Allergy Service

Introduction

More people are getting allergies worldwide (Asher et al., 2006). In our practice in Punggol, Singapore, there are many patients who doctor-hop with undiagnosed allergies. More people have allergies in Singapore compared to our surrounding countries due to our “urban environment”.

What is so allergic about our environment?

In the study done by (Andiappan et al., 2014), only about 20% of recent Chinese migrants from China are sensitive to house dust mites (compared to 70-80% in Singaporean Chinese). After 0–3 years’ stay in Singapore, this number increases to 30%, then to 50% after 3–8 years and then to 60% in the long-term residents (>8 years). So clearly, something is in our air. Unfortunately, we still don’t know why.

What happens if my/my child’s allergy is not diagnosed?

There are many direct and indirect costs, like doctor-hopping and trying alternative medications, causing you to spend more time and money going around in circles. You might get side effects from medications, yet still suffer with no relief from your symptoms. Worst of all, the disease might slowly progress through the “allergic march” (read below). If your/your child’s allergy is not diagnosed and treated, there is a chance you/his/her allergy will go from skin allergy (eczema) to food allergy (many manifestations) to nasal allergy (sensitive nose) to mild lung allergy (bronchial hyper reactivity) and then to severe lung allergy (asthma).

What’s the big deal about allergy problems?

Even a simple sensitive nose (allergic rhinitis) can cause multiple problems and symptoms (see below).

Source: Allergies in America Survey, Florham Park, NJ: Altana Pharma US, Inc., 2006

According to (Ruby Pawankar, Stephen T. Holgate, G. Walter Canonica, Richard F. Lockey, & Michael S. Blaiss, n.d.), half of adult patients and up to 88% of children with sensitive nose have sleep problems, leading to daytime fatigue and somnolence, and decreased cognitive functioning (aka stupider). These are accompanied by disorders of learning performance, behaviour and attention in children.

Why are family physicians like Zenith doctors so interested in this?

There are just so many allergic people out there.

In a survey done in France by (Demoly, Allaert, Lecasble, & Pragma, 2002) on patients with sensitive nose, patients suffered waited two and a half weeks before seeing a doctor. Many of them suffered enough to take an MC due to it and most of them had issues with their mood and sleep, and suffered nose discomfort, among many other problems. In Singapore, a survey done by (Goh, Chew, Quek, & Lee, 1996) for school-going children reported that 44% had running nose.

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What are the types of allergic illnesses?

Allergic Rhinitis (sensitive nose)

You have sensitive nose when 2 or more symptoms below persist for ≥1 hour on most days. (based on ARIA guidelines) (Bousquet et al., 2012)

1. runny nose
2. sneezing
3. nasal obstruction
4. nasal itch 

In this situation, disease severity should be classified and a confirmatory diagnosis should be established by the skin prick test.

Asthma (sensitive lungs)

The following diagnostic criteria are taken from the Global Initiative for Asthma (GINA, n.d.)

You have asthma if you have the following 2 features.

1. Different lung symptoms
   • Such as wheezing, shortness of breath, chest tightness, cough
     • there are generally more than one of these symptoms
     • can occur variably over time and vary in intensity
     • often occur or are worse at night or on waking
     • triggered by exercise, laughter, allergens or cold air
     • worsen with viral infections
2. Evidence of variable expiratory airflow limitation
   • this is detected on spirometry (a.k.a lung function test), which is available at our clinic
   • other tests include bronchial challenge test (give you something to try to trigger your asthma)

There are people with cough as the only symptom. In this case, spirometry is even more important for diagnosis. However, a normal spirometry test does not mean you have no asthma.

Allergic conjunctivitis (Sensitive Eyes)

Diagnosis is purely based on the doctor’s assessment as described by (La Rosa et al., 2013).

It is based on itching, redness, and swelling of the conjunctiva (white part of the eyes).

• compared to other eye diseases:
  • Conjunctival redness tends to be milder
  • Conjunctival swelling, or chemosis, tends to be somewhat more prominent than one would expect for a mild amount of redness
  • Itching is a fairly consistent symptom
  • Corneal (black part of the eye) involvement is rare

Atopic dermatitis (sensitive skin)

According to the UK Working Party diagnostic criteria (Williams et al., 1994), you/your child must have a history of itchy skin plus at least 3 of the following:

• History of a flexural involvement (skin folds in front of elbow or back of knees, front of ankles, wrists, or neck)
• <a picture to illustrate>
• Visible flexural dermatitis
• Personal history of asthma or allergic rhinitis (or history of allergic disease in parents or siblings if the patient is younger than 4 years of age)
• History of a generally dry skin in the last year
• Disease started before the age of 2

Other types of allergies

• Anaphylaxis
• Food allergy
• Urticaria
• Hypersensitivity to drugs and biological agents
• Insect allergy
• Occupational allergy
• Drug allergy

Why treat?

