an alternative to antihistamines in children with seasonal allergic rhinitis.

If symptoms do not improve significantly within 2–4 weeks, switch to an intranasal corticosteroid.

  • Advise parents about potential adverse psychiatric effects of montelukast

Figure. Management of allergic rhinitis in children under 12 years Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/107

How this recommendation was developed

Based on selected evidence

Based on a limited structured literature review or published systematic review, which identified the following relevant evidence:

  • Seidman et al, 201555
  • Bousquet et al, 200833
  • Brożek et al, 201017
  • Lohia et al, 20131
  • Bousquet et al, 20162
  • Wallace et al, 200831
  • Berger & Meltzer, 20153
  • Bachert & Maspero, 20114
  • Nasser et al, 20105

In preschool-aged children or children who will not tolerate intranasal medication, start treatment with a second-generation (less sedating) oral H1-antihistamine approved for use in this age‑group (e.g. cetirizine, desloratadine, fexofenadine, loratadine). Do not use sedating antihistamines.

Montelukast can be considered as an alternative to antihistamines.

If symptoms do not improve significantly within 2–4 weeks, switch to an intranasal corticosteroid if possible.

  • Advise parents about potential adverse psychiatric effects of montelukast

Figure. Management of allergic rhinitis in children under 12 years Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/107

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Provide an allergic rhinitis treatment plan.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).​

In children of any age in whom allergic rhinitis symptoms are uncontrolled despite regular use of intranasal corticosteroids, review the diagnosis and consider specialist referral.

Adenoid hypertrophy should be suspected in children who do not respond to treatment within 4 weeks.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

For children who are taking an inhaled corticosteroid for asthma and who have persistent allergic rhinitis symptoms despite treatment with an intranasal corticosteroid, consider adding montelukast.

  • Advise parents about potential adverse psychiatric effects of montelukast
How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

At each review, check adherence to medications and topical therapy technique, as for asthma.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Inspect nasal mucosa one month after starting treatment then every 6 months for improvement in symptoms, resolution of turbinate hypertrophy, and any evidence of local crusting or bleeding. Refer to an ear, nose and throat surgeon for review if symptoms do not improve and turbinate hypertrophy does not respond to medical intervention.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Consider specific allergen immunotherapy in children with allergic rhinitis who have a history of proven, clinically important sensitisation to a particular allergen that cannot feasibly be avoided and for which for specific allergen immunotherapy is available.

Note: Specific allergen immunotherapy should not be started in children with asthma unless asthma is stable. For those able to perform spirometry, this includes spirometry-demonstrated forced expiratory volume in 1 second (FEV1) greater than 80% predicted for subcutaneous immunotherapy and greater than 70% predicted for sublingual immunotherapy.

Note: Make sure parents understand that treatment must be long term (3–5 years), and understand the cost and risks of the treatment.

Note: TGA-approved indications for commercially available preparations vary according to age group. As at October 2017, the only product approved by TGA for use in children under 12 years is a mixed grass pollen preparation indicated for children over 5 years with allergic rhinitis.

How this recommendation was developed

Based on selected evidence

Based on a limited structured literature review or published systematic review, which identified the following relevant evidence:

  • Cox, 20166
  • Meadows et al, 20137
  • Durham et al, 20168
  • Passalacqua et al, 20149
  • Chelladurai et al, 201310
  • Brożek et al, 201017
  • Erekosima et al, 201411
  • Calderon et al, 201512
  • Radulovic et al, 201013
  • Canonica et al, 200914
  • Jacobsen et al, 200715
  • Pajno et al, 201716

Advise parents to provide a smoke-free environment for children with allergic rhinitis.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

More information

Links between allergic rhinitis and asthma

Prevalence, aetiology and symptoms

Asthma and allergic rhinitis frequently coexist. At least 75% of patients with asthma also have rhinitis, although estimates vary widely.17 Patients with asthma may have both allergic and non-allergic rhinitis.

Allergic rhinitis that starts early in life is usually due to a classical IgE hypersensitivity. Adult-onset asthma or inflammatory airway conditions typically have more complex causes. Chronic rhinosinusitis with nasal polyps is not a simple allergic condition and generally needs specialist care.18

Symptoms and signs of allergic rhinitis can be local (e.g. nasal discharge, congestion or itch), regional (e.g. effects on ears, eyes, throat or voice), and systemic (e.g. sleep disturbance and lethargy). Most people with allergic rhinitis experience nasal congestion or obstruction as the predominant symptom. Ocular symptoms (e.g. tearing and itch) in people with allergic rhinitis are usually due to coexisting allergic conjunctivitis.19

Patients may mistake symptoms of allergic rhinitis for asthma and vice versa. Allergic rhinitis is sometimes more easily recognised only after asthma has been stabilised.

Effects on asthma

Allergic rhinitis is an independent risk factor for developing asthma in children and adults.20, 21, 22, 23, 24 However, the use of antihistamines in children has not been shown to prevent them developing asthma.17

The presence of allergic rhinitis is associated with worse asthma control in children and adults.25, 26, 27, 28 The use of intranasal corticosteroids in patients with concommitant allergic rhinitis and asthma may improve asthma control in patients who are not already taking regular inhaled corticosteroids.1

Both rhinitis and asthma can be triggered by the same factors, whether allergic (e.g. house dust mite, pet allergens, pollen, cockroach) or non-specific (e.g. cold air, strong odours, environmental tobacco smoke).

Food allergies do not cause allergic rhinitis. Most people with allergic rhinitis are sensitised to multiple allergens (e.g. both pollens and house dust mite), so symptoms may be present throughout the year.

Pollens (e.g. grasses, weeds, trees) and moulds are typically seasonal allergens in southern regions, but can be perennial in tropical northern regions.18 However, ryegrass is not found in tropical regions (see Thunderstorm-triggered asthma).

Pollen calendars provide information on when airborne pollen levels are likely to be highest for particular plants.

Thunderstorm-triggered asthma

Seasonal allergic rhinitis, which in Australia is typically associated with sensitisation to perennial ryegrass (Lolium perenne), is an important risk factor for thunderstorm-triggered asthma.29

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Treatment of allergic rhinitis in children

 

Table. Overview of efficacy of allergic rhinitis medicines for specific symptoms Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/102

Intranasal corticosteroids

Intranasal corticosteroids are effective in reducing congestion, rhinorrhoea, sneezing and itching in school-aged children with allergic rhinitis.1, 17 However, there is weaker evidence to support their efficacy in children than in adults.17 There is limited evidence to guide the treatment of allergic rhinitis in preschool children.2

The addition of an oral H1-antihistamine or leukotriene receptor antagonist to an intranasal corticosteroid is generally no more effective than intranasal corticosteroid monotherapy.2

TGA-approved indications vary between age groups. Intranasal corticosteroids indicated for children aged under 12 years include fluticasone furoate (age 2 years and over), mometasone furoate (age 3 years and over), and budesonide (age 6 years and over).

Intranasal corticosteroids are well tolerated. Evidence from studies mainly in adults suggests that they do not cause atrophy of nasal epithelium.30 Intranasal corticosteroids are not generally associated with clinically significant systemic adverse effects in children when given in recommended doses.131 Studies in children evaluating effects on the hypothalamic-pituitary axis using morning cortisol concentrations, cosyntropin stimulation, and 24-hour urinary free cortisol excretion showed no adverse effects with ciclesonide, fluticasone propionate, fluticasone furoate, mometasone furoate, or triamcinolone acetonide.1 One knemometry study showed reduced lower leg growth rate in children using intranasal budesonide.1 In studies using stadiometry over 12 months, higher-than-recommended doses of intranasal beclomethasone dipropionate were associated with growth suppression, but fluticasone propionate and mometasone furoate showed no effects on growth compared with placebo.1

In children already taking inhaled corticosteroids, both the intranasal corticosteroid dose and the inhaled corticosteroid dose should be taken into account when calculating the total daily corticosteroid dose.

Oral antihistamines

Second-generation (less sedating) antihistamines (e.g. cetirizine, desloratadine, fexofenadine or loratadine) should be used in preference to older, more sedating antihistamines. Cetirizine is the most likely of the less sedating antihistamines to cause sedation, while fexofenadine and loratadine appear to be the least sedating.32

Less sedating oral H1-antihistamines are effective in managing allergic rhinitis symptoms of rhinorrhoea, sneezing, nasal itching and ocular symptoms,2, 4 including in preschool children. 2 They can provide adequate relief for some individuals when taken continuously or intermittently.1 Available agents appear to be equally effective.31

However, oral antihistamines are less effective than continuous intranasal corticosteroids, especially for nasal congestion.1, 33 The addition of oral antihistamines to intranasal corticosteroids has not been demonstrated to be an effective strategy in children.6

TGA-approved indications vary between age groups. Less sedating oral antihistamines indicated for children under 12 years include cetirizine (1 year and over), loratatidine (1 year and over), desloratadine (6 months and over), and fexofenadine (6 months and over).