Why spend few hundred dollars to treat allergies over a few years?

Early treatment of allergies can potentially prevent the “allergic march” (Bousquet et al., 2012).

<picture of allergic march>

We are suggesting that if we treat allergies early enough, we can save you (or your child) from developing allergic rhinitis, frequent bronchitis and asthma in the future (Novembre et al., 2004).

This is could be worth a lot in terms of time and money in the future.

So is the money spent treating allergies well spent?

(Simoens, 2012) suggests that treatment is cost-effective for patients with nasal allergies alone or nasal allergies and asthma. How do you quantify your quality of life anyway? Is there a price tag you can place on seeing your doctor less, breathing better, using less medications, getting better sleep or feeling more energetic generally?

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How to treat allergies?

Natural allergy treatment

Ventilated homes with low humidity can improve the lung functions of patients with asthma.  So please, no humidifiers. Perhaps consider a dehumidifying aircon instead.

A study (von Hertzen et al., 2009) suggested the following ways to build tolerance to allergies:

• Consumption of unpasteurised farm milk (only proven one, but too unsafe for public)
• Living on a farm (time to start a farmstay@SG)
• Spending time in nature, outdoor physical activities
• Adherence to natural lifestyle (hmm…)
• Use of probiotics (not all are the same)
• Use of other bacteria-containing (fermented) products
• Consumption of fresh fruit and vegetables
• Consumption of healthy diet (Mediterranean, Baltic, anyone knows how to cook these?)

Things that you can do at home include:

• Reduce humidity as above
• Kill house dust mites by
  • Sunning
  • Drying the bed sheets and pillow cases in somewhere hot <? 40 degrees>
  • Using a HEPA air filter
  • Dust free covers
• Reduce smoking <evidence needed>
• If you do not have pets, please do not buy one, especially when your kids are still very young (the sensitisation to the fur starts young)

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Medications

Antihistamines

They provide temporary relief for runny nose, watery eyes, itching and sneezing. It is also the treatment of choice for urticaria (hives).

Currently, there are 2 generations of antihistamines. The 2nd generation ones are less sedating.

Examples: zyrtec, cetirizine, piriton, chlorphenamine, dimenhydrinate, diphenhydramine, fexofenadine, telfast, loratidine, hydroxyzine.

The trouble with using these drugs is the “tachyphylaxis” effect: meaning that higher and higher doses of the medication is needed to give the same effect. In fact, after a while, no amount of antihistamines will work for patients with chronic allergies.

Decongestants

Can be helpful in allergic rhinitis. They are effective in reducing nasal obstruction but do not improve sneezing, itching and runny nose. They come in the form of tablets or intranasal (in-the-nose) forms.

We usually recommend nasal decongestants for children due to it being relatively safe for children’s use. Use it right before drinking milk and sleeping. Sometimes, it can be rather challenging to give it to children as they might not like the feeling of the medicine going into their noses. In these cases, the spray is easier to administer, and some other brands could be easier to use than others. Intranasal decongestant should not be used for more than 5 days as there can be side effects. Long-term usage causes a sensation of long-term nose block, swelling and other side effects (Graf & Hallén, 1996). Otherwise, they are very safe and effective medications when used in the short term.

Side effects with oral decongestants can include irritability, dizziness, headache, nightmares, tremor, poor sleep, as well as fast heart rate and high blood pressure.

Example: Iliadin (oxymetazoline) nose drops, fedac, all the antihistamines containing “D” such as zyrtec-D, telfast-D and fenfedrine.

Saline nasal medications

There are many over-the-counter saline (aka: salt) containing products over the counter. Some patients even make them at home themselves. (I’ve yet to obtain the formula from them).

They come in the following forms:

Nasal Douche

They tend to come in big empty bottles and sachets of medications. The patient will put distilled or boiled water into them and then pour the sachets inside. Then, half a bottle is used on one nostril. This is especially effective to clear the sinusitis infections, where the phlegm is thick and yellow/green. Children usually will find it hard to use these.