Intranasal antihistamines

Intranasal antihistamines are at least equally effective as second-generation, less sedating oral H1-antihistamines for the treatment of allergic rhinitis, but are generally less effective than intranasal corticosteroids.17

Intranasal antihistamines are more effective than oral antihistamines for reducing nasal congestion.1 They have a rapid onset of action (15–30 minutes).1

Montelukast

Leukotriene receptor antagonists are no more effective than oral H1-antihistamines.17, 2 Montelukast is less effective than intranasal corticosteroid in the treatment of allergic rhinitis.1, 17 In most studies, adding montelukast to an intranasal corticosteroid was not more effective than intranasal corticosteroid alone.2

Montelukast is approved by TGA for the treatment of asthma in children over 2 years, and for the treatment of seasonal allergic rhinitis.

It is generally very well tolerated, but has been infrequently associated with neuropsychiatric adverse effects, including suicidal ideation, in children and young people.34, 35, 36, 37 A recent analysis of databases of adults and children taking montelukast suggests it is associated with nightmares (especially in children), depression, and aggression (especially in children).38 Allergic granulomatous angiitis has also been reported, but a causal relationship has not been established.38

The potential association of montelukast with behaviour-related adverse events should be mentioned to parents when commencing treatment, and treatment should be stopped if such adverse events are suspected.

Specific allergen immunotherapy

Specific allergen immunotherapy (desensitisation) is effective in reducing allergic rhinitis symptoms (see separate topic).

 

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Non-recommended medications for allergic rhinitis

Intranasal decongestants have a limited role in the management of allergic rhinitis because they should only be used for very short courses (up to 5 days maximum). Repeated or long-term use can cause rebound swelling of nasal mucosa (rhinitis medicamentosa), which can lead to dose escalation by patients, with a risk of atrophic rhinitis. Intranasal decongestants can be considered for a patient with severe nasal congestion to gain rapid relief of symptoms until the full effect of intranasal corticosteroids is achieved.

Oral decongestants (e.g. pseudoephedrine or phenylephrine) should not generally be used in the management of allergic rhinitis. They are indicated for short-term use only (e.g. acute infectious rhinitis, or during air travel by a patient with symptomatic rhinitis, as a single tablet taken one hour before landing). They are associated with adverse effects including palpitations, tachycardia and insomnia.

Oral corticosteroids should be avoided as a treatment for allergic rhinitis. In exceptional circumstances, their use might be considered in consultation with an allergy specialist.

Topical ocular alpha agonist vasoconstrictors (including in combination with antihistamines) should not be used for allergic conjunctivitis because they can cause conjunctivitis medicamentosa.

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Montelukast for children: warning parents about potential psychiatric adverse effects

Montelukast is generally very well tolerated.39 However, post-marketing surveillance reports suggested a slight increase in the rate of psychiatric disorders that was possibly associated with use of leukotriene receptor antagonists in children;35 this association may have been confounded by asthma severity and concomitant medication.39 Montelukast use has also been associated with suicidal ideation, but a recent nested case-control study concluded that children with asthma aged 5–18 years taking leukotriene receptor antagonists were not at increased risk of suicide attempts.34 Behavioural and psychiatric adverse effects were rare in clinical trials.36,37

A recent analysis of databases of adults and children taking montelukast suggests it is associated with nightmares, depression, and aggression.40 Allergic granulomatous angiitis has also been reported, but a causal relationship has not been established.40

The Thoracic Society of Australia and New Zealand advises that it is prudent to mention to parents the potential association of montelukast with behaviour-related adverse events when commencing treatment, and to cease therapy if such adverse events are suspected.39

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Smoking and allergic rhinitis

Smoking may worsen both asthma and rhinitis, and exposure to tobacco smoke can reduce the effectiveness of treatment in adults and children.41, 42

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Nasal saline irrigation for allergic rhinitis

Nasal irrigation (via a syringe, rinse bottle, spray or other device) can improve nasal symptoms, mucociliary clearance, and quality of life.43 Saline administered by spray or other devices was used at least twice daily in most studies that showed a benefit.43

Isotonic solution is preferable to hypertonic solution because it supports optimal mucociliary clearance.43 Isotonic saline is solution is inexpensive and has no known adverse effects.43 Patients can use either commercially manufactured saline solutions or home-made normal saline: 1 teaspoon (5 g) rock or sea salt in 500 mL of water (preferably bottled or boiled).

There is not enough evidence to determine:

  • whether solutions should be buffered or non-buffered, sterile or non-sterile
  • whether various additives provide any advantage
  • whether inhaling steam or an irritant decongestant (e.g. eucalyptus, menthol) before saline irrigation provides any extra benefit. However, patients are more likely to adhere to simple and convenient regimens, regardless of theoretical advantages. Caution is required with steam inhalation to avoid burns.

If patients are using both saline irrigation and an intranasal corticosteroid or intranasal H1‑antihistamine, they should perform saline irrigation first. Saline can be used again after waiting at least an hour after using an intranasal corticosteroid.

Young children are unlikely to tolerate nasal irrigation.

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Specific allergen immunotherapy (desensitisation)
  • Specific allergen immunotherapy should not be started unless the patient has stable asthma, including spirometry-demonstrated forced expiratory volume in 1 second (FEV1) greater than 80% predicted for subcutaneous immunotherapy and greater than 70% predicted for sublingual immunotherapy.44, 45 For patients with unstable asthma (e.g. frequent symptoms, marked variability in airflow measured by spirometry or peak flow monitor), the risks of treatment should be considered. These patients will need specialist supervision during treatment.

Options available in Australia

Two forms of specific allergen immunotherapy are available:

  • sublingual immunotherapy
  • subcutaneous immunotherapy.

Both forms of specific allergen immunotherapy require 3–5 years of treatment. Specific allergy immunotherapy can be repeated.

Although some specific allergen therapies can be prescribed by primary care health professionals, it is recommended that they are initiated under the care of an allergy specialist (allergist or clinical immunologist), where possible.

Commercial allergen preparations for immunotherapy are available in Australia for aeroallergens including house dust mite, pollens (e.g. grass, tree and weed pollens), animal dander and moulds.

Overview of efficacy

There is strong evidence that allergen immunotherapy is effective in the treatment of seasonal and perennial allergic rhinitis.6, 7, 8 There is less evidence supporting specific allergen immunotherapy in children than in adults.7 Specific allergen immunotherapy in children with seasonal allergic rhinoconjunctivitis might prevent development of asthma.15, 46

Single-allergen specific allergen immunotherapy is effective in patients sensitised to one allergen and those sensitised to multiple allergens.32, 47, 48 In selected cases more than one allergen may be administered as separate extracts. There is weak evidence for the efficacy of allergen mixes.9

A systematic review of studies directly comparing subcutaneous immunotherapy and sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and asthma found:10

  • low-grade evidence that subcutaneous immunotherapy is more effective than sublingual immunotherapy for reducing asthma symptoms and for reducing a combined measure of rhinitis symptoms and medication use
  • moderate-grade evidence that subcutaneous immunotherapy is more effective than sublingual immunotherapy for reducing nasal and/or eye symptoms.

Sublingual immunotherapy is associated with a lower rate of severe adverse effects (anaphylaxis and death) than subcutaneous immunotherapy, based on indirect comparison.17, 11, 12

Sublingual immunotherapy

Sublingual immunotherapy (self-administered at home) is effective for the treatment of allergic rhinitis in adults and children.13 14 The greatest benefits have been demonstrated in those with allergies to temperate grass pollens or house dust mite.14 Therapeutic Goods Administration (TGA)-approved indications for commercially available preparations vary according to age group.

The extract must be held under the tongue without swallowing for 2 minutes (liquid extracts) or 1 minute (tablets).

Sublingual immunotherapy is generally well tolerated.13 Local adverse effects are common in children receiving sublingual immunotherapy.17 Systemic adverse reactions, such as anaphylaxis, are very rare.17 The majority of adverse events occur soon after beginning treatment.14

TGA-approved indications

Asthma: Acarizax (house dust mite) is indicated for adults 18–65 years with house dust mite allergic asthma that is not well controlled by inhaled corticosteroids and is associated with mild-to-severe house dust mite allergic rhinitis.49 It is contraindicated in patients with FEV1 <70% predicted after adequate treatment, and for patients who have experienced a severe flare-up within the previous 3 months.49

Allergic rhinitis: Several commercial preparations of aeroallergens for sublingual immunotherapy in patients with allergic rhinitis are used in Australia, including:

  • Acarizax (house dust mite) – indicated for adults 18–65 years with persistent moderate to severe house dust mite allergic rhinitis despite symptomatic treatment.49
  • Actair (house dust mite) – indicated for the treatment of house dust mite allergic rhinitis with or without conjunctivitis in adults and adolescents over 12 years diagnosed with house dust mite allergy.50
  • Grazax (Timothy grass [Phleum pratense] pollen extract) – indicated for adults, adolescents and children older than 5 years with allergic rhinitis induced by Timothy grass51
  • Oralair tablets (mix of grass pollens) – indicated for adults and children over 5 years with grass pollen allergic rhinitis.52

Various single allergens and/or multiple allergen mixes are available for use as advised by the treating allergist, available as liquid extracts. Age restrictions vary between products.

Note: PBS status as at October 2016: Treatment with sublingual immunotherapy specific allergen preparations is not subsidised by the PBS.

Subcutaneous immunotherapy

Subcutaneous immunotherapy involves injections in which the dose is gradually increased at regular intervals (usually weekly), or until a therapeutic/maintenance dose is reached. This can take approximately 3–6 months.53 Treatment is then continued for a further 3–5 years.

Subcutaneous immunotherapy is generally not suitable for younger children (e.g. less than 7 years) because they may not be able to tolerate frequent injections.

Several commercial preparations of aeroallergens for subcutaneous immunotherapy are available in Australia, including various single allergens and/or multiple allergen mixes for use as advised by the treating allergist. Age restrictions vary between products.

Subcutaneous immunotherapy is effective for the treatment of allergic rhinitis and asthma, particularly when single-allergen immunotherapy regimens are used.11 There is strong evidence that it reduces asthma symptoms, asthma medication usage, rhinitis/rhinoconjunctivitis symptoms, conjunctivitis symptoms, and rhinitis/rhinoconjunctivitis disease-specific quality of life, in comparison to placebo or usual care.11 There is also moderate evidence that subcutaneous immunotherapy reduces rhinitis/rhinoconjunctivitis medication usage.11

Subcutaneous immunotherapy is associated with local adverse effects (e.g. injection-site swelling) and, less frequently, serious systemic adverse effects.17, 14 The most common systemic reactions are respiratory symtoms. There have been few reports of anaphylaxis.11

Note: PBS status as at October 2016: Treatment with subcutaneous specific allergen immunotherapy preparations is not subsidised by the PBS.

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Surgical turbinate reduction

Turbinate reduction surgery can be considered when nasal obstruction is due to turbinate hypertrophy and symptoms do not respond to medical treatment. It should not be performed in young children except after thorough investigation and review.

Inferior turbinate hypertrophy secondary to inflammation is a common cause of nasal obstruction in patients with allergic rhinitis.54 Several surgical procedures are available to correct this problem.55 The ideal surgical reduction should preserve the mucosa and physiological function.54

Short-term adverse outcomes of inferior turbinate reduction include nasal bleeding, scarring and crusting. Rarely, it may worsen symptoms when patients have non-specific rhinitic conditions or sino-nasal somatisation disorders (‘empty nose syndrome’).55 There is no evidence that turbinate surgery creates these conditions, but sino-nasal surgery may exacerbate the symptoms.

 