Nasal Saline Sprays

There are a few brands out in the market. However, most of them will not work for adults with real sinusitis. Instead, try the nasal douche (above). For children however, these work quite well. They are safe for long-term use and are more tolerable for children. Do take note that some brands can be tolerated by children more so than other brands. Try to look for brands which have a less “strong” spray.

Nasal sucker

I put this one here as I’ve seen it being used on my child patients in Punggol quite frequently. I would say they work pretty well for the really small kids, but will be difficult to use on older kids. I mean, which one-year-old would sit still and let you try to suck their nose?

Anti-leukotrienes

This is a relatively new drug that was introduced in the last 15 years. It is as effective as antihistamines but less effective than steroids. It is used in both asthma and allergic rhinitis to improve nasal and bronchial symptoms. This drug is safe and well-tolerated, especially in children. Some minor side effects are sleep issues, hyperactivity and rarely, overdose (it tastes nice!).

Example: Singulair, Montelukast

Glucocorticosteroids (steroids)

Nasal steroids are very effective for allergic rhinitis, sinusitis, allergic conjunctivitis and polyposis. Due to the way steroids work, maximum effect is only achieved after 2 weeks of continuous usage. Intranasal steroids are well-tolerated, adverse effects are few in number and they work really well. Unfortunately, a long while after stopping medications, symptoms tend to recur.

Examples: Nasonex, Avamys, Flixonase, Nasacort, Rhinocort

In asthma, inhaled corticosteroids are used for moderate to severe asthma.

Inhaled corticosteroids are effective in

• reducing symptoms: like cough, breathless and tiredness
• improving quality of life: generally feel better
• improving lung function: can breath better
• decreasing airway hyperresponsiveness,: less “sudden coughs” or “sudden wheezing”
• controlling airway inflammation: less phlegm in the lungs
• reducing frequency and severity of exacerbation: see doctor less frequently
• reducing asthma mortality: less likely to die from severe asthma (yes, people do die from bad asthma)

At the recommended dose of inhaled corticosteroids, they have no long-term bad impacts on growth in children.

Examples: Seretide, Flixotide, Symbicort, Beclomethasone (Beclo-asma/Beclotide), Relvar Ellipta

Short-term oral steroids are used for bad asthma attacks. Long-term oral steroids may be used for severely uncontrolled asthma, particularly so in low-income countries. Oral steroid use is limited by its risk of significant side effects.

Examples: Prednisolone, hydrocortisone, betamethasone

For eczema, topical steroids are very effective in the short term but they may reduce repair of the skin and interfere with recovery in the long term. The use of moisturisers in the long run is still safer.

Examples: Desowen, hydrocortisone, betamethasone, clobetasol

Adrenaline

Adrenaline injections are reserved for severe anaphylaxis. They are usually given deep in the muscle or skin by the doctor to allow quick release of the medication as anaphylaxis is life-threatening. If you have repeated episodes of anaphylaxis or if the trigger is difficult to avoid, an auto-injector can be purchased and kept with you all the time to be self administered.

Bronchodilators

There are 2 types of bronchodilators, the short-acting and long-acting B2-agonists. The most common type is the salbutamol (salbuair or ventolin). Used mainly for short-term relief of symptoms only, does not modify the illness in any way.

Other medications for asthma

Ketotifen

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Doctor, is there a PERMANENT cure for my allergies?

All the above medications only give temporary response. After stopping all these medications, after a while, the symptoms do come back. Even the longest lasting inhaler or intranasal steroids only give few months of relief, and the symptoms sometimes come back after that. So is there a magic bullet for my allergies? Well, read on…

Treating the root cause of allergies

Well, it turns out the technology to treat and make you/your child not allergic anymore to the *thing-that-is-giving-you-allergies* (technical term: allergen) has been out there for the past 10 years.

Hold on, doc! What did you just say?

Yes, that’s right, we can treat the root cause of allergy and potentially cure you/your child of allergies in the air. (Sorry, food allergies are not established for treatment yet: NUH and KKH are working hard on it now.) We are hoping to stop allergies there and then and stop the progression of the allergies to something worse. (Read above on the allergic march)

Step 1:  Finding out exactly what is causing your allergies

Performing the skin prick test

The skin prick test is an essential and reliable tool in the field of allergy (Heinzerling et al., 2013). We can confirm the exact cause of your allergic symptoms. Only when the exact cause of your allergy is found can the the exact treatment be prescribed.

The process involves putting a row of plastic through drops of common allergen extracts after wiping the skin with alcohol with a little pressure. (Don’t worry, you probably can’t feel it. It will just feel a little itchy.) The skin will produce wheals (aka: bumps) in response to the allergens. After 15-20 mins, the diameter of the skin wheals is measured. The larger the wheal, the stronger the allergy.

Below is a video of such a procedure.

OMG, you are going to *prick* my (or my child’s) skin?!

The skin prick test is slightly painful itchy. It is completely harmless and safe with no reported fatalities in a 5-year USA study (Reid, Lockey, Turkeltaub, & Platts-Mills, 1993).

The test is done on only the skin, but I have nose or lung problem!

The test is meant to diagnose especially inhalant (in the air) allergies such as allergic rhinitis and asthma. The chemicals used in the test are actually found in the air and not on the skin. It has been shown to correlate highly with the things that you are allergic to in the air <reference needed>. The blood tests done for allergies have not been proven to be useful. <reference required>

Medications to avoid before coming for a skin prick test

Montelukast/Singulair is ok to continue.

Source: (Bousquet et al., 2012)

Can it be run on small children?

Yes. Skin prick test can be done on any age group. A study (Jean Luc Menardo, Jean Bousquet, & MIchel Rodiere, 1985)  in France managed to safely conduct skin prick test on 78 children between 4 days to 24 months old. What’s even more amazing is that allergies to mites, cat, egg and milk were diagnosed even in such young children.

Zenith’s allergy panel

• House dust mites: Dermatophagoides Pteronyssinus, Dermatophagoides Farinae, Blomia Tropicallis
• Cat fur
• Dog fur
• Food allergy panel: milk, egg, nuts
• Positive control and negative control (to ensure validity of test)

Results

What if i’m sensitised to House Dust Mites

• Change to newer mattresses and carpets
• Use hard floors instead of carpets
• Choice of mattress type <more specifics>
• Regular mattress replacement <how regular?>
• Use of central heating <how about central cooling?>
• Reducing relative humidity to less than 50%
• Living in a flat (like HDB/condos) as opposed to a house (like landed property)
• Bedrooms situated on a higher floor (Seems like your high floor HDB is really worth more)
• Domestic cleaning services
• Maintaining good ventilation
• Using chlorine bleach and washing textiles regularly with a detergent at higher temperatures appear to remove most HDMs.
• Focusing on the bed area as a target for allergen reduction:
  • the use of mite-impermeable mattress covers
  • daily vacuuming of mattresses
  • and choice of a more powerful model of vacuum cleaner
• The presence of an open fireplace

Reference: (Calderón et al., 2015)

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Step 2: Make the body stop reacting to the exact cause of your allergy

Sublingual Immunotherapy

How does it work?

Yes, make sure you have completed step 1 first. Then, we will try to figure out which allergens we want to treat. We will then find you a mix of allergens that you/your child will put under your tongue every day of your life for 1 minute each time for 4 years straight.

Gosh, doc, did you just say FOUR years?!

Yes, (Marogna, Spadolini, Massolo, Canonica, & Passalacqua, 2010) suggests that 4 years is the optimal treatment duration. But of course, you are the patient. Ultimately, the decision is up to you, but I would still recommend 4 years to see the best effects.

Do you mean it will take 4 years to work?

No. Actually, within 6 months, you should start seeing a difference.

Is it effective?

You bet it is. I would not ask you to waste your hard-earned money on something that does not work.

There will improvement in symptoms, reduced reliance on medications and most importantly, the effects are long-lasting years after stopping treatment (Marogna, Spadolini, Massolo, Canonica, & Passalacqua, 2010).

There is a huge body of evidence to support this therapy, yet it is almost unheard of in Singapore due to logistical constraints. Below are the local organisations which endorse this treatment.

Singapore’s MOH advocates sublingual immunotherapy as a treatment for sensitive nose when children are not keen to use medications or when all other treatment has failed (Ministry of Health, 2010). In simple words, if you/your child hate using medications for your/his/her entire life, sublingual immunotherapy is the way to go!

MOH guidelines are recommendations given by experts and immunotherapy is given Grade A, Level 1++, meaning that the level of scientific support behind it is extremely strong. The below is an excerpt from the guidelines:

Grade A evidence, level 1++: Sublingual immunotherapy (SLIT) should be considered in children above 5 years who have poor symptomatic control of allergic rhinitis despite maximal therapy or who cannot or will not take medication (pg 57).