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References

  1. Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: Allergic rhinitis. Otolaryngol Head Neck Surg. 2015; 152: S1-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25644617
  2. Girgis ST, Marks GB, Downs SH, et al. Thunderstorm-associated asthma in an inland town in south-eastern Australia. Who is at risk?. Eur Respir J. 2000; 16: 3-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10933077
  3. Davies J, Queensland University of Technology. Literature review on thunderstorm asthma and its implications for public health advice. Final report. Victorian State Government Department of Health and Human Services, Melbourne, 2017.
  4. Bachert C, Maspero J. Efficacy of second-generation antihistamines in patients with allergic rhinitis and comorbid asthma. J Asthma. 2011; 48: 965-73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21970671
  5. Nasser, M, Federowicz, Z, Aljufairi, H, McKerrow, W. Antihistamines used in addition to topical nasal steroids for intermittent and persistent allergic rhinitis in children. Cochrane Database Syst Rev. 2010; Issue 7: . Available from: [https://www.ncbi.nlm.nih.gov/pubmed/20614452; full text available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006989.pub2/full](https://www.ncbi.nlm.nih.gov/pubmed/20614452; full text available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006989.pub2/full)
  6. Nasser M, Federowicz Z, Aljufairi H, McKerrow W. Antihistamines used in addition to topical nasal steroids for intermittent and persistent allergic rhinitis in children. Cochrane Database Syst Rev. 2010; Issue 7: . Available from: https://www.ncbi.nlm.nih.gov/pubmed/20614452
  7. Berger WE, Meltzer EO. Intranasal spray medications for maintenance therapy of allergic rhinitis. Am J Rhinol Allergy. 2015; 29: 273-82. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26132312
  8. Bousquet J, Schunemann HJ, Hellings PW, et al. MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. J Allergy Clin Immunol Pract. 2016; 138: 367-374.e2. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27260321
  9. D'Amato G, Vitale C, D'Amato M, et al. Thunderstorm-related asthma: what happens and why. Clin Exp Allergy. 2016; 46: 390-6.
  10. Chelladurai, Y., Suarez-Cuervo, C., Erekosima, N., et al. Effectiveness of subcutaneous versus sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. J Allergy Clin Immunol Pract. 2013; 1: 361-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24565541
  11. Erekosima, N., Suarez-Cuervo, C., Ramanathan, M., et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope. 2014; 124: 616-27. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23832632
  12. Calderon, M. A., Kleine-Tebbe, J., Linneberg, A., et al. House dust mite respiratory allergy: an overview of current therapeutic strategies. J Allergy Clin Immunol Pract. 2015; 3: 843-55. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26342746
  13. Radulovic, S, Calderón, M A, Wilson, D, Durham, S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2010; Issue 12: . Available from: [https://www.ncbi.nlm.nih.gov/pubmed/21154351; full text available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002893/full](https://www.ncbi.nlm.nih.gov/pubmed/21154351; full text available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002893/full)
  14. Canonica, G W, Bousquet, J, Casale, T, et al. Sub-lingual immunotherapy. World Allergy Organization information position paper 2009. WAO Journal. 2009; November: 233-281. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20041860
  15. Jacobsen, L., Niggemann, B., Dreborg, S., et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007; 62: 943-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17620073
  16. Pajno, G. B., Bernardini, R., Peroni, D., et al. Clinical practice recommendations for allergen-specific immunotherapy in children: the Italian consensus report. Ital J Pediatr. 2017; 43: 13. Available from: [https://www.ncbi.nlm.nih.gov/pubmed/28257631; full text available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347813/](https://www.ncbi.nlm.nih.gov/pubmed/28257631; full text available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347813/)
  17. Brożek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 Revision. J Allergy Clin Immunol. 2010; 126: 466-476. Available from: http://www.jacionline.org/article/S0091-6749(10)01057-2/fulltext
  18. National Asthma Council Australia. Managing allergic rhinitis in people with asthma. An information paper for health professionals. National Asthma Council Australia, Melbourne, 2012. Available from: http://www.nationalasthma.org.au/publication/allergic-rhinitis-asthma-hp
  19. Spangler DL, Abelson MB, Ober A, Gotnes PJ. Randomized, double-masked comparison of olopatadine ophthalmic solution, mometasone furoate monohydrate nasal spray, and fexofenadine hydrochloride tablets using the conjunctival and nasal allergen challenge models. Clin Ther. 2003; 25: 2245-67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14512132
  20. Pallasaho, P, Juusela, M, Lindqvist, A, et al. Allergic rhinoconjunctivitis doubles the risk for incident asthma – results from a population study in Helsinki, Finland. Respir Med. 2011; 105: 1449-1456. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21600752
  21. Rochat, M K, Illi, S, Ege, M J, et al. Allergic rhinitis as a predictor for wheezing onset in school-aged children. J Allergy Clin Immunology. 2010; 126: 1170-5.e2.
  22. van den Nieuwenhof, L, Schermer, T, Bosch, Y, et al. Is physician-diagnosed allergic rhinitis a risk factor for the development of asthma?. Allergy. 2010; 65: 1049-1055.
  23. Morais-Almeida, M, Gaspar, A, Pires, G, et al. Risk factors for asthma symptoms at school age: an 8-year prospective study. Allergy Asthma Proc. 2007; 28: 183-189.
  24. Shaaban R, Zureik M, Soussan D, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008; 372: 1047-1057. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61446-4/fulltext
  25. Thomas M, Kocevar VS, Zhang Q, et al. Asthma-related health care resource use among asthmatic children with and without concomitant allergic rhinitis. Pediatrics. 2005; 115: 129-34. Available from: http://pediatrics.aappublications.org/content/115/1/129.long
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