Sublingual immunotherapy is also concluded by the World Allergy Organization to be effective in treating rhinoconjunctivitis and asthma. Besides controlling the symptoms, sublingual immunotherapy has the potential to completely cure such allergies for good or even prevent them from developing at all (Canonica et al., 2014).

These are extracts from the main article released by World Allergy Organization in 2013.

… Several large ‘definitive’ trials have now confirmed the efficacy and safety for seasonal rhinitis in both children and adults. Long-term benefits of SLIT for at least 1 or 2 years following discontinuation of treatment have been demonstrated in 2 large independent trials of immunotherapy with grass pollen allergen tablets in adults. These studies provide evidence for long-term disease remission and disease…

More extracts from this guideline:

The literature suggests that, overall, SLIT is clinically effective in rhinoconjunctivitis and asthma, although differences exist among allergens.

Sublingual immunotherapy for children has significantly reduced nasal symptoms (Penagos et al., 2006).

In children with running nose without asthma, children who were treated with sublingual immunotherapy were 3.8 times less likely to develop asthma (Novembre et al., 2004). Another study also demonstrated a reduction in frequent bronchitis symptoms and overall reduction in asthma (Möller et al., 2002), (Di Rienzo et al., 2003).

Safety and side effects

Sublingual immunotherapy is extremely safe. From the review done by (Cox et al., 2006), there were no serious life-threatening reactions reported from the 1.18 million doses administered to 4378 patients from 66 different studies. Just like any other medical treatment, sublingual immunotherapy has some possible side effects. However, only 14 adverse events were reported out of the 1 million doses given, which includes:

• Itchiness and swelling, over the
  • mouth
  • lips
  • throat
• Abdominal
  • pain
  • discomfort
  • nausea
  • diarrhea
• Asthmatic symptoms

Other milder and more common side effects include itching over the area where the medication is applied and transient worsening of existing allergic symptoms. The good news is that the milder side effects will resolve with the continuation of therapy. 

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References

Asher, M. I., Montefort, S., Björkstén, B., Lai, C. K. W., Strachan, D. P., Weiland, S. K., … ISAAC Phase Three Study Group. (2006). Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet (London, England), 368(9537), 733–743. https://doi.org/10.1016/S0140-6736(06)69283-0

Bousquet, J., Heinzerling, L., Bachert, C., Papadopoulos, N. G., Bousquet, P. J., Burney, P. G., … Allergic Rhinitis and its Impact on Asthma. (2012). Practical guide to skin prick tests in allergy to aeroallergens. Allergy, 67(1), 18–24. https://doi.org/10.1111/j.1398-9995.2011.02728.x

Bousquet, J., Schünemann, H. J., Samolinski, B., Demoly, P., Baena-Cagnani, C. E., Bachert, C., … Zuberbier, T. (2012). Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. Journal of Allergy and Clinical Immunology, 130(5), 1049–1062. https://doi.org/10.1016/j.jaci.2012.07.053

Calderón, M. A., Linneberg, A., Kleine-Tebbe, J., De Blay, F., Hernandez Fernandez de Rojas, D., Virchow, J. C., & Demoly, P. (2015). Respiratory allergy caused by house dust mites: What do we really know? Journal of Allergy and Clinical Immunology, 136(1), 38–48. https://doi.org/10.1016/j.jaci.2014.10.012

Canonica, G. W., Cox, L., Pawankar, R., Baena-Cagnani, C. E., Blaiss, M., Bonini, S., … Yusuf, O. (2014). Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organization Journal, 7, 6. https://doi.org/10.1186/1939-4551-7-6

Cox, L. S., Linnemann, D. L., Nolte, H., Weldon, D., Finegold, I., & Nelson, H. S. (2006). Sublingual immunotherapy: A comprehensive review. Journal of Allergy and Clinical Immunology, 117(5), 1021–1035. https://doi.org/10.1016/j.jaci.2006.02.040

Demoly, P., Allaert, F.-A., Lecasble, M., & Pragma. (2002). ERASM, a pharmacoepidemiologic survey on management of intermittent allergic rhinitis in every day general medical practice in France. Allergy, 57(6), 546–554. https://doi.org/10.1034/j.1398-9995.2002.t01-1-13370.x

Di Rienzo, V., Marcucci, F., Puccinelli, P., Parmiani, S., Frati, F., Sensi, L., … Passalacqua, G. (2003). Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clinical & Experimental Allergy, 33(2), 206–210. https://doi.org/10.1046/j.1365-2222.2003.01587.x

GINA. (n.d.). 2017 GINA Report, Global Strategy for Asthma Management and Prevention.

Goh, D. Y., Chew, F. T., Quek, S. C., & Lee, B. W. (1996). Prevalence and severity of asthma, rhinitis, and eczema in Singapore schoolchildren. Archives of Disease in Childhood, 74(2), 131–135. https://doi.org/10.1136/adc.74.2.131

Graf, P., & Hallén, H. (1996). Effect on the Nasal Mucosa of Long-Term Treatment With Oxymetazoline, Benzalkonium Chloride, and Placebo Nasal Sprays. The Laryngoscope, 106(5), 605–609. https://doi.org/10.1097/00005537-199605000-00016

Heinzerling, L., Mari, A., Bergmann, K.-C., Bresciani, M., Burbach, G., Darsow, U., … Lockey, R. (2013). The skin prick test – European standards. Clinical and Translational Allergy, 3, 3. https://doi.org/10.1186/2045-7022-3-3

Jean Luc Menardo, Jean Bousquet, & MIchel Rodiere. (1985). Skin Test Reactivity in Infancy. Journal of Allergy and Clinical Immunology, 75(6), 646–651.

La Rosa, M., Lionetti, E., Reibaldi, M., Russo, A., Longo, A., Leonardi, S., … Reibaldi, A. (2013). Allergic conjunctivitis: a comprehensive review of the literature. Italian Journal of Pediatrics, 39, 18. https://doi.org/10.1186/1824-7288-39-18

Marogna, M., Spadolini, I., Massolo, A., Canonica, G. W., & Passalacqua, G. (2010). Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study. Journal of Allergy and Clinical Immunology, 126(5), 969–975. https://doi.org/10.1016/j.jaci.2010.08.030

Ministry of Health. (2010). Management of Rhinosinusitis and Allergic Rhinitis | Ministry of Health. Retrieved from https://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/cpg/2010/management_of_rhinosinusitis_and_allergic_rhinitis.html

Möller, C., Dreborg, S., Ferdousi, H. A., Halken, S., Høst, A., Jacobsen, L., … Wahn, U. (2002). Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). Journal of Allergy and Clinical Immunology, 109(2), 251–256. https://doi.org/10.1067/mai.2002.121317

Novembre, E., Galli, E., Landi, F., Caffarelli, C., Pifferi, M., De Marco, E., … Vierucci, A. (2004). Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology, 114(4), 851–857. https://doi.org/10.1016/j.jaci.2004.07.012

Penagos, M., Compalati, E., Tarantini, F., Baena-Cagnani, R., Huerta, J., Passalacqua, G., & Canonica, G. W. (2006). Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Annals of Allergy, Asthma & Immunology, 97(2), 141–148. https://doi.org/10.1016/S1081-1206(10)60004-X

Poidinger, M., Connolly, J., … Rotzschke, O. (2014). Allergic airway diseases in a tropical urban environment are driven by dominant mono-specific sensitization against house dust mites. Allergy, 69(4), 501–509. https://doi.org/10.1111/all.12364

Ruby Pawankar, Stephen T. Holgate, G. Walter Canonica, Richard F. Lockey, & Michael S. Blaiss. (n.d.). WAO White Book on Allergy 2013 Update.

Simoens, S. (2012). The cost-effectiveness of immunotherapy for respiratory allergy: a review. Allergy, 67(9), 1087–1105. https://doi.org/10.1111/j.1398-9995.2012.02861.x

von Hertzen, L. C., Savolainen, J., Hannuksela, M., Klaukka, T., Lauerma, A., Mäkelä, M. J., … Haahtela, T. (2009). Scientific rationale for the Finnish Allergy Programme 2008-2018: emphasis on prevention and endorsing tolerance. Allergy, 64(5), 678–701. https://doi.org/10.1111/j.1398-9995.2009.02024.x

Williams, H. C., Burney, P. G., Hay, R. J., Archer, C. B., Shipley, M. J., Hunter, J. J., … Graham-Brown, R. A. (1994). The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. The British Journal of Dermatology, 131(3), 383–396.